Reaction products of sodium glucoheptonate with iron sulfate and ammonium hydroxide

Skin sensitisation

Administrative data

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well-documented peer-reviewed reports.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

eye irritation

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well documented peer-reviewed reports.

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reference to same study

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Qualifier:

no guideline available

Principles of method if other than guideline:

Summary of eye irritation potential of gluconates and its derivatives.

GLP compliance:

not specified

Species:

rabbit

Strain:

other: albino

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

0.1 mL

Duration of treatment / exposure:

single exposure

Observation period (in vivo):

1, 24, 48, and 72 h and 7 days after instillation.

Number of animals or in vitro replicates:

9

Irritation parameter:

other: Not irritating

Basis:

mean

Remarks:

9 animals

Time point:

other: 72 hours

Reversibility:

fully reversible within: 72 hours

Remarks on result:

no indication of irritation

Remarks:

Slight corneal swelling and slight permeability of the superficial epithelial cells were not considered to be of any toxicological significance.

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: other: reported in OECD SIDS report and in Cosmetic Ingredient review.

Conclusions:

Gluconic acid (50 %) was not irritating to rabbit's eyes

Executive summary:

In vitro

The ocular irritation potential of a 50% aq. solution of gluconic acid was evaluated in vitro in enucleated rabbit eyes. The test material was applied to four eyes and observed over a period of 4 h following application. Slight corneal swelling and slight permeability of the superficial epithelial cells were not considered to be of any toxicological significance.

In vivo

A 50% aq. solution of gluconic acid was not irritating to rabbit eyes. A 50% solution of gluconic acid (pH 1.8; 0.1 ml) was instilled into the conjunctival sac of one eye in nine New Zealand white rabbits; the contralateral eye served as an untreated control. The eyes of three animals were rinsed after 2 sec, and of another three animals after 4 sec; the eyes of the remaining three animals were not rinsed. The eyes were examined for irritation 1, 24, 48, and 72 h and 7 days after instillation. Slight redness and conjunctival swelling were observed initially; however, no signs of irritation were observed after 72 h.

Cross-reference 2

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

genetic toxicity in vitro

Remarks:

Type of genotoxicity: other: summary of mutagenicity data

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well-documented peer-reviewed report.

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

Qualifier:

no guideline followed

Principles of method if other than guideline:

Summary of genetic toxicity study results conducted with monosaccharides, disaccharides, and related ingredients as used in cosmetics.

GLP compliance:

not specified

Type of assay:

other: Summary of genetic toxicity study results

Species / strain:

other: The genotoxicity of a number of the mono- and disaccharides has been evaluated in in vitro and in vivo studies. The results of these studies are overwhelmingly negative.

Metabolic activation:

with and without

Genotoxicity:

negative

Vehicle controls validity:

other: not applicable (summary result)

Untreated negative controls validity:

other: not applicable (summary result)

Positive controls validity:

other: not applicable (summary result)

Remarks on result:

other: all strains/cell types tested

Conclusions:

The genotoxicity of a number of the mono- and disaccharides has been evaluated in in vitro and in vivo studies. The results of these studies are overwhelmingly negative.

Executive summary:

Summary of genetic toxicity study results conducted with monosaccharides, disaccharides, and related ingredients as used in cosmetics.

The genotoxicity of a number of the mono- and disaccharides has been evaluated in in vitro and in vivo studies. The results of these studies are overwhelmingly negative.

Cross-reference 3

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

in vivo mammalian germ cell study: cytogenicity / chromosome aberration

Remarks:

Type of genotoxicity: chromosome aberration

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well-documented peer-reviewed report.

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reference to same study

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Qualifier:

no guideline available

Version / remarks:

on GLP, guidelines, conditions, mitotic index, but sufficient for initial assessment.

GLP compliance:

no

Remarks:

the study was conducted prior to adoption of guidelines (in 1974).

Type of assay:

chromosome aberration assay

Species:

mouse

Strain:

C57BL

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 12 or 13 weeks

Route of administration:

oral: feed

Vehicle:

- Vehicle(s)/solvent(s) used: physiol. saline;

- Concentration of test material in vehicle:
- Amount of vehicle (if gavage or dermal): 1 mL/mouse

Duration of treatment / exposure:

single dose and 4 days

Frequency of treatment:

not specified

Post exposure period:

The animals were sacrified at 24 hours (single dose) and 27 hours after last administration (4-days repeated dose).

