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REACH

Reaction products of sodium glucoheptonate with iron sulfate and ammonium hydroxide

EC number: 946-072-5 | CAS number: -

Life Cycle description
Uses advised against

Toxicological information

Genetic toxicity: in vivo

Currently viewing:

Administrative data

Endpoint:: in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
Type of information:: experimental study
Adequacy of study:: weight of evidence
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: study well documented, meets generally accepted scientific principles, acceptable for assessment

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Cross-reference 1

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

acute toxicity: other routes

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

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Qualifier:

no guideline followed

Principles of method if other than guideline:

Acute toxicity studies have been carried out in mice, rats, rabbits and dogs.

GLP compliance:

Limit test:

Specific details on test material used for the study:

12.5 mg/mL as elemental iron, a stable macromolecular complex used to replete and maintain the total body content of iron.
The molecular formula is considered to be [NaFe2O3(C6H11O7)(C12H22O11)5] n≈200.
COMPOSITION - Each ampoule of 5 mL of FERRLECIT contains 12.5 mg/mL (62.5 mg/5 mL ampoule) of elemental iron as the sodium salt of a ferric ion gluconate complex in alkaline aqueous solution with approximately 20% sucrose w/v (195 mg/mL) in Water for Injection (pH 7.7 - 9.7). The solution contains 0.9% w/v (9 mg/mL) benzyl alcohol as preservative.
STABILITY AND STORAGE RECOMMENDATIONS Store at controlled room temperature between 20°C - 25°C. Protect from light. Do not freeze.

Species:

dog

Strain:

other: mixed

Sex:

male/female

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

intravenous

Vehicle:

other: in sucrose injection

Details on exposure:

Ferrlecit® was administered at elemental iron doses of 125 mg/kg, 78.8 mg/kg, 62.5 mg/kg and 250 mg/kg intravenously to mice, rats, rabbits and dogs, respectively.

Doses:

125 - 250 mg Fe/kg
(10 - 20 mL/kg)

No. of animals per sex per dose:

2M + 2F

Control animals:

yes

Sex:

male/female

Dose descriptor:

LC50

Effect level:

262.5 other: mg Fe/kg

Based on:

element

Remarks on result:

other: after 24 hours

Mortality:

no details

Clinical signs:

The major symptoms of acute toxicity were decreased activity, staggering, ataxia, increases in the respiratory rate, tremor, and convulsions.

Body weight:

not specified

Gross pathology:

not specified

The major symptoms of acute toxicity were decreased activity, staggering, ataxia, increases in the respiratory rate, tremor, and convulsions.

Executive summary:

Acute toxicity studies have been carried out in mice, rats, rabbits and dogs. Ferrlecit® at elemental iron doses of 125 mg Fe/kg, 78.8 mg Fe/kg, 62.5 mg Fe/kg and 250 mg Fe/kg caused deaths to mice, rats, rabbits, and dogs respectively. The major symptoms of acute toxicity were decreased activity, staggering, ataxis, inceases in the respiratory rate, tremor, and convultions.

The LC₅₀ value for male mice was 159 mg Fe/kg, the one for female mice was 155 mg Fe/kg.

After administration of 62.5 - 157.5 mg Fe/kg, the LC₅₀ value for male rats was 111.25 mg Fe/kg, the one for female rats was 90 mg Fe/kg. After 5 days: combined male/female 274 mg Fe/kg.

After administration of doses of 62.5. 87.5 and 112.5 mg Fe/kg, the LC₅₀ value for rabbits after 5 days was 70.4 mg Fe/kg.

After administration of doses of 125 - 250 mg Fe/kg, the LC₅₀ value for dogs was 262.5 mg Fe/kg after 24 hours. After administration of 5 mL (= 62.5 mg Fe/kg) no systemic toxicity was found in dogs after 96 hours.

Cross-reference 2

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

acute toxicity: other routes

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

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Qualifier:

no guideline followed

Principles of method if other than guideline:

Acute toxicity studies have been carried out in mice, rats, rabbits and dogs.

GLP compliance:

Limit test:

Specific details on test material used for the study:

Species:

dog

Strain:

other: mixed

Sex:

male/female

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

intravenous

Vehicle:

other: in sucrose injection

Details on exposure:

Ferrlecit® was administered at elemental iron doses of 125 mg/kg, 78.8 mg/kg, 62.5 mg/kg and 250 mg/kg intravenously to mice, rats, rabbits and dogs, respectively.

Doses:

5 mL per animal

No. of animals per sex per dose:

3M, 3F

Control animals:

yes

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 62.5 other: mg Fe/kg

Based on:

element

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks:

after 96 hours: no systemic toxicity

Mortality:

no details

Clinical signs:

The major symptoms of acute toxicity were decreased activity, staggering, ataxia, increases in the respiratory rate, tremor, and convulsions.

Body weight:

not specified

Gross pathology:

not specified

The major symptoms of acute toxicity were decreased activity, staggering, ataxia, increases in the respiratory rate, tremor, and convulsions.

Executive summary:

The LC₅₀ value for male mice was 159 mg Fe/kg, the one for female mice was 155 mg Fe/kg.

After administration of 62.5 - 157.5 mg Fe/kg, the LC₅₀ value for male rats was 111.25 mg Fe/kg, the one for female rats was 90 mg Fe/kg. After 5 days: combined male/female 274 mg Fe/kg.

After administration of doses of 62.5. 87.5 and 112.5 mg Fe/kg, the LC₅₀ value for rabbits after 5 days was 70.4 mg Fe/kg.

Cross-reference 3

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

acute toxicity: other routes

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

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Qualifier:

no guideline followed

Principles of method if other than guideline:

Acute toxicity studies have been carried out in mice, rats, rabbits and dogs.

GLP compliance:

Limit test:

Specific details on test material used for the study:

Species:

mouse

Strain:

CF-1

Sex:

male/female

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

intravenous

Vehicle:

other: in sucrose injection

Details on exposure:

Ferrlecit® was administered at elemental iron doses of 125 mg/kg, 78.8 mg/kg, 62.5 mg/kg and 250 mg/kg intravenously to mice, rats, rabbits and dogs, respectively.

Doses:

99.25 - 198.75 mg Fe/kg
(7.9 - 15.9 mL/kg)

No. of animals per sex per dose:

Control animals:

yes

Sex:

male

Dose descriptor:

LC50

Effect level:

159 other: mg Fe/kg

Remarks on result:

other: after 24 hours

Sex:

female

Dose descriptor:

LC50

Effect level:

155 other: mg Fe/kg

Remarks on result:

other: after 24 hours

Mortality:

no details

Clinical signs:

The major symptoms of acute toxicity were decreased activity, staggering, ataxia, increases in the respiratory rate, tremor, and convulsions.

Body weight:

not specified

Gross pathology:

not specified

The major symptoms of acute toxicity were decreased activity, staggering, ataxia, increases in the respiratory rate, tremor, and convulsions.

Executive summary:

The LC50 value for male mice was 159 mg Fe/kg, the one for female mice was 155 mg Fe/kg.

After administration of 62.5 - 157.5 mg Fe/kg, the LC50 value for male rats was 111.25 mg Fe/kg, the one for female rats was 90 mg Fe/kg. After 5 days: combined male/female 274 mg Fe/kg.

After administration of doses of 62.5. 87.5 and 112.5 mg Fe/kg, the LC50 value for rabbits after 5 days was 70.4 mg Fe/kg.

After administration of doses of 125 - 250 mg Fe/kg, the LC50 value for dogs was 262.5 mg Fe/kg after 24 hours. After administration of 5 mL (= 62.5 mg Fe/kg) no systemic toxicity was found in dogs after 96 hours.

Cross-reference 4

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

acute toxicity: other routes

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

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Qualifier:

no guideline followed

Principles of method if other than guideline:

Acute toxicity studies have been carried out in mice, rats, rabbits and dogs.

GLP compliance:

Limit test:

Specific details on test material used for the study:

Species:

rabbit

Strain:

other: morini

Sex:

male/female

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

intravenous

Vehicle:

other: in sucrose injection

Details on exposure:

Ferrlecit® was administered at elemental iron doses of 125 mg/kg, 78.8 mg/kg, 62.5 mg/kg and 250 mg/kg intravenously to mice, rats, rabbits and dogs, respectively.

Doses:

62.5, 87.5, 112.5 mg Fe/kg
(5, 7, 9 mL/kg)

No. of animals per sex per dose:

Control animals:

yes

Sex:

male

Dose descriptor:

LC50

Effect level:

70.4 other: mg Fe/kg

Based on:

element

Remarks on result:

other: after 5 days

Mortality:

no details

Clinical signs:

The major symptoms of acute toxicity were decreased activity, staggering, ataxia, increases in the respiratory rate, tremor, and convulsions.

Body weight:

not specified

Gross pathology:

not specified

The major symptoms of acute toxicity were decreased activity, staggering, ataxia, increases in the respiratory rate, tremor, and convulsions.

Executive summary:

Acute toxicity studies have been carried out in mice, rats, rabbits and dogs. Ferrlecit® at elemental iron doses of 125 mg Fe/kg, 78.8 mg Fe/kg, 62.5 mg Fe/kg and 250 mg Fe/kg caused deaths to mice, rats, rabbits, and dogs, respectively. The major symptoms of acute toxicity were decreased activity, staggering, ataxis, inceases in the respiratory rate, tremor, and convultions.

The LC₅₀ value for male mice was 159 mg Fe/kg, the one for female mice was 155 mg Fe/kg.

After administration of 62.5 - 157.5 mg Fe/kg, the LC₅₀ value for male rats was 111.25 mg Fe/kg, the one for female rats was 90 mg Fe/kg. After 5 days: combined male/female 274 mg Fe/kg.

After administration of doses of 62.5. 87.5 and 112.5 mg Fe/kg, the LC₅₀ value for rabbits after 5 days was 70.4 mg Fe/kg.

Cross-reference 5

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

acute toxicity: other routes

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

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Qualifier:

no guideline followed

Principles of method if other than guideline:

Acute toxicity studies have been carried out in mice, rats, rabbits and dogs.

GLP compliance:

Limit test:

Specific details on test material used for the study:

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

intravenous

Vehicle:

other: in sucrose injection

Details on exposure:

Ferrlecit® was administered at elemental iron doses of 125 mg/kg, 78.8 mg/kg, 62.5 mg/kg and 250 mg/kg intravenously to mice, rats, rabbits and dogs, respectively.

Doses:

62.5 - 157.5 mg Fe/kg
(5.0 - 12.6 mL/kg)

No. of animals per sex per dose:

Control animals:

yes

Sex:

male

Dose descriptor:

LC50

Effect level:

111.25 other: mg Fe/kg

Based on:

element

Remarks on result:

other: after 24 hours

Sex:

female

Dose descriptor:

LC50

Effect level:

90 other: mg Fe/kg

Based on:

element

Remarks on result:

other: after 24 hours

Mortality:

no details

Clinical signs:

The major symptoms of acute toxicity were decreased activity, staggering, ataxia, increases in the respiratory rate, tremor, and convulsions.

Body weight:

not specified

Gross pathology:

not specified

The major symptoms of acute toxicity were decreased activity, staggering, ataxia, increases in the respiratory rate, tremor, and convulsions.

Executive summary:

Acute toxicity studies have been carried out in mice, rats, rabbits and dogs. Ferrlecit® at elemental iron doses of 125 mg Fe/kg, 78.8 mg Fe/kg, 62.5 mg Fe/kg and 250 mg Fe/kg caused deaths to mice, rats, rabbits, and dogs, respectively. The major symptoms of acute toxicity were decreased activity, staggering, ataxis, inceases in the respiratory rate, tremor, and convultions.

The LC₅₀ value for male mice was 159 mg Fe/kg, the one for female mice was 155 mg Fe/kg.

After administration of 62.5 - 157.5 mg Fe/kg, the LC₅₀ value for male rats was 111.25 mg Fe/kg, the one for female rats was 90 mg Fe/kg. After 5 days: combined male/female 274 mg Fe/kg

After administration of doses of 62.5. 87.5 and 112.5 mg Fe/kg, the LC₅₀ value for rabbits after 5 days was 70.4 mg Fe/kg.

Cross-reference 6

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

acute toxicity: other routes

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

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Qualifier:

no guideline followed

Principles of method if other than guideline:

Acute toxicity studies have been carried out in mice, rats, rabbits and dogs.

GLP compliance:

Limit test:

Specific details on test material used for the study:

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

intravenous

Vehicle:

other: in sucrose injection

Details on exposure:

Ferrlecit® was administered at elemental iron doses of 125 mg/kg, 78.8 mg/kg, 62.5 mg/kg and 250 mg/kg intravenously to mice, rats, rabbits and dogs, respectively.

Doses:

62.5 - 157.5 mg Fe/kg
(5.0 - 12.6 mL/kg)

No. of animals per sex per dose:

Control animals:

yes

Sex:

male/female

Dose descriptor:

LC50

Effect level:

274 other: mg Fe/kg

Based on:

element

Remarks on result:

other: after 5 days

Mortality:

no details

Clinical signs:

The major symptoms of acute toxicity were decreased activity, staggering, ataxia, increases in the respiratory rate, tremor, and convulsions.

Body weight:

not specified

Gross pathology:

not specified

The major symptoms of acute toxicity were decreased activity, staggering, ataxia, increases in the respiratory rate, tremor, and convulsions.

Executive summary:

The LC₅₀ value for male mice was 159 mg Fe/kg, the one for female mice was 155 mg Fe/kg.

After administration of 62.5 - 157.5 mg Fe/kg, the LC₅₀ value for male rats was 111.25 mg Fe/kg, the one for female rats was 90 mg Fe/kg. After 5 days: combined male/female 274 mg Fe/kg.

After administration of doses of 62.5. 87.5 and 112.5 mg Fe/kg, the LC₅₀ value for rabbits after 5 days was 70.4 mg Fe/kg.

Cross-reference 7

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

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reference to same study

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reference to same study

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reference to same study

Objective of study:

distribution

Qualifier:

no guideline followed

Principles of method if other than guideline:

Cats (mixed breed) received intravenous injections of Ferrlecit at a dose of 1.25, 3.125, 12.5 and 31.25 mg Fe/kg for various days and several blood parameters were monitored (total lipids, triglycerides, cholesterol, free fatty acids, blood sugar). Moreover, it was evaluated, whether Ferrlecit had an anticholinergic, anticonvulsant, antitussive, anti-inflammatory, spasmolytic or broncholytic activity. In addition, its effect on kidney function or on electrolyte excretion was investigated.

GLP compliance:

Specific details on test material used for the study:

Species:

cat

Strain:

other: mixed

Sex:

not specified

Route of administration:

intravenous

Vehicle:

other: sucrose injection

Duration and frequency of treatment / exposure:

various

Dose / conc.:

1.25 other: mg Fe/kg

Remarks:

(0.1 mL/kg)

Dose / conc.:

3.125 other: mg Fe/kg

Remarks:

(0.25 mL/kg)

Dose / conc.:

12.5 other: mg Fe/kg

Remarks:

(1 mL/kg)

Dose / conc.:

31.25 other: mg Fe/kg

Remarks:

(2.5 mL/kg)

No. of animals per sex per dose / concentration:

various, not specified

There were no signs of anticholinergic, anticonvulsant, antitussive, anti-inflammatory, or broncholytic activity. There was no detectable analgesic or anesthetic activity. No spasmolytic effects were seen when tested against three different spasmogens, and there was no effect on kidney function or on electrolyte excretion.

Executive summary:

Cats (mixed breed) received intravenous injections of Ferrlecit at a dose of 1.25, 3.125, 12.5 and 31.25 mg Fe/kg for various days (sanofi-aventis Canada Inc., 2009) and several blood parameters were monitored (total lipids, triglycerides, cholesterol, free fatty acids, blood sugar). Moreover, it was evaluated, whether Ferrlecit had an anticholinergic, anticonvulsant, antitussive, anti-inflammatory, spasmolytic or broncholytic activity. In addition, its effect on kidney function or on electrolyte excretion was investigated.

A single administration of Ferrlecit® produced a lowering in total lipids, but this was not dose related. The decreases in triglycerides and cholesterol were not "uniform" and were not dose dependent. There was a large unexplained decrease in free-fatty acid levels. Ferrlecit® had no effect on blood sugar levels. There were no signs of anticholinergic, anticonvulsant, antitussive, anti-inflammatory, or broncholytic activity. There was no detectable analgesic or anesthetic activity. No spasmolytic effects were seen when tested against three different spasmogens, and there was no effect on kidney function or on electrolyte excretion.

Cross-reference 8

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

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reference to same study

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reference to same study

Objective of study:

distribution

Qualifier:

no guideline followed

Principles of method if other than guideline:

Pirbright guinea pigs received intravenous injections of Ferrlecit at a dose of 1.25, 3.125, 12.5 and 31.25 mg Fe/kg for various days and several blood parameters were monitored (total lipids, triglycerides, cholesterol, free fatty acids, blood sugar). Moreover, it was evaluated, whether Ferrlecit had an anticholinergic, anticonvulsant, antitussive, anti-inflammatory, spasmolytic or broncholytic activity. In addition, its effect on kidney function or on electrolyte excretion was investigated.

GLP compliance:

Specific details on test material used for the study:

Species:

guinea pig

Strain:

Pirbright-Hartley

Sex:

not specified

Route of administration:

intravenous

Vehicle:

other: sucrose injection

Duration and frequency of treatment / exposure:

various

Dose / conc.:

1.25 other: mg Fe/kg

Remarks:

(0.1 mL/kg)

Dose / conc.:

3.125 other: mg Fe/kg

Remarks:

(0.25 mL/kg)

Dose / conc.:

12.5 other: mg Fe/kg

Remarks:

(1 mL/kg)

Dose / conc.:

31.25 other: mg Fe/kg

Remarks:

(2.5 mL/kg)

No. of animals per sex per dose / concentration:

various, not specified

Executive summary:

Pirbright guinea pigs received intravenous injections of Ferrlecit at a dose of 1.25, 3.125, 12.5 and 31.25 mg Fe/kg for various days (sanofi-aventis Canada Inc., 2009) and several blood parameters were monitored (total lipids, triglycerides, cholesterol, free fatty acids, blood sugar). Moreover, it was evaluated, whether Ferrlecit had an anticholinergic, anticonvulsant, antitussive, anti-inflammatory, spasmolytic or broncholytic activity. In addition, its effect on kidney function or on electrolyte excretion was investigated.

Cross-reference 9

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

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reference to same study

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reference to same study

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reference to same study

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Objective of study:

absorption

distribution

excretion

Qualifier:

no guideline followed

Principles of method if other than guideline:

Multiple sequential single dose intravenous pharmacokinetic studies were performed on 14 healthy iron-deficient volunteers (single-center, non-randomized, open-label, historically-controlled study of the safety and efficacy of variable, cumulative doese of intravenous Ferrlecit in iron-deficient hemodialysis patients).

GLP compliance:

Specific details on test material used for the study:

Species:

other: humans

Details on absorption:

not applicable as intravenous injection were performed

Details on distribution in tissues:

The initial volume of distribution (VFerr) of 6 L corresponds well to calculated blood volume. VFerr did not vary by dosage or rate of administration.

Details on excretion:

The terminal elimination half-life (λz-HL) for drug-bound iron was approximately 1 hour. λz- HL varied by dose but not by rate of administration. The shortest value (0.85 h) occurred in the 62.5 mg/4 min regimen; the longest value (1.45 h) occurred in the 125 mg/7 min regimen. Total clearance of FERRLECIT was 3.02 to 5.35 L/h. There was no significant variation by rate of administration.

Toxicokinetic parameters:

Cmax: 19 mg/L

Remarks:

Peak drug levels (Cmax) varied significantly by dosage and by rate of administration with the highest Cmax observed in the regimen in which 125 mg was administered in 7 minutes

Toxicokinetic parameters:

other: Initial volume of distribution

Remarks:

The initial volume of distribution (VFerr) of 6 L corresponds well to calculated blood volume. VFerr did not vary by dosage or rate of administration.

Toxicokinetic parameters:

half-life 1st:

Remarks:

Terminal elimination half-life (λz-HL) for drug-bound iron was ca. 1h. λz- HL varied by dose but not by rate of administration. The shortest value (0.85 h) occurred in the 62.5 mg/4min regimen; the longest value (1.45h) occurred in the 125 mg/7min regimen

Toxicokinetic parameters:

other: Total clearance

Remarks:

Total clearance of FERRLECIT was 3.02 to 5.35 L/h. There was no significant variation by rate of administration.

Toxicokinetic parameters:

other: Delivery

Remarks:

Approximately 80% of drug-bound iron was delivered to transferrin as a mononuclear ionic iron species within 24 hours of administration in each dosage regimen. Direct movement of iron from FERRLECIT to transferrin was not detected.

Toxicokinetic parameters:

other: Transferrin saturation

Remarks:

Mean peak transferrin saturation did not exceed 100% and returned to near baseline by 40 hours after administration of each dosage regimen.

Peak drug levels (Cmax) varied significantly by dosage and by rate of administration with the highest Cmax observed in the regimen in which 125 mg was administered in 7 minutes (19.0 mg/L). The initial volume of distribution (VFerr) of 6 L corresponds well to calculated blood volume. VFerr did not vary by dosage or rate of administration. The terminal elimination half-life (λz-HL) for drug-bound iron was approximately 1 hour. λz- HL varied by dose but not by rate of administration. The shortest value (0.85 h) occurred in the 62.5 mg/4 min regimen; the longest value (1.45 h) occurred in the 125 mg/7 min regimen. Total clearance of FERRLECIT was 3.02 to 5.35 L/h. There was no significant variation by rate of administration. Approximately 80% of drug-bound iron was delivered to transferrin as a mononuclear ionic iron species within 24 hours of administration in each dosage regimen. Direct movement of iron from FERRLECIT to transferrin was not detected. Mean peak transferrin saturation did not exceed 100% and returned to near baseline by 40 hours after administration of each dosage regimen.