Dose / conc.:

2 000 mg/kg bw/day

Remarks:

single dose administration

Dose / conc.:

4 000 mg/kg bw/day

Remarks:

single dose administration

Dose / conc.:

8 000 mg/kg bw/day

Remarks:

single dose administration

Dose / conc.:

2 000 mg/kg bw/day

Remarks:

4 day repeated dose

Dose / conc.:

4 000 mg/kg bw/day

Remarks:

4 day repeated dose

No. of animals per sex per dose:

Single dose administration: 3 (vehicle control and test groups); 2 (positive control);
4-day repeated dose administration: 2 (vehicle control); 3 (test group 1: 4 g/kg); 2 (test group 2: 2 g/kg); 2 (positive control).

Control animals:

yes, concurrent vehicle

Positive control(s):

MMC (mitomycin C) dissolved with 0.9% physiological saline solution and administered intraperitoneally at a dose of 0.5 mL/mouse (= 5mg/kg bw).

Tissues and cell types examined:

At least 200 metaphase cells per mouse were examined for the presence or absence of chromosomal aberrations (gaps, breaks, translocation, fragments, ring chromosomes and minutes chromosomes).

Details of tissue and slide preparation:

TREATMENT AND SAMPLING TIMES: After receiving the single dose and the repeated dose test substance, the animals were sacrified at 24 hours (single dose) and 27 hours after last administration (4-days repeated dose). 0.3 mL of 500 μg/mL colchicine was intraperitoneally injected to each mouse at one hour before sacrifice so that the metaphase cells could be observed.

DETAILS OF SLIDE PREPARATION: After the bone marrow cells were washed, treated and fixed with a fixing solution (1:3 acetic acid:ethanol solution), the cells were suspended and dripped on a slide glass and stained with Giemsa solution and examined.

Sex:

male

Genotoxicity:

negative

Remarks:

in both experiments: single administration and 4-d repeated dose administration.

Toxicity:

yes

Remarks:

At 8 g/kg, all mice died (single dose administration experiment)

Vehicle controls validity:

valid

Negative controls validity:

valid

Positive controls validity:

valid

Single dose administration:

At 8 g/kg, all mice died.

MMC induced chromosomal aberrations in at least 20% of bone marrow cells.

GDL induced chromosomal aberrations in the cells at a frequency of about 0.5% comparable to the control.

4-day repeated dose administration:

MMC induced chromosomal aberrations at about 30% cells.

The frequency of cells with chromosomal aberrations was 1 % or less in the test groups which is comparable to the control group. Induction of chromosomal aberration by GDL was not detected after in vivo single and repeated dose treatment.

Conclusions:

The frequency of cells with chromosomal aberrations in the test groups was comparable to the control group in both experiments: single administration and 4-d repeat administration. The test item is considered to be negative for genetic mutagenicity.

Executive summary:

Sodium gluconate and glucono-delta-lactone were tested for induction of chromosomal aberrations in mouse bone marrow cells after an oral single and a 4 days repeated dose administration. At least 200 metaphase cells per mouse were scored (C57BL male mice) and were examined for the presence or absence of chromosomal aberrations (gaps, breaks, translocation, fragments, ring chromosomes and minutes chromosomes).

After single dose administration of glucono-delta-lactone: at 2 and 4 g/kg the number of chromosomal aberration was unchanged compared to control (both at a frequency of about 0.5 %). At 8 g/kg all mice died and the presence or absence of chromosomal aberration could not be determined. The positive control Mitomycin C induced chromosomal aberration in at least 20 % of bone marrow cells.

GDL induced chromosomal aberrations in the cells at a frequency of about 0.5% comparable to the control.

After a 4-day repeated dose administration of glucono-delta-lactone the positive control mitomycin C induced chromosomal aberrations at about 30% cells. However, the frequency of cells with chromosomal aberrations in the test groups (2 g/kg and 4 g/kg) was comparable to the control group.

In conclusion, the frequency of cells with chromosomal aberrations in the test groups was comparable to the control group in both experiments: single administration and 4-d repeat administration. The test item is considered to be negative for genetic mutagenicity.