The study demonstrated that differences in the rate of infusion had no significant effect on the pharmacokinetics of FERRLECIT. The study predicts that most patients can safely tolerate infusions of FERRLECIT at the fast infusion.

Three adverse events (palpitation, shortness of breath and dizziness) were experienced by one subject during the administration of FERRLECIT under “fast” infusion conditions at a dose of 62.5 mg FERRLECIT over 4 minutes. The adverse events began just after initiation of the drug and were resolved just as the administration of the drug was completed. They did not correlate with the time of maximum concentration of FERRLECIT in the blood of the subject and were not correlated with dose. The study predicted that most patients can safely tolerate infusions of FERRLECIT at the fast infusion rate.

Executive summary:

Multiple sequential single dose intravenous pharmacokinetic studies were performed on 14 healthy iron-deficient volunteers. Entry criteria included hemoglobin ≥ 10.5 gm/dL and transferrin saturation ≤ 15% (TSAT) or serum ferritin value ≤ 20 ng/mL. In the first stage, each subject was randomized 1:1 to undiluted FERRLECIT infusion of either 125 mg/hr or 62.5 mg/½ hr (2.1 mg/min). Five days after the first stage, each subject was rerandomized 1:1 to undiluted FERRLECIT infusion of either 125 mg/7 min or 62.5 mg/4 min (>15.5 mg/min).

Cross-reference 10

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

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reference to same study

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Objective of study:

distribution

Qualifier:

no guideline followed

Principles of method if other than guideline:

NMRI mice received intravenous injections of Ferrlecit at a dose of 1.25, 3.125, 12.5 and 31.25 mg Fe/kg for various days and several blood parameters were monitored (total lipids, triglycerides, cholesterol, free fatty acids, blood sugar). Moreover, it was evaluated, whether Ferrlecit had an anticholinergic, anticonvulsant, antitussive, anti-inflammatory, spasmolytic or broncholytic activity. In addition, its effect on kidney function or on electrolyte excretion was investigated.

GLP compliance:

Specific details on test material used for the study:

Species:

mouse

Strain:

NMRI

Sex:

not specified

Route of administration:

intravenous

Vehicle:

other: sucrose injection

Duration and frequency of treatment / exposure:

various

Dose / conc.:

1.25 other: mg Fe/kg

Remarks:

(0.1 mL/kg)

Dose / conc.:

3.125 other: mg Fe/kg

Remarks:

(0.25 mL/kg)

Dose / conc.:

12.5 other: mg Fe/kg

Remarks:

(1 mL/kg)

Dose / conc.:

31.25 other: mg Fe/kg

Remarks:

(2.5 mL/kg)

No. of animals per sex per dose / concentration:

various, not specified

Executive summary:

NMRI mice received intravenous injections of Ferrlecit at a dose of 1.25, 3.125, 12.5 and 31.25 mg Fe/kg for various days (sanofi-aventis Canada Inc., 2009) and several blood parameters were monitored (total lipids, triglycerides, cholesterol, free fatty acids, blood sugar). Moreover, it was evaluated, whether Ferrlecit had an anticholinergic, anticonvulsant, antitussive, anti-inflammatory, spasmolytic or broncholytic activity. In addition, its effect on kidney function or on electrolyte excretion was investigated.

Cross-reference 11

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:: basic toxicokinetics in vivo
Type of information:: experimental study
Adequacy of study:: supporting study
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: study well documented, meets generally accepted scientific principles, acceptable for assessment
Reason / purpose for cross-reference:: reference to same study
Reason / purpose for cross-reference:: reference to same study
Reason / purpose for cross-reference:: reference to same study
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Objective of study:: distribution
Qualifier:: no guideline followed
Principles of method if other than guideline:: Rabbits (morini) received one intravenous injection of Ferrlecit at a dose of 12.5 mg Fe/kg and subsequently the serum iron and eryththrocyte iron content were monitored. Moreover the iron content of the liver, kidney, the muscle and in the brain were determined.
GLP compliance:: no
Specific details on test material used for the study:: 12.5 mg/mL as elemental iron, a stable macromolecular complex used to replete and maintain the total body content of iron.
The molecular formula is considered to be [NaFe2O3(C6H11O7)(C12H22O11)5] n≈200.
COMPOSITION - Each ampoule of 5 mL of FERRLECIT contains 12.5 mg/mL (62.5 mg/5 mL ampoule) of elemental iron as the sodium salt of a ferric ion gluconate complex in alkaline aqueous solution with approximately 20% sucrose w/v (195 mg/mL) in Water for Injection (pH 7.7 - 9.7). The solution contains 0.9% w/v (9 mg/mL) benzyl alcohol as preservative.
STABILITY AND STORAGE RECOMMENDATIONS Store at controlled room temperature between 20°C - 25°C. Protect from light. Do not freeze.
Species:: rabbit
Strain:: other: Morini
Sex:: not specified
Route of administration:: intravenous
Vehicle:: other: sucrose injection
Dose / conc.:: 12.5 other: mg Fe/kg
Remarks:: (1 mL/kg)
No. of animals per sex per dose / concentration:: 4 animals, sex not specified
Details on dosing and sampling:: one adminstration
Details on distribution in tissues:: Increase of 35% in serum iron and 4.9% in erythrocyte iron content peaking 30 minutes after administration were observed. Both iron contents fell to normal range again approximately 120 minutes post-dose.
Increased iron in the liver and muscles were observed 120 minutes post-dose and in the brain 30 minutes post-dose. The iron content in the brain remained elevated 120 minutes post-dose. No iron increase in the kidneys.
Executive summary:: Rabbits (strain morini) received one intravenous injection of Ferrlecit at a dose of 12.5 mg Fe/kg and subsequently the serum iron and eryththrocyte iron content were monitored (sanofi-aventis Canada Inc., 2009). Moreover the iron content of the liver, kidney, the muscle and in the brain were determined. An increase of 35% in serum iron and 4.9% in erythrocyte iron content was observed peaking 30 minutes after administration. Both iron contents fell to normal range again approximately 120 minutes post-dose. Increased iron in the liver and muscles was found 120 minutes post-dose and in the brain 30 minutes post-dose. The iron content in the brain remained elevated 120 minutes post-dose. No iron increase was observed in the kidneys.

Cross-reference 12

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

Objective of study:

distribution

Qualifier:

no guideline followed

Principles of method if other than guideline:

Chinchilla rabbits received intravenous injections of Ferrlecit at a dose of 1.25, 3.125, 12.5 and 31.25 mg Fe/kg for various days and several blood parameters were monitored (total lipids, triglycerides, cholesterol, free fatty acids, blood sugar). Moreover, it was evaluated, whether Ferrlecit had an anticholinergic, anticonvulsant, antitussive, anti-inflammatory, spasmolytic or broncholytic activity. In addition, its effect on kidney function or on electrolyte excretion was investigated.

GLP compliance:

Specific details on test material used for the study:

Species:

rabbit

Strain:

Chinchilla

Sex:

not specified

Route of administration:

intravenous

Vehicle:

other: sucrose injection

Duration and frequency of treatment / exposure:

various

Dose / conc.:

1.25 other: mg Fe/kg

Remarks:

(0.1 mL/kg)

Dose / conc.:

3.125 other: mg Fe/kg

Remarks:

(0.25 mL/kg)

Dose / conc.:

12.5 other: mg Fe/kg

Remarks:

(1 mL/kg)

Dose / conc.:

31.25 other: mg Fe/kg

Remarks:

(2.5 mL/kg)

No. of animals per sex per dose / concentration:

various, not specified

Executive summary:

Chinchilla rabbits received intravenous injections of Ferrlecit at a dose of 1.25, 3.125, 12.5 and 31.25 mg Fe/kg for various days (sanofi-aventis Canada Inc., 2009) and several blood parameters were monitored (total lipids, triglycerides, cholesterol, free fatty acids, blood sugar). Moreover, it was evaluated, whether Ferrlecit had an anticholinergic, anticonvulsant, antitussive, anti-inflammatory, spasmolytic or broncholytic activity. In addition, its effect on kidney function or on electrolyte excretion was investigated.

Cross-reference 13

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

read-across source

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

Objective of study:

distribution

Qualifier:

no guideline followed

Principles of method if other than guideline:

Sprague-Dawley rats received one intravenous injection of Ferrlecit at a dose of 12.5 mg Fe/kg and subsequently the serum iron and eryththrocyte iron content were monitored. Moreover the iron content of the liver, kidney, the muscle and in the brain were determined.

GLP compliance:

Specific details on test material used for the study:

Species:

rat

Strain:

Sprague-Dawley

Sex:

not specified

Route of administration:

intravenous

Vehicle:

other: sucrose injection

Duration and frequency of treatment / exposure:

one treatment only

Dose / conc.:

12.5 other: mg Fe/kg

Remarks:

(1mL/kg)

No. of animals per sex per dose / concentration:

5 animals, sex not specified

Details on distribution in tissues:

Increase in iron in the liver and muscles 120 minutes post-dose and in the brain 30 minutes post-dose. No iron increase in the kidneys.

Transfer type:

blood/brain barrier

Observation:

other: Increase in iron in the brain 30 minutes post-dose.

Increase of 38.4% in serum iron and 7.4% in erythrocyte iron content after 30 minutes. Serum iron content fell to the normal range again 120 minutes post-dose. Erythrocyte iron content remained increased after 120 minutes post-dose.

Increase in iron in the liver and muscles 120 minutes post-dose and in the brain 30 minutes post-dose. No iron increase in the kidneys.

Executive summary:

Sprague-Dawley rats received one intravenous injection of Ferrlecit at a dose of 12.5 mg Fe/kg and subsequently the serum iron and eryththrocyte iron content were monitored (sanofi-aventis Canada Inc., 2009). Moreover the iron content of the liver, kidney, the muscle and in the brain were determined. An increase of 38.4% in serum iron and 7.4% in erythrocyte iron content was observed after 30 minutes. The serum iron content fell to the normal range again 120 minutes post-dose. Erythrocyte iron content remained increased after 120 minutes post-dose.

An increase in iron in the liver and muscles was found 120 minutes post-dose and in the brain 30 minutes post-dose. No iron increase was observed in the kidneys.

Cross-reference 14

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

Objective of study:

distribution

Qualifier:

no guideline followed

Principles of method if other than guideline:

Wistar rats with experimentally induced anemia received Ferrlecit at a dose of 0, 1.25 and 2.5 mg Fe/kg via intravenous injection for 28 days. Subsequently, mortality, weight gain, red blood cell count, red cell volume, hematocrit and hemoglobin were monitored.

GLP compliance:

Specific details on test material used for the study:

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

intravenous

Vehicle:

other: sucrose injection

Duration and frequency of treatment / exposure:

daily for 28 days

Dose / conc.:

0 other: mg Fe/kg

Remarks:

(0.0 mL/kg)

Dose / conc.:

1.25 other: mg Fe/kg

Remarks:

(0.1mL/kg)

Dose / conc.:

2.5 other: mg Fe/kg

Remarks:

(0.2 mL/kg)

No. of animals per sex per dose / concentration:

12 animals, sex ratio not specified

Control animals:

yes

Mortality reduced in the 1.25 mg/kg group (5 males and 0 females) compared to controls (13 males and 5 females).

No deaths in the 2.5 mg/kg group.

No significant difference in weight gains between the two treatment groups, but the gains in both treatment groups were statistically greater than control group.

Red blood cells (RBC) showed a marked dose dependent increase in treated male animals that was statistically significant in the 2.5 mg/kg group, and in the males at 1.25 mg/kg.

Increases in red cell volume were significantly higher in the 2.5 mg/kg group.

There was an increase in hematocrit of 145% and 219% in the males, and 77% and 197% in the females of the 1.25 and 2.5 mg/kg groups, respectively.

There was a hemoglobin increase of 83% and 120% in the males, and 97% and 102% in the females of the 1.25 and 2.5 mg/kg groups, respectively.

Executive summary:

Wistar rats with experimentally induced anemia received Ferrlecit at a dose of 0, 1.25 and 2.5 mg Fe/kg via intravenous injection for 28 days (sanofi-aventis Canada Inc., 2009). Subsequently, mortality, weight gain, red blood cell count, red cell volume, hematocrit and hemoglobin were monitored.

Mortality reduced in the 1.25 mg/kg group (5 males and 0 females) compared to controls (13 males and 5 females). No deaths in the 2.5 mg/kg group. No significant difference in weight gains between the two treatment groups, but the gains in both treatment groups were statistically greater than control group. Red blood cells (RBC) showed a marked dose dependent increase in treated male animals that was statistically significant in the 2.5 mg/kg group, and in the males at 1.25 mg/kg. Increases in red cell volume were significantly higher in the 2.5 mg/kg group. There was an increase in hematocrit of 145% and 219% in the males, and 77% and 197% in the females of the 1.25 and 2.5 mg/kg groups, respectively. There was a hemoglobin increase of 83% and 120% in the males, and 97% and 102% in the females of the 1.25 and 2.5 mg/kg groups, respectively.

Cross-reference 15

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:: basic toxicokinetics in vivo
Type of information:: experimental study
Adequacy of study:: supporting study
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: study well documented, meets generally accepted scientific principles, acceptable for assessment
Reason / purpose for cross-reference:: reference to same study
Reason / purpose for cross-reference:: reference to same study
Reason / purpose for cross-reference:: reference to same study
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Reason / purpose for cross-reference:: reference to same study
Reason / purpose for cross-reference:: reference to same study
Reason / purpose for cross-reference:: reference to same study
Reason / purpose for cross-reference:: reference to same study
Reason / purpose for cross-reference:: reference to same study
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Reason / purpose for cross-reference:: reference to same study
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Reason / purpose for cross-reference:: reference to same study
Reason / purpose for cross-reference:: reference to same study
Objective of study:: absorption; distribution
Qualifier:: no guideline followed
Principles of method if other than guideline:: Sprague-Dawley rats with experimentally induced anemia received intravenous injections of Ferrlecit at a dose of 0.188 mg Fe/kg for 60 days and subsequently the RBC coubt and the hemoglobin were monitored. Moreover the iron content of the liver, kidney, the muscle and in the brain were determined.
GLP compliance:: no
Specific details on test material used for the study:: 12.5 mg/mL as elemental iron, a stable macromolecular complex used to replete and maintain the total body content of iron.
The molecular formula is considered to be [NaFe2O3(C6H11O7)(C12H22O11)5] n≈200.
COMPOSITION - Each ampoule of 5 mL of FERRLECIT contains 12.5 mg/mL (62.5 mg/5 mL ampoule) of elemental iron as the sodium salt of a ferric ion gluconate complex in alkaline aqueous solution with approximately 20% sucrose w/v (195 mg/mL) in Water for Injection (pH 7.7 - 9.7). The solution contains 0.9% w/v (9 mg/mL) benzyl alcohol as preservative.
STABILITY AND STORAGE RECOMMENDATIONS Store at controlled room temperature between 20°C - 25°C. Protect from light. Do not freeze.
Species:: rat
Strain:: Sprague-Dawley
Sex:: not specified
Route of administration:: intravenous
Vehicle:: other: sucrose injection
Duration and frequency of treatment / exposure:: 60 dosing days
Dose / conc.:: 0.188 other: mg Fe/kg
Remarks:: (0.15 mL/kg)
No. of animals per sex per dose / concentration:: 19-21
Details on distribution in tissues:: In comparison to the controls, the treated groups showed increased RBC counts (40% above control) and a 75% increase in hemoglobin concentration.
Elevated iron levels were seen as well, especially in the liver (liver-424%, kidney-61%, muscle-43%, and brain-26%).
Transfer type:: blood/brain barrier
Observation:: other: Elevated levels were seen in the brain-26%.
Executive summary:: Sprague-Dawley rats with experimentally induced anemia received intravenous injections of Ferrlecit at a dose of 0.188 mg Fe/kg for 60 days and subsequently the RBC coubt and the hemoglobin were monitored (sanofi-aventis Canada Inc., 2009). Moreover the iron content of the liver, kidney, the muscle and in the brain were determined. In comparison to the controls, the treated groups showed increased RBC counts 40% above control) and a 75% increase in hemoglobin concentration. Elevated iron levels were seen as well, especially in the liver (liver-424%, kidney-61%, muscle-43%, and brain-26%).

Cross-reference 16

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:: basic toxicokinetics in vivo
Type of information:: experimental study
Adequacy of study:: supporting study
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: study well documented, meets generally accepted scientific principles, acceptable for assessment
Reason / purpose for cross-reference:: reference to same study
Reason / purpose for cross-reference:: reference to same study
Reason / purpose for cross-reference:: reference to same study
Reason / purpose for cross-reference:: reference to same study
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Reason / purpose for cross-reference:: reference to same study
Reason / purpose for cross-reference:: reference to same study
Objective of study:: distribution
Qualifier:: no guideline followed
Principles of method if other than guideline:: Sprague-Dawley rats with experimentally induced anemia received one intravenous injection of Ferrlecit at a dose of 5 mg Fe/kg for 5 days and subsequently the eryththrocyte content was monitored.
GLP compliance:: no
Specific details on test material used for the study:: 12.5 mg/mL as elemental iron, a stable macromolecular complex used to replete and maintain the total body content of iron.
The molecular formula is considered to be [NaFe2O3(C6H11O7)(C12H22O11)5] n≈200.
COMPOSITION - Each ampoule of 5 mL of FERRLECIT contains 12.5 mg/mL (62.5 mg/5 mL ampoule) of elemental iron as the sodium salt of a ferric ion gluconate complex in alkaline aqueous solution with approximately 20% sucrose w/v (195 mg/mL) in Water for Injection (pH 7.7 - 9.7). The solution contains 0.9% w/v (9 mg/mL) benzyl alcohol as preservative.
STABILITY AND STORAGE RECOMMENDATIONS Store at controlled room temperature between 20°C - 25°C. Protect from light. Do not freeze.
Species:: rat
Strain:: Sprague-Dawley
Sex:: male
Route of administration:: intravenous
Vehicle:: other: sucrose injection
Duration and frequency of treatment / exposure:: 5 days
Dose / conc.:: 5 other: mg Fe/kg
Remarks:: (0.4 mL/kg)
No. of animals per sex per dose / concentration:: 10M
Details on distribution in tissues:: There was a pronounced drop in erythrocyte counts before Ferrlecit® administration. However, the erythrocyte counts were in the normal range following treatment with Ferrlecit®.
Executive summary:: Sprague-Dawley rats with experimentally induced anemia received one intravenous injection of Ferrlecit at a dose of 5 mg Fe/kg for 5 days and subsequently the eryththrocyte content was monitored (sanofi-aventis Canada Inc., 2009). There was a pronounced drop in erythrocyte counts before Ferrlecit® administration. However, the erythrocyte counts were in the normal range following treatment with Ferrlecit®.

Cross-reference 17

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

Objective of study:

distribution

Qualifier:

no guideline followed

Principles of method if other than guideline:

Wistar rats received intravenous injections of Ferrlecit at a dose of 1.25, 3.125, 12.5 and 31.25 mg Fe/kg for various days and several blood parameters were monitored (total lipids, triglycerides, cholesterol, free fatty acids, blood sugar). Moreover, it was evaluated, whether Ferrlecit had an anticholinergic, anticonvulsant, antitussive, anti-inflammatory, spasmolytic or broncholytic activity. In addition, its effect on kidney function or on electrolyte excretion was investigated.

GLP compliance:

Specific details on test material used for the study:

Species:

rat

Strain:

Wistar

Sex:

not specified

Route of administration:

intravenous

Vehicle:

other: sucrose injection

Duration and frequency of treatment / exposure:

various

Dose / conc.:

1.25 other: mg Fe/kg

Remarks:

(0.1 mL/kg)

Dose / conc.:

3.125 other: mg Fe/kg

Remarks:

(0.25 mL/kg)

Dose / conc.:

12.5 other: mg Fe/kg

Remarks:

(1 mL/kg)

Dose / conc.:

31.25 other: mg Fe/kg

Remarks:

(2.5 mL/kg)

No. of animals per sex per dose / concentration:

various, not specified

Executive summary:

Wistar rats received intravenous injections of Ferrlecit at a dose of 1.25, 3.125, 12.5 and 31.25 mg Fe/kg for various days (sanofi-aventis Canada Inc., 2009) and several blood parameters were monitored (total lipids, triglycerides, cholesterol, free fatty acids, blood sugar). Moreover, it was evaluated, whether Ferrlecit had an anticholinergic, anticonvulsant, antitussive, anti-inflammatory, spasmolytic or broncholytic activity. In addition, its effect on kidney function or on electrolyte excretion was investigated.

Cross-reference 18

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

FERRLECIT (sodium ferric gluconate complex in sucrose injection) was administered at doses of elemental iron up to 100 mg/kg/day (300 mg/m²/day) to mice and at 20 mg/kg/day (120 mg/m²/day) to rats. On a body surface area basis, these doses were 1.3 and 3.24 times the recommended human dose (125 mg/day or 92.5 mg/m²/day) for a person of 50 kg body weight, average height and body surface area of 1.46 m².