Cross-reference 4

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

in vivo mammalian germ cell study: cytogenicity / chromosome aberration

Remarks:

Type of genotoxicity: chromosome aberration

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well-documented peer-reviewed reports.

Reason / purpose for cross-reference:

reference to same study

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Qualifier:

no guideline available

Version / remarks:

on GLP, guidelines, conditions, mitotic index, but sufficient for initial assessment.

GLP compliance:

no

Remarks:

the study was conducted prior to adoption of guidelines (in 1974).

Type of assay:

chromosome aberration assay

Species:

mouse

Strain:

C57BL

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 12 or 13 weeks

Route of administration:

oral: feed

Vehicle:

- Vehicle(s)/solvent(s) used: physiol. saline;

- Concentration of test material in vehicle:
- Amount of vehicle (if gavage or dermal): 1 mL/mouse

Duration of treatment / exposure:

single dose and 4 days

Frequency of treatment:

not specified

Post exposure period:

The animals were sacrified at 24 hours (single dose) and 27 hours after last administration (4-days repeated dose).

Dose / conc.:

2 500 mg/kg bw/day

Remarks:

single dose administration

Dose / conc.:

5 000 mg/kg bw/day

Remarks:

single dose administration

Dose / conc.:

10 000 mg/kg bw/day

Remarks:

single dose administration

Dose / conc.:

1 250 mg/kg bw/day

Remarks:

4 day repeated dose

Dose / conc.:

2 500 mg/kg bw/day

Remarks:

4 day repeated dose

No. of animals per sex per dose:

Single dose administration: 3 (vehicle control and test groups); 2 (positive control);
4-day repeated dose administration: 2 (vehicle control); 3 (test group 1: 2.5 g/kg); 2 (test group 2: 1.25 g/kg); 2 (positive control).

Control animals:

yes, concurrent vehicle

Positive control(s):

MMC (mitomycin C) dissolved with 0.9% physiological saline solution and administered intraperitoneally at a dose of 0.5 mL/mouse (= 5mg/kg bw).

Tissues and cell types examined:

At least 200 metaphase cells per mouse were examined for the presence or absence of chromosomal aberrations (gaps, breaks, translocation, fragments, ring chromosomes and minutes chromosomes).

Details of tissue and slide preparation:

TREATMENT AND SAMPLING TIMES: After receiving the single dose and the repeated dose test substance, the animals were sacrified at 24 hours (single dose) and 27 hours after last administration (4-days repeated dose). 0.3 mL of 500 μg/mL colchicine was intraperitoneally injected to each mouse at one hour before sacrifice so that the metaphase cells could be observed.

DETAILS OF SLIDE PREPARATION: After the bone marrow cells were washed, treated and fixed with a fixing solution (1:3 acetic acid:ethanol solution), the cells were suspended and dripped on a slide glass and stained with Giemsa solution and examined.

Sex:

male

Genotoxicity:

negative

Remarks:

in both experiments: single dose administration and 4-d repeated dose administration.

Toxicity:

yes

Remarks:

At 10 and 5 g/kg, all mice died (single dose administration); at 1.25 and 2.5 g/kg, one mouse died in each group (4-day repeated dose administration).

Vehicle controls validity:

valid

Negative controls validity:

valid

Positive controls validity:

valid

Single dose administration:

At 10 and 5 g/kg, all mice died.

At 2.5 g/kg, observation could be made only on 2 animals (preparation of the chromosome specimen failed).

MMC induced chromosomal aberrations in at least 20% of bone marrow cells. Sodium gluconate induced chromosomal aberrations in the cells at a frequency of about 0.5% is comparable to the control. (1 gap and 1 minute chromosome for 283 cells).

4-day repeated dose administration:

At 1.25 and 2.5 g/kg, one mouse died in each group.

MMC induced chromosomal aberrations at about 30% cells. The frequency of cells with chromosomal aberrations was 0.5% in the test groups which is comparable to the control group.

Conclusions:

Interpretation of results (migrated information): negative
Induction of chromosomal aberration by sodium gluconate was not detected after in vivo single and repeated dose treatment.

Executive summary:

Single dose administration tests of sodium gluconate at doses of 2.5, 5 and 10 g/kg were performed. At 10 and 5 g/kg, all mice died. At 2.5 g/kg, observations could be made only on 2 animals (preparation of the chromosome specimen failed). The positive control mitomycin C induced chromosomal aberrations in at least 20% of bone marrow cells. Sodium gluconate induced chromosomal aberrations in the cells at a frequency of about 0.5% is comparable to the control. (1 gap and 1 minute chromosome for 283 cells).

After 4-day repeated dose administration of sodium gluconate, one mouse of 2 or 3 animals, respectively, died in each group after doses of 1.25 and 2.5 g/kg. The positive control mitomycin C induced chromosomal aberrations at about 30% cells. The frequency of cells with chromosomal aberrations was 0.5% in the test groups which is comparable to the control group.

In conclusion, induction of chromosomal aberration by sodium gluconate was not detected after in vivo single and repeated dose treatment.

Cross-reference 5

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well documented peer-reviewed reports.

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reference to same study

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Qualifier:

no guideline available

Principles of method if other than guideline:

Summary of skin irritation potential of gluconates and its derivatives.

GLP compliance:

not specified

Species:

rabbit

Strain:

other: albino

Type of coverage:

not specified

Preparation of test site:

not specified

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

0.5 mL

Duration of treatment / exposure:

No data

Observation period:

72 hours

Number of animals:

12

Irritation parameter:

other: Not irritating

Basis:

mean

Remarks:

12 animals

Time point:

other: 72 hors

Reversibility:

fully reversible within: 72 hours

Primary dermal irritation tests with 0.5 ml of the 50% solution of gluconic acid (pH: 1.8) in 12 albino rabbits demonstrated, that – as all the effects have cleared up after a 72 hours observation period – the test substance is not a dermal irritant (TNO, 1984). No data were found on skin irritation for the other gluconates of the category

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: other: cited in the OECD SIDS report

Conclusions:

Gluconic acid (as 50 % solution) is not irritating to skin.

Executive summary:

Primary dermal irritation tests with 0.5 ml of the 50% solution of gluconic acid (pH: 1.8) in 12 albino rabbits demonstrated, that – as all the effects have cleared up after a 72 hours observation period – the test substance is not a dermal irritant (TNO, 1984).

The 2014 Cosmetic Ingredient Review Expert Panel acknowledged that the group of monosaccharides, disaccharides, and their related Ingredients, including calcium gluconate and gluconic acid, are safe for humans at concentrations as used in cosmetics. Based on the clinical experience of the Panel, there is little concern that these ingredients are irritants or sensitizers.

Cross-reference 6

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well documented peer-reviewed reports.

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Qualifier:

no guideline available

Principles of method if other than guideline:

Summary of acute toxicity data in animals.

GLP compliance:

not specified

Test type:

other: Summary of acute toxicity data in animals.

Species:

other: rats and dogs

Strain:

other: rats: Sprague Dawley; dogs: no data

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

not specified

Doses:

Rats: 500, 1000, 2000 mg/kg bw (Mochizuki, 1995) and 3000, 3600, 4320, 5190, 6210 mg/kg bw (TNO, 1978);
Dogs: 1000 and 2000 mg/kg bw (Okamoto, 1995).

No. of animals per sex per dose:

Rats: 5 sex/dose;
Dogs: no data

Control animals:

not specified

Details on study design:

Rats:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: on days 1, 2, 3, 7, 10, and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, and gross pathological changes in brain, pituitary, thyroid, salivary gland, thymus, heart, lung, liver, spleen, kidney, adrenals, stomach, small and large intestine, pancreas, gonads, urinary bladder, and lymph nodes.

Statistics:

no details given

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks:

sodium gluconate

Remarks on result:

other: for rats and dogs (Mochizuki, 1995; Okamoto, 1995).

Sex:

not specified

Dose descriptor:

LD50

Effect level:

6 060 mg/kg bw

Based on:

test mat.

Remarks:

potassium gluconate

Remarks on result:

other: for rats (TNO, 1978)

Mortality:

No mortality was observed (Mochizuki, 1995; Okamoto, 1995). One animal died in the 5190 mg/kg bw group and four animals in the 6210 mg/kg bw group. Deaths occurred between 5 and 21 hours after treatment. Survivors recovered gradually (TNO, 1978).