GLP compliance:

Limit test:

Specific details on test material used for the study:

Species:

mouse

Strain:

CD-1

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

intravenous

Vehicle:

other: sucrose injection

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

12.5 mg/mL as elemental iron content

Details on mating procedure:

not specified

Duration of treatment / exposure:

GD 6 - 15

Frequency of treatment:

not specified, presumable once daily

Duration of test:

10 days

Dose / conc.:

0 other: mg Fe/kg

Dose / conc.:

2.5 other: mg Fe/kg

Remarks:

(0.2 mL/kg)

Dose / conc.:

5 other: mg Fe/kg

Remarks:

(0.4 mL/kg)

Dose / conc.:

15 other: mg Fe/kg

Remarks:

(1.2 mL/kg)

Dose / conc.:

30 other: mg Fe/kg

Remarks:

(2.4 mL/kg)

No. of animals per sex per dose:

Control animals:

yes

Details on study design:

not specified

Maternal examinations:

yes

Ovaries and uterine content:

yes

Fetal examinations:

yes

Statistics:

not stated

Indices:

not specified

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Local effects at the treatment site included swelling and blue discoloration of the tail. Skin lesions and or areas of scab formation were seen on the tail in all groups, including the control.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

No treatment-related deaths

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Body weights and food consumption for the treated groups were comparable to the controls

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Body weights and food consumption for the treated groups were comparable to the controls

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Description (incidence and severity):

No gross pathological findings.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Number of abortions:

no effects observed

Description (incidence and severity):

The pregnancy rate was 100% in all groups. The number of corpora lutea, implantation sites, live fetuses, dead fetuses, resorptions, the sex ratio, and the pre- and postimplantation losses were unaffected by treatment.

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

Total litter losses by resorption:

no effects observed

Description (incidence and severity):

Early or late resorptions:

no effects observed

Description (incidence and severity):

Dead fetuses:

no effects observed

Description (incidence and severity):

Changes in pregnancy duration:

not specified

Description (incidence and severity):

Changes in number of pregnant:

no effects observed

Description (incidence and severity):

Other effects:

no effects observed

Description (incidence and severity):

Dose descriptor:

NOAEL

Effect level:

> 30 other: mg Fe/kg

Based on:

element

Basis for effect level:

body weight and weight gain

changes in number of pregnant

clinical signs

dead fetuses

early or late resorptions

food consumption and compound intake

gross pathology

mortality

number of abortions

pre and post implantation loss

total litter losses by resorption

Remarks on result:

not determinable due to absence of adverse toxic effects

Fetal body weight changes:

no effects observed

Description (incidence and severity):

Fetal weights were similar to control values.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): Fetal weights were similar to control values.

Reduction in number of live offspring:

no effects observed

Description (incidence and severity):

Changes in sex ratio:

no effects observed

Description (incidence and severity):

Changes in litter size and weights:

not specified

Changes in postnatal survival:

not specified

External malformations:

no effects observed

Description (incidence and severity):

The incidence of major malformations and minor anomalies was unaffected.

Skeletal malformations:

no effects observed

Description (incidence and severity):

The incidence of major malformations and minor anomalies was unaffected.

Visceral malformations:

no effects observed

Description (incidence and severity):

The incidence of major malformations and minor anomalies was unaffected.

Other effects:

not specified

Dose descriptor:

NOAEL

Effect level:

> 30 other: mg Fe/kg

Based on:

element

Sex:

male/female

Basis for effect level:

reduction in number of live offspring

changes in sex ratio

fetal/pup body weight changes

external malformations

skeletal malformations

visceral malformations

Remarks on result:

not determinable due to absence of adverse toxic effects

Developmental effects observed:

No treatment-related deaths. Local effects at the treatment site included swelling and blue discoloration of the tail. Skin lesions and or areas of scab formation were seen on the tail in all groups, including the control. Body weights and food consumption for the treated groups were comparable to the controls. No gross pathological findings. The pregnancy rate was 100% in all groups. The number of corpora lutea, implantation sites, live fetuses, dead fetuses, resorptions, the sex ratio, and the pre- and postimplantation losses were unaffected by treatment. Fetal weights were similar to control values. The incidence of major malformations and minor anomalies was unaffected.

Executive summary:

Ferrlecit (sodium ferric gluconate in sucrose injection) was adminstered to pregnant mice from gestation day 6 to 15 (sanofi-aventis Canada Inc., 2009). The employed doses were 2.5, 5, 15 and 30 mg Fe /kg bw. No treatment-related deaths were observed. Local effects at the treatment site included swelling and blue discoloration of the tail. Skin lesions and or areas of scab formation were seen on the tail in all groups, including the control. Body weights and food consumption for the treated groups were comparable to the controls. No gross pathological findings. The pregnancy rate was 100% in all groups. The number of corpora lutea, implantation sites, live fetuses, dead fetuses, resorptions, the sex ratio, and the pre- and postimplantation losses were unaffected by treatment. Fetal weights were similar to control values. The incidence of major malformations and minor anomalies was unaffected.

A NOAEL of > 30.0 mg Fe/kg can be established here for maternal and developmental toxicity.

Cross-reference 19

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

GLP compliance:

Limit test:

Specific details on test material used for the study:

Species:

mouse

Strain:

CD-1

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

intravenous

Vehicle:

other: sucrose injection

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

12.5 mg/mL as elemental iron content

Details on mating procedure:

not specified

Duration of treatment / exposure:

GD 6 - 15

Frequency of treatment:

not specified, presumable once daily

Duration of test:

10 days

Dose / conc.:

0 other: mg Fe/kg

Dose / conc.:

10 other: mg Fe/kg

Remarks:

(0.4 mL/kg)

Dose / conc.:

30 other: mg Fe/kg

Remarks:

(2.4 mL/kg)

Dose / conc.:

100 other: mg Fe/kg

Remarks:

(8.06 mL/kg)

No. of animals per sex per dose:

25F

Control animals:

yes

Details on study design:

not specified

Maternal examinations:

yes

Ovaries and uterine content:

yes

Fetal examinations:

yes

Statistics:

not stated

Indices:

not specified

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Effects seen at the injection sites in the 30 and 100 mg/kg groups included dry skin and ulceration on the tail, and black discoloration at the tip of the tail. Decreased activity and red vaginal discharge were also observed for some mice in the 100 mg/kg group.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

No drug related mortality.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

The body weight gains were decreased for the intervals Days 6 to 9 and Days 15 to 18 for the 100 mg/kg group.
Body weights by Day 18 of gestation were significantly decreased compared with controls.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Food consumption for the 100 mg/kg group was significantly decreased between Days 6 and 9 of gestation.

Food efficiency:

effects observed, treatment-related

Description (incidence and severity):

Food consumption for the 100 mg/kg group was significantly decreased between Days 6 and 9 of gestation.

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Gross pathological findings in the 30 and 100 mg/kg groups included splenic enlargement and focal to multi-focal hepatic pallor. Other hepatic alterations including prominent lobular architecture and/or irregular pattern were also seen for a few 100 mg/kg group mice. Subcutaneous edema, sometimes with ascites and/or edema affecting the pancreas and cecum, was seen in three 100 mg/kg mice.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Number of abortions:

no effects observed

Description (incidence and severity):

The numbers of corpora lutea, implantation sites, dead fetuses, the sex ratio and the pre-implantation losses in the control and treated groups were similar.

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

The numbers of corpora lutea, implantation sites, dead fetuses, the sex ratio and the pre-implantation losses in the control and treated groups were similar.

Total litter losses by resorption:

effects observed, treatment-related

Description (incidence and severity):

Evaluation of the number of resorptions per litter and numbers of litters with total resorption were indicative of embryolethality.

Early or late resorptions:

effects observed, treatment-related

Description (incidence and severity):

Dead fetuses:

no effects observed

Description (incidence and severity):

The numbers of corpora lutea, implantation sites, dead fetuses, the sex ratio and the pre-implantation losses in the control and treated groups were similar.

Dose descriptor:

NOAEL

Effect level:

ca. 30 other: mg Fe/kg

Based on:

element

Basis for effect level:

body weight and weight gain

clinical signs

dead fetuses

early or late resorptions

food consumption and compound intake

food efficiency

gross pathology

mortality

number of abortions

pre and post implantation loss

total litter losses by resorption

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

Fetal weights were significantly (P<0.01) reduced in the 100 mg/kg group.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): effects observed, treatment-related
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): Fetal weights were significantly (P< 0.01) reduced in the 100 mg/kg group.

Reduction in number of live offspring:

not specified

Changes in sex ratio:

no effects observed

Description (incidence and severity):

The numbers of corpora lutea, implantation sites, dead fetuses, the sex ratio and the pre-implantation losses in the control and treated groups were similar.

Changes in litter size and weights:

not specified

Changes in postnatal survival:

not specified

External malformations:

no effects observed

Description (incidence and severity):

There were no drug induced malformations seen in this study.
The overall incidence of fetuses with minor skeletal anomalies was significantly increased in the 30 and 100 mg/kg groups. This resulted primarily from increased incidences of reduced numbers of ossified caudal vertebrae and a higher incidence of reduced numbers of ossified phalanges in the fore and/or hind paws. The percentage of fetuses with sternebral variants was increased in the 30 and 100 mg/kg groups. These latter findings were probably associated with the reduced growth of the offspring which was a consequence of reduced weight gains in the maternal animals at the high dose.

Skeletal malformations:

no effects observed

Description (incidence and severity):

Visceral malformations:

no effects observed

Description (incidence and severity):

Other effects:

not specified

Dose descriptor:

NOAEL

Effect level:

ca. 30 mg/kg bw/day

Based on:

element

Sex:

male/female

Basis for effect level:

changes in sex ratio

fetal/pup body weight changes

external malformations

skeletal malformations

visceral malformations

Developmental effects observed:

No drug related mortality. Effects seen at the injection sites in the 30 and 100 mg/kg groups included dry skin and ulceration on the tail, and black discoloration at the tip of the tail. Decreased activity and red vaginal discharge were also observed for some mice in the 100 mg/kg group. The body weight gains were decreased for the intervals Days 6 to 9 and Days 15 to 18 for the 100 mg/kg group. Body weights by Day 18 of gestation were significantly decreased compared with controls. Food consumption for the 100 mg/kg group was significantly decreased between Days 6 and 9 of gestation. Gross pathological findings in the 30 and 100 mg/kg groups included splenic enlargement and focal to multi-focal hepatic pallor. Other hepatic alterations including prominent lobular architecture and/or irregular pattern were also seen for a few 100 mg/kg group mice. Subcutaneous edema, sometimes with ascites and/or edema affecting the pancreas and cecum, was seen in three 100 mg/kg mice. The number of early resorptions was slightly increased in the 100 mg/kg group. Evaluation of the number of resorptions per litter and numbers of litters with total resorption were indicative of embryolethality. The numbers of corpora lutea, implantation sites, dead fetuses, the sex ratio and the pre-implantation losses in the control and treated groups were similar. Fetal weights were significantly (P< 0.01) reduced in the 100 mg/kg group. There were no drug induced malformations seen in this study. The overall incidence of fetuses with minor skeletal anomalies was significantly increased in the 30 and 100 mg/kg groups. This resulted primarily from increased incidences of reduced numbers of ossified caudal vertebrae and a higher incidence of reduced numbers of ossified phalanges in the fore and/or hind paws. The percentage of fetuses with sternebral variants was increased in the 30 and 100 mg/kg groups. These latter findings were probably associated with the reduced growth of the offspring which was a consequence of reduced weight gains in the maternal animals at the high dose.

Executive summary:

Ferrlecit (sodium ferric gluconate in sucrose injection) was adminstered to pregnant mice from gestation day 6 to 15 (sanofi-aventis Canada Inc., 2009). The employed doses were 10, 30 and 100 mg Fe /kg bw. No drug related mortality was observed. Effects seen at the injection sites in the 30 and 100 mg/kg groups included dry skin and ulceration on the tail, and black discoloration at the tip of the tail. Decreased activity and red vaginal discharge were also observed for some mice in the 100 mg/kg group. The body weight gains were decreased for the intervals Days 6 to 9 and Days 15 to 18 for the 100 mg/kg group. Body weights by Day 18 of gestation were significantly decreased compared with controls. Food consumption for the 100 mg/kg group was significantly decreased between Days 6 and 9 of gestation. Gross pathological findings in the 30 and 100 mg/kg groups included splenic enlargement and focal to multi-focal hepatic pallor. Other hepatic alterations including prominent lobular architecture and/or irregular pattern were also seen for a few 100 mg/kg group mice. Subcutaneous edema, sometimes with ascites and/or edema affecting the pancreas and cecum, was seen in three 100 mg/kg mice. The number of early resorptions was slightly increased in the 100 mg/kg group. Evaluation of the number of resorptions per litter and numbers of litters with total resorption were indicative of embryolethality. The numbers of corpora lutea, implantation sites, dead fetuses, the sex ratio and the pre-implantation losses in the control and treated groups were similar. Fetal weights were significantly (P< 0.01) reduced in the 100 mg/kg group. There were no drug induced malformations seen in this study. The overall incidence of fetuses with minor skeletal anomalies was significantly increased in the 30 and 100 mg/kg groups. This resulted primarily from increased incidences of reduced numbers of ossified caudal vertebrae and a higher incidence of reduced numbers of ossified phalanges in the fore and/or hind paws. The percentage of fetuses with sternebral variants was increased in the 30 and 100 mg/kg groups. These latter findings were probably associated with the reduced growth of the offspring which was a consequence of reduced weight gains in the maternal animals at the high dose.

A NOAEL of 30.0 mg Fe/kg can be established here for maternal and developmental toxicity.

Cross-reference 20

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

FERRLECIT (sodium ferric gluconate complex in sucrose injection) was administered at doses of elemental iron at 1.875 mg Fe/kg/day to rabbits.

GLP compliance:

Limit test:

Specific details on test material used for the study:

Species:

rabbit

Strain:

other: Morini

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

intravenous

Vehicle:

other: sucrose injection

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

12.5 mg/mL as elemental iron content

Details on mating procedure:

not specified

Duration of treatment / exposure:

GD 1 - 23
GD 1 - 28

Frequency of treatment:

not specified, presumably once daily

Duration of test:

23 and 28 days, respectively

Dose / conc.:

0 other: mg Fe/kg

Dose / conc.:

1.875 other: mg Fe/kg

Remarks:

(0.15 mL/kg)

No. of animals per sex per dose:

Control animals:

yes

Details on study design:

not specified

Maternal examinations:

yes

Ovaries and uterine content:

yes

Fetal examinations:

yes

Statistics:

not stated

Indices:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

no mortality observed

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Number of abortions:

no effects observed

Description (incidence and severity):

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

Total litter losses by resorption:

no effects observed

Description (incidence and severity):

Early or late resorptions:

no effects observed

Description (incidence and severity):

Dead fetuses:

no effects observed

Description (incidence and severity):

Changes in pregnancy duration:

not specified

Description (incidence and severity):

Changes in number of pregnant:

no effects observed

Description (incidence and severity):

Other effects:

no effects observed

Description (incidence and severity):

Dose descriptor:

NOAEL

Effect level:

> 1.875 other: mg Fe/kg

Based on:

element

Basis for effect level:

changes in number of pregnant

dead fetuses

early or late resorptions

number of abortions

pre and post implantation loss

total litter losses by resorption

Remarks on result:

not determinable due to absence of adverse toxic effects

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

IV injections of Ferrlecit® at 1.875 mg/kg/day in pregnant rabbits did not result in changes in the number and weight of the fetuses, in the number of live births, or in the structures of the main organs of the fetuses.
The fetuses were similar in number and weight to those from the animals treated with vehicle.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): IV injections of Ferrlecit® at 1.875 mg/kg/day in pregnant rabbits did not result in changes in the number and weight of the fetuses, in the number of live births, or in the structures of the main organs of the fetuses.
The fetuses were similar in number and weight to those from the animals treated with vehicle.

Reduction in number of live offspring:

no effects observed

Description (incidence and severity):

Changes in sex ratio:

not specified

Changes in litter size and weights:

no effects observed

Description (incidence and severity):

Changes in postnatal survival:

not specified

External malformations:

no effects observed

Description (incidence and severity):

There was no teratogenic effect on the morphology of the skeleton, limbs, or viscera.

Skeletal malformations:

no effects observed

Description (incidence and severity):

There was no teratogenic effect on the morphology of the skeleton, limbs, or viscera.

Visceral malformations:

no effects observed

Description (incidence and severity):

There was no teratogenic effect on the morphology of the skeleton, limbs, or viscera.

Other effects:

not specified

Dose descriptor:

NOAEL

Effect level:

> 1.875 other: mg Fe/kg

Based on:

element

Sex:

male/female

Basis for effect level:

reduction in number of live offspring

fetal/pup body weight changes

changes in litter size and weights

external malformations

skeletal malformations

visceral malformations

Remarks on result:

not determinable due to absence of adverse toxic effects

Developmental effects observed:

There was no teratogenic effect on the morphology of the skeleton, limbs, or viscera.

The fetuses were similar in number and weight to those from the animals treated with vehicle.

Executive summary:

Ferrlecit (sodium ferric gluconate in sucrose injection) was adminstered to pregnant rabbits from gestation day 1 to 23 and 28. The employed dose was 1.875 mg Fe /kg bw. IV injections of Ferrlecit® at 1.875 mg/kg/day in pregnant rabbits did not result in changes in the number and weight of the fetuses, in the number of live births, or in the structures of the main organs of the fetuses. There was no teratogenic effect on the morphology of the skeleton, limbs, or viscera. The fetuses were similar in number and weight to those from the animals treated with vehicle.

A NOAEL of > 1.875 mg Fe/kg can be established here for maternal and developmental toxicity.

FERRLECIT (sodium ferric gluconate complex in sucrose injection) was not teratogenic at doses of elemental iron of 1.875 mg/kg/day in rabbits.

Cross-reference 21

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

GLP compliance:

Limit test:

Specific details on test material used for the study:

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

intravenous

Vehicle:

other: sucrose injection

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

12.5 mg/mL as elemental iron content

Details on mating procedure:

not specified

Duration of treatment / exposure:

GD 6 - 17

Frequency of treatment:

not specified, presumably once daily

Duration of test:

12 days

Dose / conc.:

0 other: mg Fe/kg

Dose / conc.:

2.5 other: mg Fe/kg

Remarks:

(0.2 mL/kg)

Dose / conc.:

5 other: mg Fe/kg

Remarks:

(0.4 mL/kg)

Dose / conc.:

15 other: mg Fe/kg

Remarks:

(1.2 mL/kg)

Dose / conc.:

30 other: mg Fe/kg

Remarks:

(2.42 mL/kg)

No. of animals per sex per dose:

Control animals:

yes

Details on study design:

not specified

Maternal examinations:

yes

Ovaries and uterine content:

yes

Fetal examinations:

yes

Statistics:

not stated

Indices:

not specified

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Clinical findings prior to sacrifice or death included vaginal discharge, pallor, fur staining, cold to touch, hunched posture, dehydration, weakness, lying on side, and/or decreased respiratory rate/labored breathing, and one dam had started to litter. Common findings for the animals in the 15 and 30 mg/kg groups included yellow/orange/red urine staining of the urogenital region. Local effects included blue discoloration of the tail seen primarily in the 5 mg/kg group and above.

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, treatment-related

Description (incidence):

Two animals in the 15 mg/kg group and one animal in the 30 mg/kg group died or were sacrificed in poor condition during the study.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Dose-related body weight decreases were evident between Days 6 and 9 of gestation, with body weights for the 30 mg/kg group were remained lower through gestation Day 18.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Food consumption from Days 6 to 9 of gestation showed dose-related reductions. Food consumption was decreased in the 15 and 30 mg/kg/Day groups between Days 15 to 18 and Days 9 to 18 of gestation, respectively.

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Sacrificed animals:
Necropsy findings for the respective animals included dark discoloration of the ingesta, multiple dark areas on the stomach, pale or irregular area/foci on the livers, enlarged spleen, dark area/small thymus and dark fluid in the uterus or bladder.

Animals examined at cesarean section:
Necropsy of the animals examined at cesarean section revealed clear fluid in the abdomen, discolored / enlarged or dark lymph nodes, multiple pale areas on the liver, swollen or discolored pancreas, enlarged spleen. Dark areas on the uterus were seen among the dams in the 15 and/or 30 mg/kg groups.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Number of abortions:

no effects observed

Description (incidence and severity):

The pregnancy rate was at least 83% in all groups. The number of corpora lutea, implantation sites, live fetuses, dead fetuses, the sex ratio, and the pre and postimplantation losses were unaffected by treatment.

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

Total litter losses by resorption:

no effects observed

Description (incidence and severity):

Early or late resorptions:

no effects observed

Description (incidence and severity):

Dead fetuses:

no effects observed

Description (incidence and severity):

Changes in pregnancy duration:

not specified

Description (incidence and severity):

Changes in number of pregnant:

no effects observed

Description (incidence and severity):

Other effects:

no effects observed

Description (incidence and severity):

Dose descriptor:

NOAEL

Effect level:

ca. 5 other: mg Fe/kg

Based on:

element

Basis for effect level:

body weight and weight gain

changes in number of pregnant

clinical signs

dead fetuses

early or late resorptions

food consumption and compound intake

gross pathology

mortality

number of abortions

pre and post implantation loss

total litter losses by resorption

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

Fetal weights were slightly reduced in the 15 and 30 mg/kg groups.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): effects observed, treatment-related
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): Fetal weights were slightly reduced in the 15 and 30 mg/kg groups.