Clinical signs:

Soft faeces and diarrhoea, seen in one male and three females at 2000 mg/kg bw, were the only clinical effects observed 2-3 h after treatment (Mochizuki, 1995).

Body weight:

The body weights of treated rats were comparable to those of controls (Mochizuki, 1995).

Gross pathology:

No gross abnormalities were observed at necropsy (Mochizuki, 1995).

Other findings:

The minimum lethal dose was > 2000 mg/kg bw, although a transient, initial laxative effect was observed in rats at doses > 1000 mg/kg bw (Mochizuki, 1995).

Data on acute oral toxicity for sodium gluconate in rat (Mochizuki, M, Bozo Research Center 1995) (doses: 500, 1000, 2000 mg/kg) and dog (Okamoto M., 1995) (doses: 1000 and 2000 mg/kg) fed by gavage showed no death at any dose, hence the minimum lethal dose was estimated > 2000 mg/kg for both species.

Rats were fed by gavage 3000, 3600, 4320, 5190, 6210 mg/kg bw (30% (w/v) aqueous solution) potassium gluconate and were observed for signs of toxicity during a 14-day period. One animal died in the 5190 mg/kg bw group and four animals in the 6210 mg/kg bw group. Deaths occurred between 5 and 21 hours after treatment. Survivors recovered gradually. The LD50 was calculated (according to the method of Weil) to be 6060 mg/kg bw. However, the effects that were observed occurred at doses that exceed the accepted limit dose of 5000 mg/kg bw and the LD₅₀ may be related to high dosing (TNO, 1978). No relevant oral toxicity data were found in the literature for the other substances of the category. Conclusion Studies with sodium gluconate in the rat and dog report LD₅₀ values > 2000 mg/kg bw for both species. A gavage study with potassium gluconate and rats reported an LD₅₀ of 6060 mg/kg bw.

Interpretation of results:

Category 5 based on GHS criteria

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Oral LD50 > 2000 mg/kg bw was established for rats and dogs for gluconates.

Executive summary:

Data on acute oral toxicity for sodium gluconate in rat (Mochizuki, M, Bozo Research Center 1995) (doses: 500, 1000, 2000 mg/kg) and dog (Okamoto M., 1995) (doses: 1000 and 2000 mg/kg) fed by gavage showed no death at any dose, hence the minimum lethal dose was estimated > 2000 mg/kg for both species.

Rats were fed by gavage 3000, 3600, 4320, 5190, 6210 mg/kg bw (30% (w/v) aqueous solution) potassium gluconate and were observed for signs of toxicity during a 14-day period. One animal died in the 5190 mg/kg bw group and four animals in the 6210 mg/kg bw group. Deaths occurred between 5 and 21 hours after treatment. Survivors recovered gradually. The LD50 was calculated (according to the method of Weil) to be 6060 mg/kg bw. However, the effects that were observed occurred at doses that exceed the accepted limit dose of 5000 mg/kg bw and the LD50 may be related to high dosing (TNO, 1978). No relevant oral toxicity data were found in the literature for the other substances of the category. In conclusion, the studies with sodium gluconate in the rat and dog report LD50 values > 2000 mg/kg bw for both species. A gavage study with potassium gluconate and rats reported an LD50 of 6060 mg/kg bw.

Cross-reference 7

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

biodegradation in water: ready biodegradability

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well documented report; Study conducted according to guideline in compliance with GLP

Qualifier:

according to guideline

Guideline:

EU Method C.4-E (Determination of the "Ready" Biodegradability - Closed Bottle Test)

Version / remarks:

Cited as Directive 92/69/EEC, C.4-E

GLP compliance:

yes

Oxygen conditions:

aerobic

Inoculum or test system:

other: secondary effluent of a municipal sewage plant (Breisgauer Bucht, 500000 population equivalent), 0.4 mL/L

Duration of test (contact time):

28 d

Initial conc.:

3 mg/L

Based on:

test mat.

Reference substance:

acetic acid, sodium salt

Parameter:

% degradation (O2 consumption)

Value:

89

Sampling time:

28 d

Details on results:

Blanks:

Maximum deviation between parallels = 8.9%
Oxygen consumption after 28 days = 0.79-1.18 mg/L
pH : 7.2 at the beginning and 6.7 at the end of the test

----------------------------------
Sodium gluconate:

Maximum deviation between parallels = 4.6% at day 3
Biological degradation : 61% of ThOD after 3 days
Maximum degradation = 89% of the ThOD at day 28
pH : 7.2 at the beginning and 6.7 at the end of the test

Oxygen concentration during test never felt below 5.9 mg/lL.
----------------------------------------
Reference item (sodium acetate):

Maximum deviation between parallels = 3.8% at day 14.
Biological degradation : 67% after 3 days
pH : 7.2 at the beginning and 6.7 at the end of the test

Kinetic of test substance (in %):
= 61.13 after 3 day(s)
= 74.35 after 7 day(s)
= 66.09 after 14 day(s)
= 71.94 after 21 day(s)
= 88.88 after 28 day(s)

Kinetic of control substance (in %):
= 67.15 after 3 day(s)
= 80.93 after 28 day(s)
Degradation products: not measured

The 89% degradation indicated here relates to the Theoritical Oxygen Demand (ThOD).

Validity criteria fulfilled:

yes

Remarks:

Oxygen depletion in the inoculum blank did not exceed 1.5 mg dissolved oxygen/litre after 28 days.

Interpretation of results:

readily biodegradable

Conclusions:

Sodium gluconate (CAS 527-07-1) is readily biodegradable with 89% degradation (based on ThOD) after 28 days.

Executive summary:

The biodegradation of the test substance sodium gluconate (CAS 527-07-1) was investigated according to EU Method C.4-E (Closed bottle test) in compliance with GLP.

All in all, 16 test bottles with a test item concentration of 3 mg/L with 4 mL/L inoculum (secondary effluent of a municipal sewage plant) were filled bubble-free and incubated in the dark at 20°C for 28 days. On days 3, 7, 10, 14, 21 and 28, at least duplicate bottles were removed for determination of dissolved oxygen and pH. At the end of the test, dissolved oxygen concentration in all remaining bottles was measured. Reference item bottles containing sodium acetate stock solution (concentration= 4 mg/L) with 0.4 mL/L inoculum were also filled and incubated in the dark at 20°C. A blank was also prepared without any stock solution.

Referring to the test substance and based on the ThOD, 61.13% degradation were reported after 3 days, followed by 74.35% after 7 days, 66.09% after 14 days, 71.94% after 21 days and 88.88% after 28 days. With regard to the reference substance, 67.15% degradation were measured after 3 days and 80.93% after 28 days – both based on the ThOD.

Cross-reference 8

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

biodegradation in water: ready biodegradability

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study conducted according to guideline in compliance with GLP; Acceptable well documented report

Qualifier:

according to guideline

Guideline:

other: DIN EN ISO 11734

GLP compliance:

yes

Oxygen conditions:

anaerobic

Inoculum or test system:

other: Digesting sludge of a municipal sewage plant (Breisgauer Bucht, 500000 population equivalent), 2.9 g total solids/L

Duration of test (contact time):

35 d

Initial conc.:

303 mg/L

Based on:

test mat.

Reference substance:

benzoic acid, sodium salt

Parameter:

% degradation (TOC removal)

Value:

100

Sampling time:

35 d

Details on results:

Test item:
The percentage biodegradation is calculated from the total carbon transformed to biogas and DIC and the measured or calculated amount of carbon added as test item. The test item was degraded to 50% by day 8 and to 66% by day 35.

The summing up of the net-mass carbon in the liquor shows that the test item is completely anaerobically degraded after 35 days.

The pH at the end of the test was 6.8 in every bottle.
Bottles with blanks showed a pH of 7.1-7.2.

------------------------------------------
Reference (sodium benzoate) :
The degradation of the reference item took some time to get started. Between days 18 and 22 this lag-phase was over and the curve reached 67% by day 35. After considering the DIC in the liquor, the reference item was also anaerobically degraded completely in 35 days. The pH at the end of the test was 6.8 in every bottle.

Kinetic of test substance (in %):
= 8 after 1 day(s)
= 51 after 8 day(s)
= 57 after 15 day(s)
= 61 after 22 day(s)
= 100 after 35 day(s)

Kinetic of control substance (in %):
= 6 after 8 day(s)
= 100 after 35 day(s)
Degradation products: not measured

At day 35, the average degradation percentage is 66% but the value shown includes the dissolved inorganic carbon (DIC).