Reduction in number of live offspring:

no effects observed

Description (incidence and severity):

Changes in sex ratio:

no effects observed

Description (incidence and severity):

Changes in litter size and weights:

not specified

Changes in postnatal survival:

not specified

External malformations:

no effects observed

Description (incidence and severity):

There were no major malformations or minor anomalies observed externally.

Skeletal malformations:

no effects observed

Description (incidence and severity):

There were no major malformations or minor anomalies observed externally.

Visceral malformations:

no effects observed

Description (incidence and severity):

There were no major malformations or minor anomalies observed externally.

Other effects:

not specified

Dose descriptor:

NOAEL

Effect level:

ca. 5 other: mg Fe/kg

Based on:

element

Sex:

male/female

Basis for effect level:

reduction in number of live offspring

changes in sex ratio

fetal/pup body weight changes

external malformations

skeletal malformations

visceral malformations

Developmental effects observed:

Two animals in the 15 mg/kg group and one animal in the 30 mg/kg group died or were sacrificed in poor condition during the study. Clinical findings prior to sacrifice or death included vaginal discharge, pallor, fur staining, cold to touch, hunched posture, dehydration, weak, lying on side, and/or decreased respiratory rate/labored breathing, and one dam had started to litter. Necropsy findings for the respective animals included dark discoloration of the ingesta, multiple dark areas on the stomach, pale or irregular area/foci on the livers, enlarged spleen, dark area/small thymus and dark fluid in the uterus or bladder. Common findings for the animals in the 15 and 30 mg/kg groups included yellow/orange/red urine staining of the urogenital region. Local effects included blue discoloration of the tail seen primarily in the 5 mg/kg group and above. Dose-related body weight decreases were evident between Days 6 and 9 of gestation, with body weights for the 30 mg/kg group were remained lower through gestation Day 18. Food consumption from Days 6 to 9 of gestation showed dose-related reductions. Food consumption was decreased in the 15 and 30 mg/kg/Day groups between Days 15 to 18 and Days 9 to 18 of gestation, respectively. Necropsy of the animals examined at cesarean section revealed clear fluid in the abdomen, discolored / enlarged or dark lymph nodes, multiple pale areas on the liver, swollen or discolored pancreas, enlarged spleen. Dark areas on the uterus were seen among the dams in the 15 and/or 30 mg/kg groups. The pregnancy rate was at least 83% in all groups. The number of corpora lutea, implantation sites, live fetuses, dead fetuses, the sex ratio, and the pre- and postimplantation losses were unaffected by treatment. Fetal weights were slightly reduced in the 15 and 30 mg/kg groups. There were no major malformations or minor anomalies observed externally.

Executive summary:

Ferrlecit (sodium ferric gluconate in sucrose injection) was administered to pregnant rats from gestation day 6 to 17 (sanofi-aventis Canada Inc., 2009). The employed doses were 2.5, 5, 15 and 30 mg Fe /kg bw. Two animals in the 15 mg/kg group and one animal in the 30 mg/kg group died or were sacrificed in poor condition during the study. Clinical findings prior to sacrifice or death included vaginal discharge, pallor, fur staining, cold to touch, hunched posture, dehydration, weak, lying on side, and/or decreased respiratory rate/labored breathing, and one dam had started to litter. Necropsy findings for the respective animals included dark discoloration of the ingesta, multiple dark areas on the stomach, pale or irregular area/foci on the livers, enlarged spleen, dark area/small thymus and dark fluid in the uterus or bladder. Common findings for the animals in the 15 and 30 mg/kg groups included yellow/orange/red urine staining of the urogenital region. Local effects included blue discoloration of the tail seen primarily in the 5 mg/kg group and above. Dose-related body weight decreases were evident between Days 6 and 9 of gestation, with body weights for the 30 mg/kg group were remained lower through gestation Day 18. Food consumption from Days 6 to 9 of gestation showed dose-related reductions. Food consumption was decreased in the 15 and 30 mg/kg/Day groups between Days 15 to 18 and Days 9 to 18 of gestation, respectively. Necropsy of the animals examined at cesarean section revealed clear fluid in the abdomen, discolored / enlarged or dark lymph nodes, multiple pale areas on the liver, swollen or discolored pancreas, enlarged spleen. Dark areas on the uterus were seen among the dams in the 15 and/or 30 mg/kg groups. The pregnancy rate was at least 83% in all groups. The number of corpora lutea, implantation sites, live fetuses, dead fetuses, the sex ratio, and the pre and postimplantation losses were unaffected by treatment. Fetal weights were slightly reduced in the 15 and 30 mg/kg groups. There were no major malformations or minor anomalies observed externally.

A NOAEL of 5.0 mg Fe/kg can be established here for maternal toxicity.

Cross-reference 22

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

GLP compliance:

Limit test:

Specific details on test material used for the study:

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

intravenous

Vehicle:

other: sucrose injection

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

12.5 mg/mL as elemental iron content

Details on mating procedure:

not specified

Duration of treatment / exposure:

GD 6 - PPD 21

Frequency of treatment:

not specified, presumably once daily

Duration of test:

12 days in pregancy and 21 days post partum

Dose / conc.:

0 other: mg Fe/kg

Dose / conc.:

1 other: mg Fe/kg

Remarks:

(0.08 mL/kg)

Dose / conc.:

5 other: mg Fe/kg

Remarks:

(0.4 mL/kg)

Dose / conc.:

10 other: mg Fe/kg

Remarks:

(0.81 mL/kg)

No. of animals per sex per dose:

20 presumably only females (data not specified)

Control animals:

yes

Details on study design:

not specified

Maternal examinations:

yes

Ovaries and uterine content:

yes

Fetal examinations:

yes

Statistics:

not stated

Indices:

not specified

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Local clinical effects at the injection site, including blue discoloration of the tail, were seen at a higher incidence in the 5 and 10 mg/kg groups. Dark discoloration of the urine was seen in the 10 mg/kg group.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

No deaths, and no animals were sacrificed in poor condition during the study.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

There were significant dose-related weight losses for the 5 and 10 mg/kg groups from Days 6 to 9 of gestation. There was an increased weight gain at the 10 mg/kg level for Days 9 to 12 of gestation, and between Days 12 and 15 of gestation there was again a lower weight gain. During lactation there was marked variability of weight gains with lower values being seen in the period Days 0 to 4 post partum for the 5 and 10 mg/kg groups and smaller weight losses between Days 17 and 21 post partum at 10 mg/kg.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Food intakes from Days 6 to 9 and Days 15 to 18 of gestation showed dose-related reductions which were significant (P<0.05) in the 10 mg/kg group.

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

There were no treatment-related gross pathological changes.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Details on results:

Maternal performance in terms of the length of gestation, duration of parturition, and number of live, dead and malformed pups at birth was unaffected by treatment.

Number of abortions:

no effects observed

Description (incidence and severity):

Maternal performance in terms of the length of gestation, duration of parturition, and number of live, dead and malformed pups at birth was unaffected by treatment.

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

Maternal performance in terms of the length of gestation, duration of parturition, and number of live, dead and malformed pups at birth was unaffected by treatment.

Total litter losses by resorption:

no effects observed

Description (incidence and severity):

Maternal performance in terms of the length of gestation, duration of parturition, and number of live, dead and malformed pups at birth was unaffected by treatment.

Early or late resorptions:

no effects observed

Description (incidence and severity):

Maternal performance in terms of the length of gestation, duration of parturition, and number of live, dead and malformed pups at birth was unaffected by treatment.

Dead fetuses:

no effects observed

Description (incidence and severity):

Maternal performance in terms of the length of gestation, duration of parturition, and number of live, dead and malformed pups at birth was unaffected by treatment.

Changes in pregnancy duration:

not specified

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): Maternal performance in terms of the length of gestation, duration of parturition, and number of live, dead and malformed pups at birth was unaffected by treatment.

Changes in number of pregnant:

no effects observed

Description (incidence and severity):

Maternal performance in terms of the length of gestation, duration of parturition, and number of live, dead and malformed pups at birth was unaffected by treatment.

Other effects:

no effects observed

Description (incidence and severity):

Maternal performance in terms of the length of gestation, duration of parturition, and number of live, dead and malformed pups at birth was unaffected by treatment.

Dose descriptor:

NOAEL

Effect level:

ca. 1 mg/kg bw/day

Based on:

element

Basis for effect level:

body weight and weight gain

changes in number of pregnant

clinical signs

dead fetuses

early or late resorptions

effects on pregnancy duration

food consumption and compound intake

gross pathology

mortality

number of abortions

pre and post implantation loss

total litter losses by resorption

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

Pup weights (male, female, and total) were slightly lower at birth in the 10 mg/kg group. These differences were significantly lower on Day 4 post partum and continued to be significant until Day 21 post partum. Slightly lower pup weights were seen on Day 7 post partum, with significantly lower values on Days 14 and 21 post partum in the 5 mg/kg group.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): effects observed, treatment-related
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): Pup weights (male, female, and total) were slightly lower at birth in the 10 mg/kg group. These differences were significantly lower on Day 4 post partum and continued to be significant until Day 21 post partum. Slightly lower pup weights were seen on Day 7 post partum, with significantly lower values on Days 14 and 21 post partum in the 5 mg/kg group.

Reduction in number of live offspring:

no effects observed

Description (incidence and severity):

The viability and survival indices were unaffected.

Changes in sex ratio:

not specified

Changes in litter size and weights:

not specified

Changes in postnatal survival:

no effects observed

Description (incidence and severity):

The viability and survival indices were unaffected.
Evaluation of the data from the F1 adult animals indicated that there were no adverse clinical observations. Behavioral and maturational assessments indicated that there were no direct effects of drug treatment on normal development.

External malformations:

not specified

Skeletal malformations:

not specified

Visceral malformations:

not specified

Other effects:

no effects observed

Description (incidence and severity):

Behavioral and maturational assessments indicated that there were no direct effects of drug treatment on normal development. At the highest dose, there was an increase in the mean time to vaginal opening and an increase in exploration activity counts on Day 35 postpartum (but not on Day 60). Both of these findings are attributed to the decrease in the rate of maternal weight gains. The reproductive capacity of the F1 generation was not affected and their offspring were normal with respect to clinical observations and weight gains.

Dose descriptor:

NOAEL

Effect level:

ca. 1 other: mg Fe/kg

Based on:

element

Sex:

male/female

Basis for effect level:

reduction in number of live offspring

fetal/pup body weight changes

changes in postnatal survival

Developmental effects observed:

F0 Generation: No deaths, and no animals were sacrificed in poor condition during the study. Local clinical effects at the injection site, including blue discoloration of the tail, were seen at a higher incidence in the 5 and 10 mg/kg groups. Dark discoloration of the urine was seen in the 10 mg/kg group. There were significant dose-related weight losses for the 5 and 10 mg/kg groups from Days 6 to 9 of gestation. There was an increased weight gain at the 10 mg/kg level for Days 9 to 12 of gestation, and between Days 12 and 15 of gestation there was again a lower weight gain. During lactation there was marked variability of weight gains with lower values being seen in the period Days 0 to 4 post partum for the 5 and 10 mg/kg groups and smaller weight losses between Days 17 and 21 post partum at 10 mg/kg. Food intakes from Days 6 to 9 and Days 15 to 18 of gestation showed dose-related reductions which were significant (P<0.05) in the 10 mg/kg group. There were no treatment-related gross pathological changes. Maternal performance in terms of the length of gestation, duration of parturition, and number of live, dead and malformed pups at birth was unaffected by treatment.

F1 Generation: The viability and survival indices were unaffected. There were no treatment-related clinical findings. Pup weights (male, female, and total) were slightly lower at birth in the 10 mg/kg group. These differences were significantly lower on Day 4 post partum and continued to be significant until Day 21 post partum. Slightly lower pup weights were seen on Day 7 post partum, with significantly lower values on Days 14 and 21 post partum in the 5 mg/kg group. Evaluation of the data from the F1 adult animals indicated that there were no adverse clinical observations. Behavioral and maturational assessments indicated that there were no direct effects of drug treatment on normal development. At the highest dose, there was an increase in the mean time to vaginal opening and an increase in exploration activity counts on Day 35 postpartum (but not on Day 60). Both of these findings are attributed to the decrease in the rate of maternal weight gains. The reproductive capacity of the F1 generation was not affected and their offspring were normal with respect to clinical observations and weight gains.

Executive summary:

Ferrlecit (sodium ferric gluconate in sucrose injection) was administered to pregnant rats from gestation day 6 to 17 and throughout postpartum day 21 (sanofi-aventis Canada Inc., 2009). The employed doses were 1, 5 and 10 mg Fe /kg bw.

A NOAEL of 1.0 mg Fe/kg can be established here for maternal toxicity.

Cross-reference 23

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

FERRLECIT (sodium ferric gluconate complex in sucrose injection) was administered at doses of elemental iron up to 100 mg/kg/day (300 mg/m²/day) to mice and at 20 mg/kg/day (120 mg/m²/day) or up to 30 mg Fe/kg to rats. On a body surface area basis, these doses were 1.3 and 3.24 times the recommended human dose (125 mg/day or 92.5 mg/m²/day) for a person of 50 kg body weight, average height and body surface area of 1.46 m².

GLP compliance:

Limit test:

Specific details on test material used for the study:

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

intravenous

Vehicle:

other: sucrose injection

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

12.5 mg/mL as elemental iron content

Details on mating procedure:

not specified

Duration of treatment / exposure:

GD 6 - 15

Frequency of treatment:

not specified, presumably once daily

Duration of test:

10 days

Dose / conc.:

0 other: mg Fe/kg

Dose / conc.:

4 other: mg Fe/kg

Remarks:

(0.5 mL/kg)

Dose / conc.:

20 other: mg Fe/kg

Remarks:

(2.5 mL/kg)

No. of animals per sex per dose:

20 presumably only females (data not specified)

Control animals:

yes

Details on study design:

not specified

Maternal examinations:

yes

Ovaries and uterine content:

yes

Fetal examinations:

yes

Statistics:

not stated

Indices:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

no effects observed

Description (incidence and severity):

Both treatment groups consumed more water than the controls, but a significant difference was not observed.

Ophthalmological findings:

not examined

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Description (incidence and severity):

There were no treatment-related gross pathological changes.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Details on results:

The fertility index was identical between all groups. There was no difference between the control and the 4 mg/kg group regarding the gestation index or the number of dead fetuses. There was no difference in the litter size or birth weights between the controls and 4 mg/kg group. There was a significant difference in the birth weights of both the males and females in the 20 mg/kg group compared to the control and 4 mg/kg groups. No treatment related anomalies were observed. However, many of the 20 mg/kg fetuses showed a retardation in ossification of the cranial bones. This was interpreted to indicate a delay in general development associated with reduced maternal weight gains and food consumption. There was no evidence of teratogenicity at any dose level.

Number of abortions:

not specified

Pre- and post-implantation loss:

not specified

Total litter losses by resorption:

not specified

Early or late resorptions:

not specified

Dead fetuses:

no effects observed

Description (incidence and severity):

The fertility index was identical between all groups. There was no difference between the control and the 4 mg/kg group regarding the gestation index or the number of dead fetuses.

Changes in pregnancy duration:

not specified

Description (incidence and severity):

The fertility index was identical between all groups. There was no difference between the control and the 4 mg/kg group regarding the gestation index or the number of dead fetuses.
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified

Changes in number of pregnant:

no effects observed

Description (incidence and severity):

The fertility index was identical between all groups. There was no difference between the control and the 4 mg/kg group regarding the gestation index or the number of dead fetuses.

Other effects:

not specified

Dose descriptor:

NOAEL

Effect level:

ca. 4 other: mg Fe/kg

Based on:

element

Basis for effect level:

body weight and weight gain

changes in number of pregnant

changes in pregnancy duration

food consumption and compound intake

gross pathology

mortality

water consumption and compound intake

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

There was no difference in the litter size or birth weights between the controls and 4 mg/kg group.
There was a significant difference in the birth weights of both the males and females in the 20 mg/kg group compared to the control and 4 mg/kg groups.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): effects observed, treatment-related
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): There was no difference in the litter size or birth weights between the controls and 4 mg/kg group.
There was a significant difference in the birth weights of both the males and females in the 20 mg/kg group compared to the control and 4 mg/kg groups.

Reduction in number of live offspring:

not specified

Changes in sex ratio:

not specified

Changes in litter size and weights:

not specified

Description (incidence and severity):

There was no difference in the litter size or birth weights between the controls and 4 mg/kg group.

Changes in postnatal survival:

not specified

External malformations:

no effects observed

Description (incidence and severity):

No treatment related anomalies were observed.

Skeletal malformations:

effects observed, treatment-related

Description (incidence and severity):

No treatment related anomalies were observed.
However, many of the 20 mg/kg fetuses showed a retardation in ossification of the cranial bones. This was interpreted to indicate a delay in general development associated with reduced maternal weight gains and food consumption. There was no evidence of teratogenicity at any dose level.

Visceral malformations:

no effects observed

Description (incidence and severity):

No treatment related anomalies were observed.

Other effects:

no effects observed

Description (incidence and severity):

Dose descriptor:

NOAEL

Effect level:

ca. 4 other: mg Fe/kg

Based on:

element

Sex:

male/female

Basis for effect level:

fetal/pup body weight changes

changes in litter size and weights

external malformations

skeletal malformations

visceral malformations

Developmental effects observed:

Treatment of pregnant rats at a dose of 20 mg/kg resulted in marked effects that included lower maternal weight gain, lower food consumption, reduced gestation index, a significantly lower litter size, increased resorption sites, and fetal mortality. Treatment at 4 mg/kg did not show any difference from controls regarding weight gain or food intake. Both treatment groups consumed more water than the controls, but a significant difference was not observed. The fertility index was identical between all groups. There was no difference between the control and the 4 mg/kg group regarding the gestation index or the number of dead fetuses. There was no difference in the litter size or birth weights between the controls and 4 mg/kg group. There was a significant difference in the birth weights of both the males and females in the 20 mg/kg group compared to the control and 4 mg/kg groups. No treatment related anomalies were observed. However, many of the 20 mg/kg fetuses showed a retardation in ossification of the cranial bones. This was interpreted to indicate a delay in general development associated with reduced maternal weight gains and food consumption. There was no evidence of teratogenicity at any dose level.

Executive summary:

Ferrlecit (sodium ferric gluconate in sucrose injection) was adminstered to pregnant rats from gestation day 6 to 15 (sanofi-aventis Canada Inc., 2009). The employed doses were 4 and 20 mg Fe /kg bw. Treatment of pregnant rats at a dose of 20 mg/kg resulted in marked effects that included lower maternal weight gain, lower food consumption, reduced gestation index, a significantly lower litter size, increased resorption sites, and fetal mortality. Treatment at 4 mg/kg did not show any difference from controls regarding weight gain or food intake. Both treatment groups consumed more water than the controls, but a significant difference was not observed. The fertility index was identical between all groups. There was no difference between the control and the 4 mg/kg group regarding the gestation index or the number of dead fetuses. There was no difference in the litter size or birth weights between the controls and 4 mg/kg group. There was a significant difference in the birth weights of both the males and females in the 20 mg/kg group compared to the control and 4 mg/kg groups. No treatment related anomalies were observed. However, many of the 20 mg/kg fetuses showed a retardation in ossification of the cranial bones. This was interpreted to indicate a delay in general development associated with reduced maternal weight gains and food consumption. There was no evidence of teratogenicity at any dose level.

A NOAEL of 4.0 mg Fe/kg can be established here for maternal toxicity.

Cross-reference 24

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

direct observations: clinical cases, poisoning incidents and other

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

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reference to same study

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Study type:

study with volunteers

Endpoint addressed:

basic toxicokinetics

other: adverse events

Qualifier:

no guideline followed

Principles of method if other than guideline:

In a small pharmacokinetic study, 14 subjects were given either 62.5 mg or 125 mg of Ferrlecit at a “slow” infusion rate at approximately 2 mg/min and subsequently at a “fast” infusion rate at 15-18 mg/min.

GLP compliance:

Specific details on test material used for the study:

Type of population:

general

Subjects:

14 subjects, no furthr details given

Ethical approval:

confirmed, but no further information available

Route of exposure:

other: intravenous

Reason of exposure:

intentional

Exposure assessment:

measured

Details on exposure:

Examinations:

not specified

Medical treatment:

not specified

Clinical signs:

Results of examinations:

no details available

Outcome of incidence:

Three adverse events (palpitation, shortness of breath and dizziness) were experienced by one subject during the administration of Ferrlecit under “fast” infusion conditions at a dose of 62.5 mg Ferrlecit over 4 minutes. The adverse events began just after initiation of the drug and were resolved just as the administration of the drug was completed. They did not correlate with the time of maximum concentration of Ferrlecit in the blood of the subject and were not correlated with dose. The study predicted that most patients can safely tolerate infusions of Ferrlecit at the fast infusion rate.

Executive summary:

Cross-reference 25

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

exposure-related observations in humans: other data

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

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reference to same study

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Type of study / information:

This study was a three-center, randomized, open-label study of the safety and efficacy of two doses of Ferrlecit® administered intravenously to iron-deficient hemodialysis patients.

Endpoint addressed:

other: acute toxicity: intravenous

Qualifier:

no guideline followed

Principles of method if other than guideline:

This study was a three-center, randomized, open-label study of the safety and efficacy of two doses of Ferrlecit® administered intravenously to iron-deficient hemodialysis patients.

GLP compliance:

Specific details on test material used for the study:

Ethical approval:

confirmed, but no further information available

Details on study design:

This study was a three-center, randomized, open-label study of the safety and efficacy of two doses of Ferrlecit® administered intravenously to iron-deficient hemodialysis patients. The study included both a dose-response concurrent control and an historical control. Enrolled patients received a test dose of Ferrlecit® (25 mg of elemental iron) and were then randomly assigned to receive Ferrlecit® at cumulative doses of either 500 mg (low dose) or 1000 mg (high dose) of elemental iron. Ferrlecit® was given to both dose groups in eight divided doses during sequential dialysis sessions (a period of 16 to 17 days). At each dialysis session, patients in the low-dose group received Ferrlecit® 62.5 mg of elemental iron over 30 minutes, and those in the high-dose group received Ferrlecit® 125 mg of elemental iron over 60 minutes. The primary endpoint was the change in hemoglobin from baseline to the last available observation through Day 40.
Eligibility for this study included chronic hemodialysis patients with a hemoglobin below 10 g/dL (or hematocrit at or below 32%) and either serum ferritin below 100 ng/mL or transferrin saturation below 18%. Exclusion criteria included significant underlying disease or inflammatory conditions or an epoetin requirement of greater than 10,000 units three times per week. Parenteral iron and red cell transfusion were not allowed for two months before the study. Oral iron and red cell transfusion were not allowed during the study for Ferrlecit® treated patients.
The historical control population consisted of 25 chronic hemodialysis patients who received only oral iron supplementation for 14 months and did not receive red cell transfusion. All patients had stable epoetin doses and hematocrit values for at least two months before initiation of oral iron therapy.
The evaluated population consisted of 39 patients in the lowdose Ferrlecit® group, 44 patients in the high-dose Ferrlecit® group, and 25 historical control patients.

Exposure assessment:

measured

Details on exposure:

Enrolled patients received a test dose of Ferrlecit® (25 mg of elemental iron) and were then randomly assigned to receive Ferrlecit® at cumulative doses of either 500 mg (low dose) or 1000 mg (high dose) of elemental iron. Ferrlecit® was given to both dose groups in eight divided doses during sequential dialysis sessions (a period of 16 to 17 days). At each dialysis session, patients in the low-dose group received Ferrlecit® 62.5 mg of elemental iron over 30 minutes, and those in the high-dose group received Ferrlecit® 125 mg of elemental iron over 60 minutes. The primary endpoint was the change in hemoglobin from baseline to the last available observation through Day 40.

Results:

Patients in the high-dose Ferrlecit® group achieved significantly higher increases in hemoglobin and hematocrit than either patients in the low-dose Ferrlecit® group or patients in the historical control group (oral iron). Patients in the low-dose Ferrlecit® group did not achieve significantly higher increases in hemoglobin and hematocrit than patients receiving oral iron.

The mean baseline hemoglobin and hematocrit were similar between treatment and historical control patients: 9.8 g/dL and 29% and 9.6 g/dL and 29% in low- and high-dose Ferrlecit® treated patients, respectively, and 9.4 g/dL and 29% in historical control patients. Baseline serum transferrin saturation was 20% in the low-dose group, 16% in the high-dose group, and 14% in the historical control. Baseline serum ferritin was 106 ng/mL in the low-dose group, 88 ng/mL in the high-dose group, and 606 ng/mL in the historical control.

Table 1: Hemoglobin, Hematocrit, and Iron Studies
Study A	Mean Change from Baseline to Two Weeks After Cessation of Therapy
Study A	Ferrlecit ® 1000 mg IV (N=44)	Ferrlecit ® 500 mg IV (N=39)	Historical Control-Oral Iron (N=25)
Hemoglobin	1.1 g/dL*	0.3 g/dL	0.4 g/dL
Hematocrit	3.6%*	1.4%	0.8%
Transferrin Saturation	8.5%	2.8%	6.1%
Serum Ferritin	199 ng/mL	132 ng/mL	NA
*p<0.01 versus both the 500 mg group and the historical control group.

Conclusions:

Executive summary:

The historical control population consisted of 25 chronic hemodialysis patients who received only oral iron supplementation for 14 months and did not receive red cell transfusion. All patients had stable epoetin doses and hematocrit values for at least two months before initiation of oral iron therapy.

The evaluated population consisted of 39 patients in the lowdose Ferrlecit® group, 44 patients in the high-dose Ferrlecit® group, and 25 historical control patients.

Table 1: Hemoglobin, Hematocrit, and Iron Studies
Study A	Mean Change from Baseline to Two Weeks After Cessation of Therapy
Study A	Ferrlecit ® 1000 mg IV (N=44)	Ferrlecit ® 500 mg IV (N=39)	Historical Control-Oral Iron (N=25)
Hemoglobin	1.1 g/dL*	0.3 g/dL	0.4 g/dL
Hematocrit	3.6%*	1.4%	0.8%
Transferrin Saturation	8.5%	2.8%	6.1%
Serum Ferritin	199 ng/mL	132 ng/mL	NA
*p<0.01 versus both the 500 mg group and the historical control group.

Cross-reference 26

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

exposure-related observations in humans: other data

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

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Type of study / information:

This study was a single-center, non-randomized, open-label, historically-controlled, study of the safety and efficacy of variable, cumulative doses of intravenous Ferrlecit® in irondeficient hemodialysis patients. Enrolled patients received a test dose of Ferrlecit® (25 mg of elemental iron) and were then randomly assigned to receive Ferrlecit® at cumulative doses of either 500 mg (low dose) or 1000 mg (high dose) of elemental iron. Ferrlecit® was given to both dose groups in eight divided doses during sequential dialysis sessions (a period of 16 to 17 days). At each dialysis session, patients in the low-dose group received Ferrlecit® 62.5 mg of elemental iron over 30 minutes, and those in the high-dose group received Ferrlecit® 125 mg of elemental iron over 60 minutes. The primary efficacy variable was the change in hemoglobin from baseline to the last available observation through Day 50.

Endpoint addressed:

other: acute toxicity: intravenous

Qualifier:

no guideline followed

Principles of method if other than guideline:

GLP compliance:

Specific details on test material used for the study:

Ethical approval:

confirmed, but no further information available

Details on study design:

Eligibility for this study included chronic hemodialysis patients with a hemoglobin below 10 g/dL (or hematocrit at or below 32%) and either serum ferritin below 100 ng/mL or transferrin saturation below 18%. Exclusion criteria included significant underlying disease or inflammatory conditions or an epoetin requirement of greater than 10,000 units three times per week. Parenteral iron and red cell transfusion were not allowed for two months before the study. Oral iron and red cell transfusion were not allowed during the study for Ferrlecit® treated patients.
Sixty-three patients were evaluated in this study: 38 in the Ferrlecit®-treated group and 25 in the historical control group. The historical control population consisted of 25 chronic hemodialysis patients who received only oral iron supplementation for 14 months and did not receive red cell transfusion. All patients had stable epoetin doses and hematocrit values for at least two months before initiation of oral iron therapy.
Ferrlecit®-treated patients were considered to have completed the study per protocol if they received at least eight Ferrlecit® doses of either 62.5 mg or 125 mg of elemental iron. A total of 14 patients (37%) completed the study per protocol. Twelve (32%) Ferrlecit®-treated patients received less than eight doses, and 12 (32%) patients had incomplete information on the sequence of dosing. Not all patients received Ferrlecit® at consecutive dialysis sessions and many received oral iron during the study.

Exposure assessment:

measured

Details on exposure:

Results:

In this patient population, only the Ferrlecit®-treated group achieved significant increase in hemoglobin and hematocrit from baseline. This increase was significantly greater than that seen in the historical oral iron treatment group.

Baseline hemoglobin and hematocrit values were similar between the treatment and control groups, and were 9.1 g/dL and 27.3%, respectively, for Ferrlecit®-treated patients. Serum iron studies were also similar between treatment and control groups, with the exception of serum ferritin, which was 606 ng/mL for historical control patients, compared to 77 ng/mL for Ferrlecit®-treated patients.

Table 2: Hemoglobin, Hematocrit, and Iron Studies
Study B	Mean Change from Baseline One Month after Treatment
Study B	Ferrlecit ® (N=38)	Oral iron (N=25)
	change	change
Hemoglobin (g/dL)	1.3a,b	0.4
Hematocrit (%)	3.8a,b	0.2
Transferrin Saturation (%)	6.7b	1.7
Serum Ferritin (ng/mL)	73b	-145
^a- p<0.05 on group comparison by the ANCOVA method
^b- p<0.001 from baseline by the paired t-test method

Executive summary:

Inclusion and exclusion criteria were as follows: Eligibility for this study included chronic hemodialysis patients with a hemoglobin below 10 g/dL (or hematocrit at or below 32%) and either serum ferritin below 100 ng/mL or transferrin saturation below 18%. Exclusion criteria included significant underlying disease or inflammatory conditions or an epoetin requirement of greater than 10,000 units three times per week. Parenteral iron and red cell transfusion were not allowed for two months before the study. Oral iron and red cell transfusion were not allowed during the study for Ferrlecit® treated patients. Sixty-three patients were evaluated in this study: 38 in the Ferrlecit®-treated group and 25 in the historical control group. The historical control population consisted of 25 chronic hemodialysis patients who received only oral iron supplementation for 14 months and did not receive red cell transfusion. All patients had stable epoetin doses and hematocrit values for at least two months before initiation of oral iron therapy.

Ferrlecit®-treated patients were considered to have completed the study per protocol if they received at least eight Ferrlecit® doses of either 62.5 mg or 125 mg of elemental iron. A total of 14 patients (37%) completed the study per protocol. Twelve (32%) Ferrlecit®- treated patients received less than eight doses, and 12 (32%) patients had incomplete information on the sequence of dosing. Not all patients received Ferrlecit® at consecutive dialysis sessions and many received oral iron during the study.

Table 2: Hemoglobin, Hematocrit, and Iron Studies
Study B	Mean Change from Baseline One Month after Treatment
Study B	Ferrlecit ® (N=38)	Oral iron (N=25)
	change	change
Hemoglobin (g/dL)	1.3a,b	0.4
Hematocrit (%)	3.8a,b	0.2
Transferrin Saturation (%)	6.7b	1.7
Serum Ferritin (ng/mL)	73b	-145
^a- p<0.05 on group comparison by the ANCOVA method
^b- p<0.001 from baseline by the paired t-test method

Cross-reference 27

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

exposure-related observations in humans: other data

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

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reference to same study

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Type of study / information:

Endpoint addressed:

skin sensitisation

other: acute toxicity: intravenous

Qualifier:

no guideline followed

Principles of method if other than guideline:

GLP compliance:

Specific details on test material used for the study:

Ethical approval:

confirmed, but no further information available

Details on study design:

This study was a multicentre (n = 69), crossover, randomized, double-blind, prospective study of the safety of Ferrlecit® in hemodialysis patients who required at least 125 mg of elemental intravenous iron.
A primary objective of the study was to compare outcome (drug intolerance) events and lifethreatening adverse events after Ferrlecit® administration compared to placebo and an historical control. The historical control was based on a conservative analysis of exposure to iron dextran in defined patient populations from three independent publications which were combined by meta-analysis. The drugs were three different marketed formats of iron
dextrans, used in three different populations. Two of the studies were retrospective and one study was prospective. Iron dextran was administered intravenously in doses which varied from 25 mg to 100 mg in these studies.
Another primary objective of this study was to assess the safety of Ferrlecit® when administered undiluted at a rate of 12.5 mg/minute without a test dose in a large patient population. Each patient received a total of 125 mg of Ferrlecit® (10 mL undiluted) by slow injection via the venous return over 10 minutes. Treatment was administered during the first hour of hemodialysis.

Details on exposure:

The historical control was three different marketed formats of iron dextrans, used in three different populations. Ferrlecit® was administered undiluted at a rate of 12.5 mg/minute without a test dose in a large patient population. Each patient received a total of 125 mg of Ferrlecit® (10 mL undiluted) by slow injection via the venous return over 10 minutes. Treatment was administered during the first hour of hemodialysis. Patients received a course of four sequential dialysis sessions over a duration of approximately one week. At the first hemodialysis session, patients underwent screening procedures. If eligible to continue the study, patients were randomized to one of two crossover treatment schedules as follows: Ferrlecit® at session 2 and placebo at session 3 or placebo at session 2 and Ferrlecit® at session 3.

In the final analysis, 2512 patients were exposed to Ferrlecit® and 2487 were exposed to placebo in the cross-over design for Study C. 2489 patients were evaluable for protocol events, having received both Ferrlecit® and placebo infusions and having completed the study according to protocol.

Ferrlecit® was well tolerated, with an overall incidence of all adverse events (12.3%, 310/2514) which compared favourably to placebo (9.8%, 245/2509), although with statistical significance (p < 0.05 by McNemar’s test).

The safety of Ferrlecit® was also demonstrated by the incidence of outcome (0.4%, 11/2493) and life-threatening (0.0%, 1/2493) adverse events which was not significantly different (McNemar’s test) than for the placebo treatment (outcome events 0.1%, 2/2487, lifethreatening events 0%, 0/2487). The incidence of adverse events for Ferrlecit® was lower than reported historically with iron dextran (2.47%, 64/2589 for outcome events and 0.61%, 23/37684 for life-threatening events). The incidence of serious adverse events following Ferrlecit® was 0.6%, 14/2514 while the ncidence following placebo was 0.5%, 12/2509. The difference was not statistically

significant by McNemar’s test.

Three of 11 outcome events after Ferrlecit® were considered immediate serious adverse events (pruritus, hypotension and anaphylactoid reaction). Both the pruritus and the anaphylactoid reaction were also classified as clinically suspected allergic events; however both were subsequently confirmed by tryptase assay to be non-allergic.

The third event (anaphylactoid reaction) was also considered by the investigator to be a life-threatening adverse event. The patient had a suspected anaphylactoid reaction (diaphoresis, dyspnea and wheezing for 20 minutes) immediately following administration of Ferrlecit®. However the event was not anaphylactic per protocol because the patient’s serum tryptase level decreased from 11.7 ng/mL to 10.8 ng/mL. Additionally the patient had prior

history of severe anaphylactoid reaction to iron dextran, had experienced rash when given penicillin and pruritus when given cephalosporin. This patient most probably had a high constitutive leak of tryptase with resultant drug idiosyncratic intolerance rather than a specific drug allergy.

Ferrlecit® was not statistically different (by McNemar’s test) from placebo in suspected allergic reactions (rash, pruritus, nausea, dizziness, chills, dyspnea, chest pain, dry throat, vomiting, headache, malaise). The rate of reaction following Ferrlecit® was 0.5% (12/2493) compared to 0.2% (5/2487) for placebo.

For confirmed allergic events (based on tryptase assay), the rate following Ferrlecit® was 0.1% (2/2493, facial redness with rise in serum tryptase from 2.1 to 4.9 ng/mL, and back pain with rise in serum tryptase from 3.8 to 7.8 ng/mL). No allergic events were confirmed by tryptase assay following placebo; calculated incidence 0% (0/2487).

There were no patients in this study who experienced an anaphylactic event as defined by the protocol.

All life-threatening, outcome and suspected allergic adverse events in the Intent-To-Treat population are summarized below in Table 1:

Table 1: Life-threatening, Outcome and Suspected Allergic Adverse Events in the Intent-To-Treat Population
Event/s per patient n=20	Treatment	Life-threatening adverse event	Outcome event (drug intolerance)	Suspected allergic event			Onset time	Severity
Event/s per patient n=20	Treatment	Life-threatening adverse event	Outcome event (drug intolerance)	Confirmed Non-allergic	Confirmed allergic	Unconfirmed	Onset time	Severity
allergic reaction (nausea, unease, dry throat)	Ferrlecit			X			immed²	mild
allergic reaction (abdominal cramps [immediate], diarrhea, nausea, itching and flushing [delayed])	placebo		X	X			immed.	mod.
nausea	Ferrlecit		X				instant¹	mild
pruritus	Ferrlecit		X	X			immed.	mod.
hypotension	Ferrlecit		X				immed.	severe
allergic reaction (nausea, dizziness, headache & vomiting)	placebo			X			instant.	mild
dizziness, nausea	Ferrlecit			X			instant.	mild
allergic reaction (flushing & malaise)	placebo			X			immed.	mild
allergic reaction (pronounced facial flushing)	Ferrlecit		X		X		instant.	severe
allergic reaction (chills)	Ferrlecit		X	X			immed.	mild
anaphylactoid reaction (diaphoresis, dyspnea & wheezing)	Ferrlecit	X	X	X			immed.	severe
hypotension	placebo		X				immed.	mod.
porphyria	Ferrlecit		X				delayed³	mod.
rash	placebo						delayed
pruritus	Ferrlecit		X	X		X	immed.	mild
allergic reaction (dyspnea and chest pain)	Ferrlecit		X	X			instant.	mod.
allergic reaction (rash)	Ferrlecit		X			X	delayed	mild
back pain	Ferrlecit		X		X		immed.	mild
rash	Ferrlecit			X			immed.	mild
pruritus	Ferrlecit			X			immed.	mild
pruritus	placebo			X			immed.	mild
1 AE during infusion 2 AE after infusion but before dialysis was complete 3 AE after dialysis was completed.

The cardiovascular system and the digestive system were the only two body systems for which adverse events occurred statistically (p<0.05 by McNemar’s test) more frequently among patients receiving Ferrlecit® versus placebo. The percentage of patients who experience at least one cardiovascular event was 5.4%, 136/2514 for Ferrlecit®-treated patients and 4.1% 103/2509 for placebo-treated patients. The majority of the cardiovascular incidents were hypotension, hypertension and vasodilation. Hypotension is known to be a frequent concomitant event during hemodiaylsis and in fact, there was no statistically significant difference between Ferrlecit® and placebo for this adverse event.

Within the digestive system, 2.5%, 64/2514 of patients experienced an event following Ferrlecit® and 1.6%, 39/2509 of patients experienced an event after placebo. The majority of these events were diarrhea and nausea.

Prior iron dextran sensitivity and concomitant angiotensin converting enzyme (ACE) inhibitor therapy were monitored as secondary study objectives, and were found to be not predisposing factors for adverse events. Finally, the overall low incidence of all adverse events, including allergic outcome, serious, and life-threatening events supports the safety of administering Ferrlecit® at a rate of 12.5 mg/minutes without a test dose.

Executive summary:

A primary objective of the study was to compare outcome (drug intolerance) events and lifethreatening adverse events after Ferrlecit® administration compared to placebo and an historical control. The historical control was based on a conservative analysis of exposure to iron dextran in defined patient populations from three independent publications which were combined by meta-analysis. The drugs were three different marketed formats of iron

dextrans, used in three different populations. Two of the studies were retrospective and one study was prospective. Iron dextran was administered intravenously in doses which varied from 25 mg to 100 mg in these studies.

Another primary objective of this study was to assess the safety of Ferrlecit® when administered undiluted at a rate of 12.5 mg/minute without a test dose in a large patient population. Each patient received a total of 125 mg of Ferrlecit® (10 mL undiluted) by slow injection via the venous return over 10 minutes. Treatment was administered during the first hour of hemodialysis.

Patients received a course of four sequential dialysis sessions over a duration of approximately one week. At the first hemodialysis session, patients underwent screening procedures. If eligible to continue the study, patients were randomized to one of two crossover treatment schedules as follows: Ferrlecit® at session 2 and placebo at session 3 or placebo at session 2 and Ferrlecit® at session 3.

A third primary objective of this study was to compare the incidence of all immediate-type suspected and confirmed allergic reactions following Ferrlecit® administration with those following placebo administration.

A rise in serum tryptase is a marker for an immediate anaphylactic or anaphylactoid event or an allergic event. The first 200 patients from selected centres had serum tryptase assays performed on samples obtained during dialysis. Blood from these patients was also drawn at session 2 prior to and 60 minutes after study drug administration, to define the normal range for changes in tryptase in this population, and to identify the effect of dialysis, Ferrlecit® administration, and normal saline / benzyl alcohol solution (placebo) on circulating tryptase levels. In the event that one of these selected patients had a suspected allergic event, their blood was not included in the analysis defining the normal range, and a replacement was selected. A significant increase in tryptase level was defined as two standard deviations from the mean change defined in the reference (n = 200) population.

In all patients, a baseline blood sample was obtained at initiation of dialysis before study drug administration. In patients who had a suspected allergic event during administration of either study drug (Ferrlecit® or placebo), then another blood sample was obtained one hour following the beginning of the event, and both samples for the patient were analyzed for serum tryptase levels. A confirmed allergic event was defined as one that had a post-event

increase in tryptase level that was at least two times greater than baseline (at or above 100% increase).

23/37684 for life-threatening events). The incidence of serious adverse events following Ferrlecit® was 0.6%, 14/2514 while the ncidence following placebo was 0.5%, 12/2509. The difference was not statistically

significant by McNemar’s test.

There were no patients in this study who experienced an anaphylactic event as defined by the protocol.

All life-threatening, outcome and suspected allergic adverse events in the Intent-To-Treat population are summarized below in Table 1:

Table 1: Life-threatening, Outcome and Suspected Allergic Adverse Events in the Intent-To-Treat Population
Event/s per patient n=20	Treatment	Life-threatening adverse event	Outcome event (drug intolerance)	Suspected allergic event			Onset time	Severity
Event/s per patient n=20	Treatment	Life-threatening adverse event	Outcome event (drug intolerance)	Confirmed Non-allergic	Confirmed allergic	Unconfirmed	Onset time	Severity
allergic reaction (nausea, unease, dry throat)	Ferrlecit			X			immed²	mild
allergic reaction (abdominal cramps [immediate], diarrhea, nausea, itching and flushing [delayed])	placebo		X	X			immed.	mod.
nausea	Ferrlecit		X				instant¹	mild
pruritus	Ferrlecit		X	X			immed.	mod.
hypotension	Ferrlecit		X				immed.	severe
allergic reaction (nausea, dizziness, headache & vomiting)	placebo			X			instant.	mild
dizziness, nausea	Ferrlecit			X			instant.	mild
allergic reaction (flushing & malaise)	placebo			X			immed.	mild
allergic reaction (pronounced facial flushing)	Ferrlecit		X		X		instant.	severe
allergic reaction (chills)	Ferrlecit		X	X			immed.	mild
anaphylactoid reaction (diaphoresis, dyspnea & wheezing)	Ferrlecit	X	X	X			immed.	severe
hypotension	placebo		X				immed.	mod.
porphyria	Ferrlecit		X				delayed³	mod.
rash	placebo						delayed
pruritus	Ferrlecit		X	X		X	immed.	mild
allergic reaction (dyspnea and chest pain)	Ferrlecit		X	X			instant.	mod.
allergic reaction (rash)	Ferrlecit		X			X	delayed	mild
back pain	Ferrlecit		X		X		immed.	mild
rash	Ferrlecit			X			immed.	mild
pruritus	Ferrlecit			X			immed.	mild
pruritus	placebo			X			immed.	mild
1 AE during infusion 2 AE after infusion but before dialysis was complete 3 AE after dialysis was completed.

Cross-reference 28

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:: in vitro gene mutation study in bacteria
Type of information:: experimental study
Adequacy of study:: weight of evidence
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: comparable to guideline study with acceptable restrictions
Remarks:: study meets generally accepted scientific principles but report not well document
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Qualifier:: no guideline followed
Principles of method if other than guideline:: Gene Mutation was evaluated in an Ames Test (in the Salmonella Escherichia Coli/Mammalian-Microsome Reverse Mutation). The employed doses were 0.625 - 5.00 mg Fe/plate. The number of revertants per plate was counted.
GLP compliance:: no
Type of assay:: bacterial reverse mutation assay
Specific details on test material used for the study:: 12.5 mg/mL as elemental iron, a stable macromolecular complex used to replete and maintain the total body content of iron.
The molecular formula is considered to be [NaFe2O3(C6H11O7)(C12H22O11)5] n≈200.
COMPOSITION - Each ampoule of 5 mL of FERRLECIT contains 12.5 mg/mL (62.5 mg/5 mL ampoule) of elemental iron as the sodium salt of a ferric ion gluconate complex in alkaline aqueous solution with approximately 20% sucrose w/v (195 mg/mL) in Water for Injection (pH 7.7 - 9.7). The solution contains 0.9% w/v (9 mg/mL) benzyl alcohol as preservative.
STABILITY AND STORAGE RECOMMENDATIONS Store at controlled room temperature between 20°C - 25°C. Protect from light. Do not freeze.
Test concentrations with justification for top dose:: 0.625 - 5.00 mg Fe/plate (recommended highest dose was employed)
Vehicle / solvent:: sucrose injection
Species / strain:: other: all strains tested
Metabolic activation:: with and without
Genotoxicity:: negative
Cytotoxicity / choice of top concentrations:: not specified
Vehicle controls validity:: not specified
Untreated negative controls validity:: not specified
Positive controls validity:: not specified
Executive summary:: Gene Mutation was evaluated in an Ames Test (sanofi-aventis Canada Inc., 2009). The employed doses were 0.625 - 5.00 mg Fe/plate. The number of revertants per plate was counted. No positive increase in the number of revertants per plate of any of the tester strains with / without microsomal enzymes prepared from AroclorTM -induced rat liver (S9). The results of the tests show that Ferrlecit is negative for genetic mutagenicity.

Cross-reference 29

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

in vitro cytogenicity / chromosome aberration study in mammalian cells

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

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Qualifier:

no guideline followed

Principles of method if other than guideline:

Clastogenicity was evaluated in chinese hamster ovary cells. The employed doses were 225 - 1250 µg Fe/mL. The number of cells with chromosomal aberrations was counted.

GLP compliance:

Type of assay:

other: Chromosomal aberration assay

Specific details on test material used for the study:

Species / strain / cell type:

Chinese hamster Ovary (CHO)

Metabolic activation:

with and without

Metabolic activation system:

S9 system

Test concentrations with justification for top dose:

125 - 1250 μg Fe/mL

Vehicle / solvent:

sucrose injection

Species / strain:

other: all strains tested

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not specified

No significant increase in cells with chromosomal aberrations was observed in the cultures analyzed from the non-activation assay. In the assay with metabolic activation, however, significant increases in cells with chromosomal aberrations were observed at the 10-hour harvest in the cultures dosed with 1250 μg Fe/mL Ferrlecit® and at all dose levels (313 to 1250 μg Fe/mL Ferrlecit®) at the 20-hour harvest. The response was highly variable between replicate cultures and was not dose-related. These results were indicative of ferric ion potentiated formation of active oxygen species by the S9 system rather than any metabolic activation of the test article. Such a "test system-generated" response would make the utilization of S9 inappropriate for screening this test article for clastogenic activity.

Executive summary:

Clastogenicity was evaluated in chinese hamster ovary cells. The employed doses were 225 - 1250 µg Fe/mL. The number of cells with chromosomal aberrations was counted.

Cross-reference 30

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:: sub-chronic toxicity: other route
Type of information:: experimental study
Adequacy of study:: weight of evidence
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: study well documented, meets generally accepted scientific principles, acceptable for assessment
Reason / purpose for cross-reference:: reference to same study
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Qualifier:: no guideline followed
Principles of method if other than guideline:: Repeated dose toxicity studies have been carried out in rats and rabbits.
GLP compliance:: no
Limit test:: no
Specific details on test material used for the study:: 12.5 mg/mL as elemental iron, a stable macromolecular complex used to replete and maintain the total body content of iron.
The molecular formula is considered to be [NaFe2O3(C6H11O7)(C12H22O11)5] n≈200.
COMPOSITION - Each ampoule of 5 mL of FERRLECIT contains 12.5 mg/mL (62.5 mg/5 mL ampoule) of elemental iron as the sodium salt of a ferric ion gluconate complex in alkaline aqueous solution with approximately 20% sucrose w/v (195 mg/mL) in Water for Injection (pH 7.7 - 9.7). The solution contains 0.9% w/v (9 mg/mL) benzyl alcohol as preservative.
STABILITY AND STORAGE RECOMMENDATIONS Store at controlled room temperature between 20°C - 25°C. Protect from light. Do not freeze.
Species:: rabbit
Strain:: other: Morini
Details on species / strain selection:: no details
Sex:: not specified
Route of administration:: intravenous
Vehicle:: other: in sucrose injection
Analytical verification of doses or concentrations:: yes
Duration of treatment / exposure:: 90 days
Frequency of treatment:: not specified, presumably once daily
Dose / conc.:: 0 other: mg Fe/kg
Remarks:: (0.0 mL/kg)
Dose / conc.:: 1.875 other: mg Fe/kg
Remarks:: (0.15 mL/kg)
No. of animals per sex per dose:: 10 animals, not further specified
Control animals:: yes
Observations and examinations performed and frequency:: yes
Sacrifice and pathology:: yes
Clinical signs:: not specified
Mortality:: not specified
Body weight and weight changes:: not specified
Food consumption and compound intake (if feeding study):: not specified
Food efficiency:: not specified
Water consumption and compound intake (if drinking water study):: not specified
Ophthalmological findings:: not specified
Haematological findings:: effects observed, treatment-related
Description (incidence and severity):: No changes in the hematology or blood chemistry tests except for an increase in hemoglobin and SGPT
Clinical biochemistry findings:: effects observed, treatment-related
Description (incidence and severity):: No changes in the hematology or blood chemistry tests except for an increase in hemoglobin and SGPT
Urinalysis findings:: not specified
Behaviour (functional findings):: not specified
Immunological findings:: not specified
Organ weight findings including organ / body weight ratios:: no effects observed
Description (incidence and severity):: No signs of toxic effects observed in organ weights, macroscopic, or microscopic examinations.
Gross pathological findings:: no effects observed
Description (incidence and severity):: No signs of toxic effects observed in organ weights, macroscopic, or microscopic examinations.
No signs of iron deposits in duodenum, pancreas, adrenal cortex, or liver.
Neuropathological findings:: not specified
Histopathological findings: non-neoplastic:: no effects observed
Description (incidence and severity):: No signs of toxic effects observed in organ weights, macroscopic, or microscopic examinations.
No signs of iron deposits in duodenum, pancreas, adrenal cortex, or liver.
Histopathological findings: neoplastic:: not specified
Other effects:: not specified
Dose descriptor:: NOAEC
Effect level:: 1.875 other: mg Fe/kg
Critical effects observed:: no
Executive summary:: Repeated dose toxicity studies have been carried out in rats and rabbits (sanofi-aventis Canada Inc., 2009). The rabbits (10 animals) received via intravenous injection Ferrlecit at doses of 1.875 mg Fe/kg for 90 days. No changes in the hematology or blood chemistry tests except for an increase in hemoglobin and SGPT. No signs of toxic effects observed in organ weights, macroscopic, or microscopic examinations. No signs of iron deposits in duodenum, pancreas, adrenal cortex, or liver.

Cross-reference 31

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:: short-term repeated dose toxicity: other route
Type of information:: experimental study
Adequacy of study:: weight of evidence
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: study well documented, meets generally accepted scientific principles, acceptable for assessment
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Qualifier:: no guideline followed
Principles of method if other than guideline:: Repeated dose toxicity studies have been carried out in rats and rabbits.
GLP compliance:: no
Limit test:: no
Specific details on test material used for the study:: 12.5 mg/mL as elemental iron, a stable macromolecular complex used to replete and maintain the total body content of iron.
The molecular formula is considered to be [NaFe2O3(C6H11O7)(C12H22O11)5] n≈200.
COMPOSITION - Each ampoule of 5 mL of FERRLECIT contains 12.5 mg/mL (62.5 mg/5 mL ampoule) of elemental iron as the sodium salt of a ferric ion gluconate complex in alkaline aqueous solution with approximately 20% sucrose w/v (195 mg/mL) in Water for Injection (pH 7.7 - 9.7). The solution contains 0.9% w/v (9 mg/mL) benzyl alcohol as preservative.
STABILITY AND STORAGE RECOMMENDATIONS Store at controlled room temperature between 20°C - 25°C. Protect from light. Do not freeze.
Species:: rat
Strain:: Sprague-Dawley
Details on species / strain selection:: no details
Sex:: male/female
Route of administration:: intravenous
Vehicle:: other: in sucrose injection
Analytical verification of doses or concentrations:: yes
Duration of treatment / exposure:: 28 days
Frequency of treatment:: not specified, presumably once daily
Dose / conc.:: 42.25 other: mg Fe/kg
Remarks:: (3.3 mL/kg)
No. of animals per sex per dose:: 20M + 20F
Control animals:: yes
Observations and examinations performed and frequency:: yes
Sacrifice and pathology:: yes
Clinical signs:: effects observed, treatment-related
Description (incidence and severity):: Rats showed evidence of pain and aggressiveness.
Mortality:: no mortality observed
Description (incidence):: No deaths.
Body weight and weight changes:: effects observed, treatment-related
Description (incidence and severity):: Body weight gain was inhibited.
Food consumption and compound intake (if feeding study):: effects observed, treatment-related
Description (incidence and severity):: Food consumption dropped.
Food efficiency:: not specified
Water consumption and compound intake (if drinking water study):: not specified
Ophthalmological findings:: not specified
Haematological findings:: effects observed, treatment-related
Description (incidence and severity):: Leukocytes increased at four weeks.
Clinical biochemistry findings:: effects observed, treatment-related
Description (incidence and severity):: Plasma iron content increased and iron binding capacity increased in all except the females in one group.
Urinalysis findings:: not specified
Behaviour (functional findings):: not specified
Immunological findings:: not specified
Organ weight findings including organ / body weight ratios:: effects observed, treatment-related
Description (incidence and severity):: Some organ weights including the heart, lungs, kidneys, adrenals, thymus, hypophysis, gonads, thyroid, and liver, were reduced compared to controls.
Gross pathological findings:: effects observed, treatment-related
Description (incidence and severity):: Hemorrhage and some thrombosis and necrosis occurred at the injection site. Gross examination at necropsy revealed only enlargement of the spleen.
Neuropathological findings:: not specified
Histopathological findings: non-neoplastic:: effects observed, treatment-related
Description (incidence and severity):: In almost all treated animals, a discrete reticular activation was found on the hilus and in the alveolar parenchyma. All treated animals revealed pronounced siderophilic deposition in the lymphatic r eticulum, but no signs of system activation.
Histopathological findings: neoplastic:: effects observed, treatment-related
Description (incidence and severity):: A small bladder papilloma was seen in a treated male rat.
Other effects:: not specified
Dose descriptor:: NOAEC
Remarks on result:: not determinable due to adverse toxic effects at highest dose / concentration tested
Critical effects observed:: no
Executive summary:: Repeated dose toxicity studies have been carried out in rats and rabbits (sanofi-aventis, Canada Inc, 2009). The rats (20M and 20F) received via intravenous injection Ferrlecit at doses of 42.25 mg Fe/kg for 28 days. No deaths were observed. Rats showed evidence of pain and aggressiveness. Body weight gain was inhibited and food consumption dropped. Leukocytes increased at four weeks. Plasma iron content increased and iron binding capacity increased in all except the females in one group. Hemorrhage and some thrombosis and necrosis occurred at the injection site. Gross examination at necropsy revealed only enlargement of the spleen. Some organ weights including the heart, lungs, kidneys, adrenals, thymus, hypophysis, gonads, thyroid, and liver, were reduced compared to controls. In almost all treated animals, a discrete reticular activation was found on the hilus and in the alveolar parenchyma. A small bladder papilloma was seen in a treated male rat. All treated animals revealed pronounced siderophilic deposition in the lymphatic reticulum, but no signs of system activation

Cross-reference 32

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

sub-chronic toxicity: other route

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

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reference to same study

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Qualifier:

no guideline followed

Principles of method if other than guideline:

Repeated dose toxicity studies have been carried out in rats and rabbits.

GLP compliance:

Limit test:

Specific details on test material used for the study:

Species:

rat

Strain:

Wistar

Details on species / strain selection:

no details

Sex:

male/female

Route of administration:

intravenous

Vehicle:

other: in sucrose injection

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

84 days

Frequency of treatment:

not specified, presumably once daily

Dose / conc.:

0 other: mg Fe/kg

Remarks:

(0.0 mL/kg)

Dose / conc.:

2.5 other: mg Fe/kg

Remarks:

(0.2 mL/kg)

Dose / conc.:

6.25 other: mg Fe/kg

Remarks:

(0.5 mL/kg)

Dose / conc.:

12.5 other: mg Fe/kg

Remarks:

(1.0 mL/kg)

No. of animals per sex per dose:

20M + 20F

Control animals:

yes

Observations and examinations performed and frequency:

yes

Sacrifice and pathology:

yes

Clinical signs:

not specified

Mortality:

not specified

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Body weight of the males in the 6.25 and 12.50 mg/kg groups was slightly, but not dose-dependently reduced. A slight reduction in body weight was found in the 12.50 mg/kg group females.

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Serum iron values were increased dose-dependently in all groups of both sexes. Total lipids were increased in both sexes of the 6.25 and 12.50 mg/kg groups. Phospholipids were increased in the males of the 12.50 mg/kg group and the females of the
6.25 and 12.5 mg/kg groups. Total cholesterol was dose-dependently increased in the males of all groups and in the 12.50 mg/kg group females. Triglycerides were elevated in the 6.25 and 12.50 mg/kg group females.

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

Urinalysis revealed a substantial increase in protein values in the 6.25 mg/kg group males.

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Adrenals were reduced in size and the spleen and liver enlarged. The liver weights in the 6.25 and 12.50 mg/kg group males and in the 12.50 mg/kg group females were considerably increased. Spleen weights were increased dosedependently in both sexes of the 6.25 and 12.50 mg/kg groups.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Organs revealed light to dark brown coloration in virtually all rats of the 12.50 mg/kg group: pancreas, spleen, liver, adrenals, intestine, and subcutaneous fatty tissue.

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Histology examination revealed increased deposits of iron-containing pigment in the liver, spleen, lymph nodes, and kidneys, and sporadic deposits in other organs, apparently dose-dependent.

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Dose descriptor:

NOAEC

Effect level:

2.5 other: mg Fe/kg

Based on:

element

Critical effects observed:

Body weight of the males in the 6.25 and 12.50 mg/kg groups was slightly, but not dose-dependently reduced. A slight reduction in body weight was found in the 12.50 mg/kg group females. Serum iron values were increased dose-dependently in all groups of both sexes. Total lipids were increased in both sexes of the 6.25 and 12.50 mg/kg groups. Phospholipids were increased in the males of the 12.50 mg/kg group and the females of the 6.25 and 12.5 mg/kg groups. Total cholesterol was dose-dependently increased in the males of all groups and in the 12.50 mg/kg group females. Triglycerides were elevated in the 6.25 and 12.50 mg/kg group females. Urinalysis revealed a substantial increase in protein values in the 6.25 mg/kg group males. Organs revealed light to dark brown coloration in virtually all rats of the 12.50 mg/kg group: pancreas, spleen, liver, adrenals, intestine, and subcutaneous fatty tissue. Adrenals were reduced in size and the spleen and liver enlarged. The liver weights in the 6.25 and 12.50 mg/kg group males and in the 12.50 mg/kg group females were considerably increased. Spleen weights were increased dosedependently in both sexes of the 6.25 and 12.50 mg/kg groups. Histology examination revealed increased deposits of iron-containing pigment in the liver, spleen, lymph nodes, and kidneys, and sporadic deposits in other organs, apparently dose-dependent.

Executive summary:

Repeated dose toxicity studies have been carried out in rats and rabbits (sanofi-aventis Canada Inc, 2009). The rats (20M and 20F) received via intravenous injection Ferrlecit at doses of 2.5, 6.25 and 12.5 mg Fe/kg for 84 days.

Body weight of the males in the 6.25 and 12.50 mg/kg groups was slightly, but not dose-dependently reduced. A slight reduction in body weight was found in the 12.50 mg/kg group females. Serum iron values were increased dose-dependently in all groups of both sexes. Total lipids were increased in both sexes of the 6.25 and 12.50 mg/kg groups. Phospholipids were increased in the males of the 12.50 mg/kg group and the females of the 6.25 and 12.5 mg/kg groups. Total cholesterol was dose-dependently increased in the males of all groups and in the 12.50 mg/kg group females. Triglycerides were elevated in the 6.25 and 12.50 mg/kg group females. Urinalysis revealed a substantial increase in protein values in the 6.25 mg/kg group males. Organs revealed light to dark brown coloration in virtually all rats of the 12.50 mg/kg group: pancreas, spleen, liver, adrenals, intestine, and subcutaneous fatty tissue. Adrenals were reduced in size and the spleen and liver enlarged. The liver weights in the 6.25 and 12.50 mg/kg group males and in the 12.50 mg/kg group females were considerably increased. Spleen weights were increased dose-dependently in both sexes of the 6.25 and 12.50 mg/kg groups. Histology examination revealed increased deposits of iron-containing pigment in the liver, spleen, lymph nodes, and kidneys, and sporadic deposits in other organs, apparently dose-dependent.

The results of the animals treated with 2.5 mg Fe/kg were not considered adverse, therfore a NOAEC of 2.5 mg Fe/kg was derived.

Cross-reference 33

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

sensitisation data (humans)

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

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reference to same study

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Qualifier:

no guideline followed

GLP compliance:

Specific details on test material used for the study:

Type of population:

general

Ethical approval:

confirmed, but no further information available

Route of administration:

other: intravenous

Results of examinations:

Serious hypersensitivity reactions have been reported from the spontaneous reporting system in the United States, however rarely in patients receiving FERRLECIT.
From 1976 to 1996 where spontaneous reporting in Europe and U.S. can be reliably compared, there were only 74 allergic adverse events reported for FERRLECIT to the World Health Organization (WHO), German Health Bureau, and the manufacturer all combined. The estimated usage of FERRLECIT in Europe is about 2.7 million IV doses per year (1992 to 1996 figures). For the same period, FERRLECIT had an allergy event reporting rate of 3.3 allergy episodes per million doses per year compared with a similar rate of 8.7 reported allergy events per million doses per year for iron dextran in the U.S. in 1995. This difference is unlikely to be significant for epidemiologic studies. Case fatalities for FERRLECIT and iron dextran within these reports were also compared (see table below). For FERRLECIT, there were no reports of deaths over the entire time period (1976 to 1996). However, for iron dextrans, there were 31 fatalities among 196 allergy/anaphylaxis cases reported in the U.S. yielding a case-fatality rate of 15.8%. The case fatality rate among iron dextran reports is similar to the case severity rates reported in the literature of 20 to 29% severe-to-total cases of anaphylaxis.
Hypotension has been reported following administration of FERRLECIT in European case reports. Of the 226 renal dialysis patients exposed to FERRLECIT and reported in the literature, 3 (1.3%) patients experienced hypotensive events which were accompanied by flushing in two. All completely reversed after one hour without sequelae. In Study C, no specific drug relationship of FERRLECIT to hypotension could be identified.
In multiple dose Studies A and B, no fatal hypersensitivity reactions occurred among the 126 patients who received FERRLECIT. FERRLECIT-associated hypersensitivity events in Study A resulting in premature study discontinuation occurred in three out of a total 88 (3.4%) FERRLECIT-treated patients.
A post-marketing clinical safety study FERRLECIT was well tolerated, with an overall incidence of all adverse events (12.3%, 310/2514) which compared favourably to placebo (9.8%, 245/2509), although with statistical significance (p<0.05 by McNemar’s test). FERRLECIT had a lower incidence of outcome (0.4%; 11/2493; confidence intervals 0.21, 0.71%) adverse events than reported historically with iron dextran (2.47%; 64/2589; confidence intervals 1.87, 3.07%). Ferrlecit also had a lower incidence of life-threatening (0.0%; 1/2493; confidence intervals 0.00, 0.22%) adverse events than reported historically with iron dextran (0.61%; 23/3768; confidence intervals 0.36, 0.86%). There was no difference in the incidence of life-threatening, outcome, suspected or confirmed allergic, or serious adverse events in patients with prior iron dextran sensitivity compared with patients without iron dextran sensitivity. No patients in Study C experienced an anaphylactic allergic adverse event as defined by the protocol.
In the small pharmacokinetic study (14 subjects), three adverse events (palpitation, shortness of breath and dizziness) were experienced by one subject during the administration of FERRLECIT under “fast” infusion conditions at a dose of 62.5 mg FERRLECIT over 4 minutes. The adverse events began just after initiation of the drug and were resolved just as the administration of the drug was completed. They did not correlate with the time of maximum concentration of FERRLECIT in the blood of the subject and were not correlated with dose.

Serious hypersensitivity reactions have been reported from the spontaneous reporting system in the United States, however rarely in patients receiving FERRLECIT.

From 1976 to 1996, there were only 74 allergic adverse events reported for FERRLECIT. The estimated usage of FERRLECIT in Europe is about 2.7 million IV doses per year (1992 to 1996 figures). For the same period, FERRLECIT had an allergy event reporting rate of 3.3 allergy episodes per million doses per year (without any case fatalities) compared with a similar rate of 8.7 reported allergy events per million doses per year for iron dextran in the U.S. in 1995.

Hypotension associated with light-headedness, malaise, fatigue, weakness or severe pain in the chest, back, flanks, or groin has been associated with rapid administration of intravenous iron. These hypotensive reactions are not associated with signs of drug hypersensitivity and have usually resolved within one or two hours.

Hypotension has been reported following administration of FERRLECIT in European case reports. Of the 226 renal dialysis patients exposed to FERRLECIT and reported in the literature, 3 (1.3%) patients experienced hypotensive events which were accompanied by flushing in two. All completely reversed after one hour without sequelae. Transient hypotension is a frequent concomitant event during hemodialysis. In Study C, no specific drug relationship of FERRLECIT to hypotension could be identified.

In multiple dose Studies A and B, no fatal hypersensitivity reactions occurred among the 126 patients who received FERRLECIT. FERRLECIT-associated hypersensitivity events in Study A resulting in premature study discontinuation occurred in three out of a total 88 (3.4%) FERRLECIT-treated patients. The first patient withdrew after the development of pruritus and chest pain following the test dose of FERRLECIT. The second patient, in the high-dose group, experienced nausea, abdominal and flank pain, fatigue and rash following the first dose of FERRLECIT. The third patient, in the low-dose group, experienced a “red blotchy rash” following the first dose of FERRLECIT. Of the 38 patients exposed to FERRLECIT in Study B, none reported hypersensitivity reactions. No serum tryptase determinations were made in these studies.

It should be noted that many chronic renal failure patients experience cramps, pain, nausea, rash, flushing, and pruritus.

Serious hypersensitivity reactions have been reported from the spontaneous reporting system in the United States. There have been eleven serious events which were described by the reporters as allergic or anaphylactoid since the product was introduced in the United States in June of 1999. All resolved without sequelae after withdrawal of FERRLECIT and administration of appropriate therapy.

In addition, the following is stated, without the possiblity to relate it to the above mentionned three patients: one patient experienced a transient decreased level of consciousness without hypotension. Another patient discontinued treatment prematurely because of dizziness, lightheadedness, diplopia, malaise, and weakness without hypotension that resulted in a 3-4 hour hospitalization for observation following drug administration. The syndrome resolved spontaneously.

The most frequent adverse reactions observed in study A and B following FERRLECIT were:

Body as a Whole: injection site reaction, chest pain, pain, asthenia, headache, abdominal pain, fatigue, fever, malaise, infection, abscess, back pain, chills, rigours, arm pain, carcinoma, flu-like syndrome, sepsis.

Nervous System: cramps, dizziness, paresthesias, agitation, somnolence.

Respiratory System: dyspnea, coughing, upper respiratory infections, rhinitis, pneumonia.

Cardiovascular System: hypotension, hypertension, syncope, tachycardia, bradycardia, vasodilatation, angina pectoris, myocardial infarction, pulmonary edema.

Gastrointestinal System: nausea, vomiting and/or diarrhea, anorexia, rectal disorder, dyspepsia, eructation, flatulence, gastrointestinal disorder, melena.

Musculoskeletal System: leg cramps, myalgia, arthralgia.

Skin and Appendages: pruritus, rash, increased sweating.

Genitourinary System: urinary tract infection.

Special Senses: conjunctivitis, abnormal vision, ear disorder.

Metabolic and Nutritional Disorders: hyperkalemia, generalized edema, leg edema, peripheral edema, hypoglycemia, edema, hypervolemia, hypokalemia.

Hematologic System: abnormal erythrocytes, anemia, leukocytosis, lymphadenopathy.

A post-marketing clinical safety study conducted in North America which included 2,534 Ferrlecit-naive patients (Study C) was undertaken and the patients received a single-dose of undiluted FERRLECIT intravenously in a placebo-controlled, crossover, postmarketing safety study. FERRLECIT was administered over ten minutes (125 mg at 12.5 mg/min) during the first hour of hemodialysis. No test dose was used.

A rise in serum tryptase is a marker for an immediate anaphylactic or anaphylactoid event or an allergic event and this parameter was therefore evaluated as well.

FERRLECIT was well tolerated, with an overall incidence of all adverse events (12.3%, 310/2514) which compared favourably to placebo (9.8%, 245/2509), although with statistical significance (p<0.05 by McNemar’s test). FERRLECIT had a lower incidence of outcome (0.4%; 11/2493; confidence intervals 0.21, 0.71%) adverse events than reported historically with iron dextran (2.47%; 64/2589; confidence intervals 1.87, 3.07%). Ferrlecit also had a lower incidence of life-threatening (0.0%; 1/2493; confidence intervals 0.00, 0.22%) adverse events than reported historically with iron dextran (0.61%; 23/3768; confidence intervals 0.36, 0.86%). There was no difference in the incidence of life-threatening, outcome, suspected or confirmed allergic, or serious adverse events in patients with prior iron dextran sensitivity compared with patients without iron dextran sensitivity. Concomitant angiotensin converting enzyme (ACE) inhibitor use was also not a predisposing factor for adverse events with FERRLECIT.

The cardiovascular system and the digestive system were the only two body systems for which adverse events occurred statistically (p<0.05 by McNemar’s test) more frequently among patients receiving FERRLECIT versus placebo. The percentage of patients who experienced at least one cardiovascular event was 5.4%, 136/2514 for FERRLECIT-treated patients and 4.1% 103/2509 for placebo-treated patients. The majority of the cardiovascular incidents were hypotension, hypertension and vasodilation. Within the digestive system, 2.5%, 64/2514 of patients experienced an event following FERRLECIT and 1.6%, 39/2509 of patients experienced an event after placebo. The majority of these events were diarrhea and nausea.

One patient in this study experienced an immediate suspected hypersensitivity reaction which was considered to be life-threatening in the judgment of the clinical investigator. The patient’s reaction, while severe, was not confirmed by serum tryptase test to be a hypersensitivity reaction. Serum tryptase data substantiated the lack of clinically significant immediate hypersensitivity to FERRLECIT. It appeared to be an idiosyncratic drug intolerance reaction rather than a specific drug allergy.

One patient experienced a suspected life-threatening anaphylactoid reaction (diaphoresis, dyspnea, and wheezing, for 20 minutes) following FERRLECIT administration. However, the event was not confirmed as a hypersensitivity reaction by laboratory test. This patient had experienced prior sensitivities to iron dextran and other drugs and the reaction to FERRLECIT is best described as idiosyncratic. Overall in Study C, 16 (0.6%; 16/2512) had 18 suspected allergic events according to the clinical investigator’s judgment. In only two (0.1%; 2/2512) of the 16 patients were the allergic events (facial redness and back pain) after FERRLECIT administration confirmed as drug intolerance events by a significant rise in serum tryptase levels. There was no significant difference in the occurrence of suspected hypersensitivity reactions between FERRLECIT and placebo treatment. The study concluded that FERRLECIT is not an allergen.

No patients in Study C experienced an anaphylactic allergic adverse event as defined by the protocol.

Only a single patient was determined to have mast cell degranulation by pre-defined criteria in the entire study. This patient exhibited facial and upper body flushing when given 12.5 mg of FERRLECIT, which resolved without any treatment other than withdrawal of drug. The reaction was accompanied by a rise in tryptase from 2.1 to 4.9 ng/mL. The reaction was not considered life-threatening or even serious in the judgment of the clinical investigator.

In a small pharmacokinetic study, 14 subjects were given either 62.5 mg or 125 mg of FERRLECIT at a “slow” infusion rate at approximately 2 mg/min and subsequently at a “fast” infusion rate at 15-18 mg/min. Three adverse events (palpitation, shortness of breath and dizziness) were experienced by one subject during the administration of FERRLECIT under “fast” infusion conditions at a dose of 62.5 mg FERRLECIT over 4 minutes. The adverse events began just after initiation of the drug and were resolved just as the administration of the drug was completed. They did not correlate with the time of maximum concentration of FERRLECIT in the blood of the subject and were not correlated with dose. The study predicted that most patients can safely tolerate infusions of FERRLECIT at the fast infusion rate.

Executive summary:

Serious hypersensitivity reactions have been reported from the spontaneous reporting system in the United States, however rarely in patients receiving FERRLECIT.

From 1976 to 1996 where spontaneous reporting in Europe and U.S. can be reliably compared, there were only 74 allergic adverse events reported for FERRLECIT to the World Health Organization (WHO), German Health Bureau, and the manufacturer all combined. The estimated usage of FERRLECIT in Europe is about 2.7 million IV doses per year (1992 to 1996 figures). For the same period, FERRLECIT had an allergy event reporting rate of 3.3 allergy episodes per million doses per year compared with a similar rate of 8.7 reported allergy events per million doses per year for iron dextran in the U.S. in 1995. This difference is unlikely to be significant for epidemiologic studies. Case fatalities for FERRLECIT and iron dextran within these reports were also compared (see table below). For FERRLECIT, there were no reports of deaths over the entire time period (1976 to 1996). However, for iron dextrans, there were 31 fatalities among 196 allergy/anaphylaxis cases reported in the U.S. yielding a case-fatality rate of 15.8%. The case fatality rate among iron dextran reports is similar to the case severity rates reported in the literature of 20 to 29% severe-to-total cases of anaphylaxis.

Allergy and Anaphylaxis Reporting From European and US Sources

Drug Rate	Number of Reports	Number of Deaths	Number of Unknown Outcomes	Case Fatality
Iron Dextrans	196	31	129	15.8%
Ferrlecit Injection	74	0	3	0%

It should be noted that many chronic renal failure patients experience cramps, pain, nausea, rash, flushing, and pruritus.

The most frequent adverse reactions observed in study A and B following FERRLECIT were:

Nervous System: cramps, dizziness, paresthesias, agitation, somnolence.

Respiratory System: dyspnea, coughing, upper respiratory infections, rhinitis, pneumonia.

Cardiovascular System: hypotension, hypertension, syncope, tachycardia, bradycardia, vasodilatation, angina pectoris, myocardial infarction, pulmonary edema.

Gastrointestinal System: nausea, vomiting and/or diarrhea, anorexia, rectal disorder, dyspepsia, eructation, flatulence, gastrointestinal disorder, melena.

Musculoskeletal System: leg cramps, myalgia, arthralgia.

Skin and Appendages: pruritus, rash, increased sweating.

Genitourinary System: urinary tract infection.

Special Senses: conjunctivitis, abnormal vision, ear disorder.

Metabolic and Nutritional Disorders: hyperkalemia, generalized edema, leg edema, peripheral edema, hypoglycemia, edema, hypervolemia, hypokalemia.

Hematologic System: abnormal erythrocytes, anemia, leukocytosis, lymphadenopathy.

A rise in serum tryptase is a marker for an immediate anaphylactic or anaphylactoid event or an allergic event and this parameter was therefore evaluated as well.

The cardiovascular system and the digestive system were the only two body systems for which adverse events occurred statistically (p<0.05 by McNemar’s test) more frequently among patients receiving FERRLECIT versus placebo. The percentage of patients who experienced at least one cardiovascular event was 5.4%, 136/2514 for FERRLECIT-treated patients and 4.1% 103/2509 for placebo-treated patients. The majority of the cardiovascular incidents were hypotension, hypertension and vasodilation. Within the digestive system, 2.5%, 64/2514 of patients experienced an event following FERRLECIT and 1.6%, 39/2509 of patients experienced an event after placebo. The majority of these events were diarrhea and nausea.

No patients in Study C experienced an anaphylactic allergic adverse event as defined by the protocol.

Cross-reference 34

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

one-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

Reason / purpose for cross-reference:

reference to same study

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reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

GLP compliance:

Limit test:

Specific details on test material used for the study:

Species:

mouse

Strain:

CD-1

Sex:

female

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

intravenous

Vehicle:

other: sucrose injection

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

12.5 mg/mL as elemental iron content

Duration of treatment / exposure:

GD 6 - 15

Frequency of treatment:

not specified, presumable once daily

Details on study schedule:

10 days

Dose / conc.:

0 other: mg Fe/kg

Dose / conc.:

10 other: mg Fe/kg

Remarks:

(0.4 mL/kg)

Dose / conc.:

30 other: mg Fe/kg

Remarks:

(2.4 mL/kg)

Dose / conc.:

100 other: mg Fe/kg

Remarks:

(8.06 mL/kg)

No. of animals per sex per dose:

25F

Control animals:

yes

Details on study design:

not specified

Parental animals: Observations and examinations:

yes

Litter observations:

yes

Postmortem examinations (parental animals):

yes

Postmortem examinations (offspring):

yes

Statistics:

not stated

Reproductive indices:

not specified

Offspring viability indices:

not specified

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

No drug related mortality.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

The body weight gains were decreased for the intervals Days 6 to 9 and Days 15 to 18 for the 100 mg/kg group.
Body weights by Day 18 of gestation were significantly decreased compared with controls.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Food consumption for the 100 mg/kg group was significantly decreased between Days 6 and 9 of gestation.

Food efficiency:

effects observed, treatment-related

Description (incidence and severity):

Food consumption for the 100 mg/kg group was significantly decreased between Days 6 and 9 of gestation.

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Reproductive function: oestrous cycle:

no effects observed

Description (incidence and severity):

The numbers of corpora lutea, implantation sites, dead fetuses, the sex ratio and the pre-implantation losses in the control and treated groups were similar.

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Description (incidence and severity):

The numbers of corpora lutea, implantation sites, dead fetuses, the sex ratio and the pre-implantation losses in the control and treated groups were similar.

The number of early resorptions was slightly increased in the 100 mg/kg group. Evaluation of the number of resorptions per litter and numbers of litters with total resorption were indicative of embryolethality. Fetal weights were significantly (P<0.01) reduced in the 100 mg/kg group.
There were no drug induced malformations seen in this study.
The overall incidence of fetuses with minor skeletal anomalies was significantly increased in the 30 and 100 mg/kg groups. This resulted primarily from increased incidences of reduced numbers of ossified caudal vertebrae and a higher incidence of reduced numbers of ossified phalanges in the fore and/or hind paws. The percentage of fetuses with sternebral variants was increased in the 30 and 100 mg/kg groups. These latter findings were probably associated with the reduced growth of the offspring which was a consequence of reduced weight gains in the maternal animals at the high dose.

Dose descriptor:

NOAEL

Effect level:

ca. 30 mg/kg bw/day

Based on:

element

Sex:

female

Basis for effect level:

clinical signs

mortality

body weight and weight gain

food consumption and compound intake

food efficiency

gross pathology

reproductive performance

Remarks on result:

not determinable due to adverse toxic effects at highest dose / concentration tested

Remarks on result:

not measured/tested

Reproductive effects observed:

Executive summary:

Ferrlecit (sodium ferric gluconate in sucrose injection) was administered to pregnant mice from gestation day 6 to 15 (sanofi-aventis Canada Inc., 2009). The employed doses were 10, 30 and 100 mg Fe /kg bw. No drug related mortality was observed. Effects seen at the injection sites in the 30 and 100 mg/kg groups included dry skin and ulceration on the tail, and black discoloration at the tip of the tail. Decreased activity and red vaginal discharge were also observed for some mice in the 100 mg/kg group. The body weight gains were decreased for the intervals Days 6 to 9 and Days 15 to 18 for the 100 mg/kg group. Body weights by Day 18 of gestation were significantly decreased compared with controls. Food consumption for the 100 mg/kg group was significantly decreased between Days 6 and 9 of gestation. Gross pathological findings in the 30 and 100 mg/kg groups included splenic enlargement and focal to multi-focal hepatic pallor. Other hepatic alterations including prominent lobular architecture and/or irregular pattern were also seen for a few 100 mg/kg group mice. Subcutaneous edema, sometimes with ascites and/or edema affecting the pancreas and cecum, was seen in three 100 mg/kg mice. The number of early resorptions was slightly increased in the 100 mg/kg group. Evaluation of the number of resorptions per litter and numbers of litters with total resorption were indicative of embryolethality. The numbers of corpora lutea, implantation sites, dead fetuses, the sex ratio and the pre-implantation losses in the control and treated groups were similar. Fetal weights were significantly (P< 0.01) reduced in the 100 mg/kg group. There were no drug induced malformations seen in this study. The overall incidence of fetuses with minor skeletal anomalies was significantly increased in the 30 and 100 mg/kg groups. This resulted primarily from increased incidences of reduced numbers of ossified caudal vertebrae and a higher incidence of reduced numbers of ossified phalanges in the fore and/or hind paws. The percentage of fetuses with sternebral variants was increased in the 30 and 100 mg/kg groups. These latter findings were probably associated with the reduced growth of the offspring which was a consequence of reduced weight gains in the maternal animals at the high dose.

FERRLECIT (sodium ferric gluconate complex in sucrose injection) was not teratogenic at doses of elemental iron up to 100 mg/kg/day (300 mg/m²/day) in mice and 20 mg/kg/day (120 mg/m²/day) in rats. On a body surface area basis, these doses were 1.3 and 3.24 times the recommended human dose (125 mg/day or 92.5 mg/m²/day) for a person of 50 kg body weight, average height and body surface area of 1.46 m². There were no adequate and well-controlled studies in pregnant women.

Cross-reference 35

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

one-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

GLP compliance:

Limit test:

Specific details on test material used for the study:

Species:

mouse

Strain:

CD-1

Sex:

female

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

intravenous

Vehicle:

other: sucrose injection

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

12.5 mg/mL as elemental iron content

Duration of treatment / exposure:

GD 6 - 15

Frequency of treatment:

not specified, presumable once daily

Details on study schedule:

10 days

Dose / conc.:

0 other: mg Fe/kg

Dose / conc.:

2.5 other: mg Fe/kg

Remarks:

(0.2 mL/kg)

Dose / conc.:

5 other: mg Fe/kg

Remarks:

(0.4 mL/kg)

Dose / conc.:

15 other: mg Fe/kg

Remarks:

(1.2 mL/kg)

Dose / conc.:

30 other: mg Fe/kg

Remarks:

(2.4 mL/kg)

No. of animals per sex per dose:

Control animals:

yes

Details on study design:

not specified

Parental animals: Observations and examinations:

yes

Litter observations:

yes

Postmortem examinations (parental animals):

yes

Postmortem examinations (offspring):

yes

Statistics:

not stated

Reproductive indices:

not specified

Offspring viability indices:

not specified

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Local effects at the treatment site included swelling and blue discoloration of the tail. Skin lesions and or areas of scab formation were seen on the tail in all groups, including the control.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

No treatment-related deaths

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Body weights and food consumption for the treated groups were comparable to the controls

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Body weights and food consumption for the treated groups were comparable to the controls

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Reproductive function: oestrous cycle:

no effects observed

Description (incidence and severity):

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Description (incidence and severity):

Dose descriptor:

NOAEL

Effect level:

> 30 mg/kg bw/day

Based on:

element

Sex:

female

Basis for effect level:

clinical signs

mortality

body weight and weight gain

food consumption and compound intake

gross pathology

reproductive performance

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks on result:

not measured/tested

Reproductive effects observed:

Executive summary:

Ferrlecit (sodium ferric gluconate in sucrose injection) was administered to pregnant mice from gestation day 6 to 15 (sanofi-aventis Canada, Inc., 2009). The employed doses were 2.5, 5, 15 and 30 mg Fe /kg bw. No treatment-related deaths were observed. Local effects at the treatment site included swelling and blue discoloration of the tail. Skin lesions and or areas of scab formation were seen on the tail in all groups, including the control. Body weights and food consumption for the treated groups were comparable to the controls. No gross pathological findings. The pregnancy rate was 100% in all groups. The number of corpora lutea, implantation sites, live fetuses, dead fetuses, resorptions, the sex ratio, and the pre- and postimplantation losses were unaffected by treatment. Fetal weights were similar to control values. The incidence of major malformations and minor anomalies was unaffected.

Cross-reference 36

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

one-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

FERRLECIT (sodium ferric gluconate complex in sucrose injection) was administered at doses of elemental iron at 1.875 mg Fe/kg/day to rabbits.

GLP compliance:

Limit test:

Specific details on test material used for the study:

Species:

rabbit

Strain:

other: Morini

Sex:

female

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

intravenous

Vehicle:

other: sucrose injection

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

12.5 mg/mL as elemental iron content

Duration of treatment / exposure:

GD 1 - 23
GD 1 - 28

Frequency of treatment:

not specified, presumably once daily

Details on study schedule:

23 and 28 days, respectively

Dose / conc.:

0 other: mg Fe/kg

Dose / conc.:

1.875 other: mg Fe/kg

Remarks:

(0.15 mL/kg)

No. of animals per sex per dose:

Control animals:

yes

Details on study design:

not specified

Parental animals: Observations and examinations:

yes

Sperm parameters (parental animals):

not examined

Litter observations:

yes

Postmortem examinations (parental animals):

yes

Postmortem examinations (offspring):

yes

Statistics:

no data

Reproductive indices:

not specified

Offspring viability indices:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

no mortality observed

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Description (incidence and severity):

IV injections of Ferrlecit® at 1.875 mg/kg/day in pregnant rabbits did not result in changes in the number and weight of the fetuses, in the number of live births, or in the structures of the main organs of the fetuses.
There was no teratogenic effect on the morphology of the skeleton, limbs, or viscera. The fetuses were similar in number and weight to those from the animals treated with vehicle.

Dose descriptor:

NOAEL

Effect level:

> 1.875 mg/kg bw/day

Based on:

element

Sex:

female

Basis for effect level:

mortality

reproductive performance

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks on result:

not measured/tested

Reproductive effects observed:

There was no teratogenic effect on the morphology of the skeleton, limbs, or viscera.

The fetuses were similar in number and weight to those from the animals treated with vehicle.

Executive summary:

Ferrlecit (sodium ferric gluconate in sucrose injection) was adminstered to pregnant rabbits from gestation day 1 to 23 and 28 (sanofi-aventis Canada Inc., 2009). The employed dose was 1.875 mg Fe /kg bw. IV injections of Ferrlecit® at 1.875 mg/kg/day in pregnant rabbits did not result in changes in the number and weight of the fetuses, in the number of live births, or in the structures of the main organs of the fetuses. There was no teratogenic effect on the morphology of the skeleton, limbs, or viscera. The fetuses were similar in number and weight to those from the animals treated with vehicle.

A NOAEL of > 1.875 mg Fe/kg can be established here for maternal toxicity.

FERRLECIT (sodium ferric gluconate complex in sucrose injection) was not teratogenic at doses of elemental iron of 1.875 mg/kg/day in rabbits.

Cross-reference 37

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

one-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

Reason / purpose for cross-reference:

reference to same study

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reference to same study

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reference to same study

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reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

GLP compliance:

Limit test:

Specific details on test material used for the study:

Species:

rat

Strain:

Sprague-Dawley

Sex:

not specified

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

intravenous

Vehicle:

other: sucrose injection

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

12.5 mg/mL as elemental iron content

Duration of treatment / exposure:

GD 6 - 17

Frequency of treatment:

not specified, presumably once daily

Details on study schedule:

duration of test: 12 days

Dose / conc.:

2.5 other: mg Fe/kg

Remarks:

(0.2 mL/kg)

Dose / conc.:

5 other: mg Fe/kg

Remarks:

(0.4 mL/kg)

Dose / conc.:

15 other: mg Fe/kg

Remarks:

(1.2 mL/kg)

Dose / conc.:

30 other: mg Fe/kg

Remarks:

(2.42 mL/kg)

No. of animals per sex per dose:

Control animals:

yes

Details on study design:

not specified

Parental animals: Observations and examinations:

yes

Sperm parameters (parental animals):

not examined

Litter observations:

no, offsprings killed at caesarean section

Postmortem examinations (parental animals):

yes

Postmortem examinations (offspring):

yes

Statistics:

not stated

Reproductive indices:

not specified

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Clinical findings prior to sacrifice or death included vaginal discharge, pallor, fur staining, cold to touch, hunched posture, dehydration, weak, lying on side, and/or decreased respiratory rate/labored breathing, and one dam had started to litter. Common findings for the animals in the 15 and 30 mg/kg groups included yellow/orange/red urine staining of the urogenital region. Local effects included blue discoloration of the tail seen primarily in the 5 mg/kg group and above.

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, treatment-related

Description (incidence):

Two animals in the 15 mg/kg group and one animal in the 30 mg/kg group died or were sacrificed in poor condition during the study.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Dose-related body weight decreases were evident between Days 6 and 9 of gestation, with body weights for the 30 mg/kg group were remained lower through gestation Day 18.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Food consumption from Days 6 to 9 of gestation showed dose-related reductions. Food consumption was decreased in the 15 and 30 mg/kg/day groups between Days 15 to 18 and Days 9 to 18 of gestation, respectively.

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Description (incidence and severity):

Fetal weights were slightly reduced in the 15 and 30 mg/kg groups. There were no major malformations or minor anomalies observed externally.

Dose descriptor:

NOAEL

Effect level:

ca. 5 other: mg Fe/kg

Based on:

element

Sex:

not specified

Basis for effect level:

clinical signs

mortality

body weight and weight gain

food consumption and compound intake

gross pathology

reproductive performance

Critical effects observed:

Remarks on result:

not measured/tested

Reproductive effects observed:

Two animals in the 15 mg/kg group and one animal in the 30 mg/kg group died or were sacrificed in poor condition during the study. Clinical findings prior to sacrifice or death included vaginal discharge, pallor, fur staining, cold to touch, hunched posture, dehydration, weakness, lying on side, and/or decreased respiratory rate/labored breathing, and one dam had started to litter. Necropsy findings for the respective animals included dark discoloration of the ingesta, multiple dark areas on the stomach, pale or irregular area/foci on the livers, enlarged spleen, dark area/small thymus and dark fluid in the uterus or bladder. Common findings for the animals in the 15 and 30 mg/kg groups included yellow/orange/red urine staining of the urogenital region. Local effects included blue discoloration of the tail seen primarily in the 5 mg/kg group and above. Dose-related body weight decreases were evident between Days 6 and 9 of gestation, with body weights for the 30 mg/kg group were remained lower through gestation Day 18. Food consumption from Days 6 to 9 of gestation showed dose-related reductions. Food consumption was decreased in the 15 and 30 mg/kg/day groups between Days 15 to 18 and Days 9 to 18 of gestation, respectively. Necropsy of the animals examined at cesarean section revealed clear fluid in the abdomen, discolored / enlarged or dark lymph nodes, multiple pale areas on the liver, swollen or discolored pancreas, enlarged spleen. Dark areas on the uterus were seen among the dams in the 15 and/or 30 mg/kg groups. The pregnancy rate was at least 83% in all groups. The number of corpora lutea, implantation sites, live fetuses, dead fetuses, the sex ratio, and the pre- and postimplantation losses were unaffected by treatment. Fetal weights were slightly reduced in the 15 and 30 mg/kg groups. There were no major malformations or minor anomalies observed externally.

Executive summary:

Ferrlecit (sodium ferric gluconate in sucrose injection) was administered to pregnant rats from gestation day 6 to 17 (sanofi-aventis Canada Inc., 2009). The employed doses were 2.5, 5, 15 and 30 mg Fe /kg bw. Two animals in the 15 mg/kg group and one animal in the 30 mg/kg group died or were sacrificed in poor condition during the study. Clinical findings prior to sacrifice or death included vaginal discharge, pallor, fur staining, cold to touch, hunched posture, dehydration, weakness, lying on side, and/or decreased respiratory rate/labored breathing, and one dam had started to litter. Necropsy findings for the respective animals included dark discoloration of the ingesta, multiple dark areas on the stomach, pale or irregular area/foci on the livers, enlarged spleen, dark area/small thymus and dark fluid in the uterus or bladder. Common findings for the animals in the 15 and 30 mg/kg groups included yellow/orange/red urine staining of the urogenital region. Local effects included blue discoloration of the tail seen primarily in the 5 mg/kg group and above. Dose-related body weight decreases were evident between Days 6 and 9 of gestation, with body weights for the 30 mg/kg group were remained lower through gestation Day 18. Food consumption from Days 6 to 9 of gestation showed dose-related reductions. Food consumption was decreased in the 15 and 30 mg/kg/day groups between Days 15 to 18 and Days 9 to 18 of gestation, respectively. Necropsy of the animals examined at cesarean section revealed clear fluid in the abdomen, discolored / enlarged or dark lymph nodes, multiple pale areas on the liver, swollen or discolored pancreas, enlarged spleen. Dark areas on the uterus were seen among the dams in the 15 and/or 30 mg/kg groups. The pregnancy rate was at least 83% in all groups. The number of corpora lutea, implantation sites, live fetuses, dead fetuses, the sex ratio, and the pre- and postimplantation losses were unaffected by treatment. Fetal weights were slightly reduced in the 15 and 30 mg/kg groups. There were no major malformations or minor anomalies observed externally.

Cross-reference 38

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

two-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

GLP compliance:

Limit test:

Specific details on test material used for the study:

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

not specified

Sex:

female

Route of administration:

intravenous

Vehicle:

other: sucrose injection

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

12.5 mg/mL as elemental iron content

Duration of treatment / exposure:

GD 6 - PPD 21

Frequency of treatment:

not specified, presumably once daily

Details on study schedule:

Duration of test: 12 days in pregancy and 21 days post partum

Dose / conc.:

0 other: mg Fe/kg

Dose / conc.:

1 other: mg Fe/kg

Remarks:

(0.08 mL/kg)

Dose / conc.:

5 other: mg Fe/kg

Remarks:

(0.4 mL/kg)

Dose / conc.:

10 other: mg Fe/kg

Remarks:

(0.81 mL/kg)

No. of animals per sex per dose:

20 presumably only females (data not specified)

Control animals:

yes

Details on study design:

not specified

Parental animals: Observations and examinations:

yes

Sperm parameters (parental animals):

not examined

Litter observations:

yes

Postmortem examinations (parental animals):

yes

Postmortem examinations (offspring):

yes

Statistics:

not stated

Reproductive indices:

not specified

Offspring viability indices:

not specified

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

No deaths, and no animals were sacrificed in poor condition during the study.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Food intakes from Days 6 to 9 and Days 15 to 18 of gestation showed dose-related reductions which were significant (P<0.05) in the 10 mg/kg group.

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Description (incidence and severity):

Maternal performance in terms of the length of gestation, duration of parturition, and number of live, dead and malformed pups at birth was unaffected by treatment.

Dose descriptor:

NOAEL

Effect level:

ca. 1 mg/kg bw/day

Based on:

element

Sex:

female

Basis for effect level:

clinical signs

mortality

body weight and weight gain

food consumption and compound intake

gross pathology

reproductive performance

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

no mortality observed

Description (incidence):

The viability and survival indices were unaffected. Evaluation of the data from the F1 adult animals indicated that there were no adverse clinical observations. Behavioral and maturational assessments indicated that there were no direct effects of drug treatment on normal development.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

no effects observed

Description (incidence and severity):

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

no effects observed

Description (incidence and severity):

The reproductive capacity of the F1 generation was not affected and their offspring were normal with respect to clinical observations and weight gains.

Reproductive function: oestrous cycle:

no effects observed

Description (incidence and severity):

The reproductive capacity of the F1 generation was not affected and their offspring were normal with respect to clinical observations and weight gains.

Reproductive function: sperm measures:

no effects observed

Description (incidence and severity):

The reproductive capacity of the F1 generation was not affected and their offspring were normal with respect to clinical observations and weight gains.

Reproductive performance:

no effects observed

Description (incidence and severity):

The reproductive capacity of the F1 generation was not affected and their offspring were normal with respect to clinical observations and weight gains.

Dose descriptor:

NOAEL

Effect level:

ca. 1 mg/kg bw/day

Based on:

element

Sex:

male/female

Basis for effect level:

mortality

body weight and weight gain

reproductive performance

Critical effects observed:

Remarks on result:

not measured/tested

Clinical signs:

no effects observed

Description (incidence and severity):

The reproductive capacity of the F1 generation was not affected and their offspring (F2) were normal with respect to clinical observations and weight gains.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

The reproductive capacity of the F1 generation was not affected and their offspring (F2) were normal with respect to clinical observations and weight gains.

Reproductive effects observed:

Executive summary:

Ferrlecit (sodium ferric gluconate in sucrose injection) was administered to pregnant rats from gestation day 6 to 17 and throughout postpartum day 21. The employed doses were 1, 5 and 10 mg Fe /kg bw.

A NOAEL of 1.0 mg Fe/kg can be established here for maternal toxicity.

Cross-reference 39

Reason / purpose for cross-reference:: reference to same study

Reference

Endpoint:

one-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

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reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

FERRLECIT (sodium ferric gluconate complex in sucrose injection) was administered at doses of elemental iron up to 100 mg/kg/day (300 mg/m²/day) to mice and at 20 mg/kg/day (120 mg/m²/day) or up to 30 mg Fe/kg to rats. On a body surface area basis, these doses were 1.3 and 3.24 times the recommended human dose (125 mg/day or 92.5 mg/m²/day) for a person of 50 kg body weight, average height and body surface area of 1.46 m².

GLP compliance:

Limit test:

Specific details on test material used for the study:

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

intravenous

Vehicle:

other: sucrose injection

Details on mating procedure:

not specified

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

12.5 mg/mL as elemental iron content

Duration of treatment / exposure:

GD 6 - 15

Frequency of treatment:

not specified, presumably once daily

Details on study schedule:

Duration of test: 10 days

Dose / conc.:

0 other: mg Fe/kg

Dose / conc.:

4 other: mg Fe/kg

Remarks:

(0.5 mL/kg)

Dose / conc.:

20 other: mg Fe/kg

Remarks:

(2.5 mL/kg)

No. of animals per sex per dose:

20 presumably only females (data not specified)

Control animals:

yes

Details on study design:

not specified

Parental animals: Observations and examinations:

yes

Sperm parameters (parental animals):

not examined

Litter observations:

no, as the offsprings were killed at cesarean section

Postmortem examinations (parental animals):

yes

Postmortem examinations (offspring):

yes

Statistics:

not stated

Reproductive indices:

not specified

Offspring viability indices:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

no effects observed

Description (incidence and severity):

Both treatment groups consumed more water than the controls, but a significant difference was not observed.

Ophthalmological findings:

not examined

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Description (incidence and severity):

Dose descriptor:

NOAEL

Effect level:

4 mg/kg bw/day

Based on:

element

Sex:

female

Basis for effect level:

mortality

food consumption and compound intake

water consumption and compound intake

gross pathology

reproductive performance

Critical effects observed:

Clinical signs:

not specified

Dermal irritation (if dermal study):

not examined

Mortality / viability:

not specified

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not examined

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Dose descriptor:

NOAEL

Generation:

Effect level:

ca. 4 other: mg Fe/kg

Based on:

element

Sex:

male/female

Basis for effect level:

body weight and weight gain

gross pathology

Dose descriptor:

NOAEL

Effect level:

20 other: mg Fe/kg

Based on:

element

Basis for effect level:

body weight and weight gain

gross pathology

Remarks on result:

other: There was no evidence of teratogenicity at any dose level.

Critical effects observed:

Reproductive effects observed:

Executive summary:

Ferrlecit (sodium ferric gluconate in sucrose injection) was administered to pregnant rats from gestation day 6 to 15 (snaofi-aventis Canada Inc., 2009). The employed doses were 4 and 20 mg Fe /kg bw. Treatment of pregnant rats at a dose of 20 mg/kg resulted in marked effects that included lower maternal weight gain, lower food consumption, reduced gestation index, a significantly lower litter size, increased resorption sites, and fetal mortality. Treatment at 4 mg/kg did not show any difference from controls regarding weight gain or food intake. Both treatment groups consumed more water than the controls, but a significant difference was not observed. The fertility index was identical between all groups. There was no difference between the control and the 4 mg/kg group regarding the gestation index or the number of dead fetuses. There was no difference in the litter size or birth weights between the controls and 4 mg/kg group. There was a significant difference in the birth weights of both the males and females in the 20 mg/kg group compared to the control and 4 mg/kg groups. No treatment related anomalies were observed. However, many of the 20 mg/kg fetuses showed a retardation in ossification of the cranial bones. This was interpreted to indicate a delay in general development associated with reduced maternal weight gains and food consumption. There was no evidence of teratogenicity at any dose level.

Data source

Reference

Reference Type:: publication
Title:: Unnamed
Year:: 2009
Report date:: 2009

Materials and methods

Test guideline

Qualifier:: no guideline followed

Principles of method if other than guideline:: Clastogenicity was evaluated in an rat micronucleus test. The employed doses were 26, 52.1; and 104 mg Fe/kg. The number of micronucleated polychromatic erythrocytes was counted.
GLP compliance:: no
Type of assay:: other: rat micronucleus test

Test material

Test material information

Test material form:: liquid
Details on test material:: Each vial of 5 mL of FERRLECIT contains 12.5 mg/mL (62.5 mg/5 mL vial) of elemental iron as the sodium salt of a ferric ion gluconate complex in alkaline aqueous solution with approximately 20% sucrose w/v (195 mg/mL) in Water for Injection (pH 7.7 - 9.7). The solution contains 0.9% w/v (9 mg/mL) benzyl alcohol as preservative.

Specific details on test material used for the study:: 12.5 mg/mL as elemental iron, a stable macromolecular complex used to replete and maintain the total body content of iron.
The molecular formula is considered to be [NaFe2O3(C6H11O7)(C12H22O11)5] n≈200.
COMPOSITION - Each ampoule of 5 mL of FERRLECIT contains 12.5 mg/mL (62.5 mg/5 mL ampoule) of elemental iron as the sodium salt of a ferric ion gluconate complex in alkaline aqueous solution with approximately 20% sucrose w/v (195 mg/mL) in Water for Injection (pH 7.7 - 9.7). The solution contains 0.9% w/v (9 mg/mL) benzyl alcohol as preservative.
STABILITY AND STORAGE RECOMMENDATIONS Store at controlled room temperature between 20°C - 25°C. Protect from light. Do not freeze.

Test animals

Species:: rat
Strain:: not specified
Sex:: male/female

Administration / exposure

Route of administration:: intravenous
Vehicle:: sucrose injection
Duration of treatment / exposure:: 1 day

Doses / concentrationsopen all close all

Doses / concentrations 1

Dose / conc.:: 0 other: mg Fe/kg

Doses / concentrations 2

Dose / conc.:: 26 other: mg Fe/kg

Doses / concentrations 3

Dose / conc.:: 52.1 other: mg Fe/kg

Doses / concentrations 4

Dose / conc.:: 104 other: mg Fe/kg

No. of animals per sex per dose:: 5 M + 5 F
Control animals:: yes
Positive control(s):: cyclophosphamide
- Justification for choice of positive control(s): not stated
- Route of administration: intravenous
- Doses / concentrations:

Results and discussion

Test results

Sex:: male/female
Genotoxicity:: negative

Any other information on results incl. tables

No significant increases in micronucleated polychromatic erythrocytes over the levels observed in the vehicle controls in either sex or at any of the harvest times, except in the 104 mg/kg males at the 72-hour harvest time. This is a statistical anomaly, since this was not significant compared with the female vehicle control animals and not very different from the female 104 mg/kg group at the 24-hour harvest time. Due to toxicity, the PCE/NCE (poly- to normochromatic erythrocyte) ratio of the 26.0, 52.1, and 104 mg/kg dose groups at the 48-hour harvest time, and the positive control males and females were significantly lower than the vehicle control group. The positive control, cyclophosphamide, induced significant increases in micronucleated PCEs in both sexes as compared to the vehicle control, with means and standard errors of 3.44%"0.66% and 2.02%"0.36% for the males and females, respectively.

Applicant's summary and conclusion

Executive summary:

Clastogenicity was evaluated in an rat micronucleus test. The employed doses were 26, 52.1; and 104 mg Fe/kg. The number of micronucleated polychromatic erythrocytes was counted.

No significant increases in micronucleated polychromatic erythrocytes over the levels observed in the vehicle controls in either sex or at any of the harvest times, except in the 104 mg/kg males at the 72-hour harvest time. This is a statistical anomaly, since this was not significant compared with the female vehicle control animals and not very different from the female 104 mg/kg group at the 24-hour harvest time. Due to toxicity, the PCE/NCE (poly- to normochromatic erythrocyte) ratio of the 26.0, 52.1, and 104 mg/kg dose groups at the 48 -hour harvest time, and the positive control males and females were significantly lower than the vehicle control group. The positive control, cyclophosphamide, induced significant increases in micronucleated PCEs in both sexes as compared to the vehicle control, with means and standard errors of 3.44%"0.66% and 2.02%"0.36% for the males and females, respectively.

The results indicate that Ferrlecit is not mutagenic in the rat micronucleus test.

Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.

Registration Dossier

Registration Dossier

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Diss Factsheets

Reaction products of sodium glucoheptonate with iron sulfate and ammonium hydroxide

Genetic toxicity: in vivo

Administrative data

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Materials and methods

Test guideline

Test material

Constituent 1

Constituent 2

additive 1

Constituent 3

Test animals

Administration / exposure

Doses / concentrationsopen allclose all

Results and discussion

Test results

Any other information on results incl. tables

Applicant's summary and conclusion

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