Validity criteria fulfilled:

not specified

Interpretation of results:

other: The test item is ultimately biodegradable under anaerob test conditions.

Conclusions:

The test substance Sodium gluconate (CAS 527-07-1) is ultimately biodegradable under anaerobic test conditions.

Executive summary:

The biodegradation of the test substance Sodium gluconate (CAS 527-07-1) was investigated according to DIN EN ISO 11734 in compliance with GLP.

Washed digested sludge containing very low amounts of inorganic carbon (IC) was diluted to 1-3 g/L total solids concentration and incubated in the absence of oxygen at 35 +/-2°C in sealed vessels with the test item (303 mg/L) at a concentration of 20-200 mg/L total organic carbon (TOC) for 35 days. As reference substance, sodium benzoate (0.069 g/400 mL) has been used. The percentage biodegradation is calculated from the total carbon transformed to biogas and DIC and the measured or calculated amount of carbon added as test item.

Referring to the test substance, 8% degradation has been determined after 1 day, followed by 51% after 8 days, 57% after 15 days, 61% after 22 days and 100% after 35 days. With regard to the reference substance, 6% degradation was determined after 8 days and 100% after 35 days.

Cross-reference 9

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:

other: Acceptable well documented peer-reviewed report.

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

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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

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

Principles of method if other than guideline:

The only available studies reported on the developmental toxicity for the gluconates of the category are for glucono-delta-lactone. These studies (unpublished) investigated teratogenicity following oral daily dosing of glucono-delta-lactone in in the rat, mouse, hamster and rabbit (Food & Drug Research Laboratories - Unpublished data (1973).

GLP compliance:

not specified

Limit test:

no

Species:

hamster

Details on test animals or test system and environmental conditions:

no data available

Route of administration:

oral: unspecified

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: not specified

DIET PREPARATION - not specified

VEHICLE - not specified

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

not applicable, as already pregnant hamsters were used

Duration of treatment / exposure:

5 days (from day 6 to day 10 of gestation)

Frequency of treatment:

once daily

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

5.6 mg/kg bw/day (nominal)

Dose / conc.:

26 mg/kg bw/day (nominal)

Dose / conc.:

121 mg/kg bw/day (nominal)

Dose / conc.:

560 mg/kg bw/day (nominal)

No. of animals per sex per dose:

not specified

Control animals:

yes

Statistics:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not examined

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:

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 specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

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:

not specified

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): not specified

Changes in number of pregnant:

not specified

Other effects:

not specified

Dose descriptor:

NOAEL

Effect level:

> 560 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: not specified

Fetal body weight changes:

not specified

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified

Reduction in number of live offspring:

not specified

Changes in sex ratio:

not specified

Changes in litter size and weights:

not specified

Changes in postnatal survival:

not specified

External malformations:

not specified

Skeletal malformations:

not specified

Visceral malformations:

not specified

Other effects:

not examined

Dose descriptor:

NOAEL

Effect level:

> 560 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: not specified

Developmental effects observed:

no

Conclusions:

In summary, these negative data on the teratogenicity of glucono-delta-lactone, together with the natural occurrence of gluconic acid in the human metabolism sufficiently support the lack of developmental toxicity for all the gluconates of the category.

Executive summary:

Glucono-delta-lactone was administered to hamster for 5 days (from day 6 - 10 of gestation) at doses of 0, 5.60, 26.0, 121, 560 mg/kg.. A NOAEL of > 560 mg/kg bw for maternal and developmental toxicity (teratogenicity) was determined.

Cross-reference 10

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:

other: Acceptable well documented peer-reviewed report.

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

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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

Reason / purpose for cross-reference:

reference to same study

Principles of method if other than guideline:

The only available studies reported on the developmental toxicity for the gluconates of the category are for glucono-delta-lactone. These studies (unpublished) investigated teratogenicity following oral daily dosing of glucono-delta-lactone in in the rat, mouse, hamster and rabbit (Food & Drug Research Laboratories - Unpublished data (1973).

GLP compliance:

not specified

Limit test:

no

Species:

mouse

Strain:

CD-1

Details on test animals or test system and environmental conditions:

no data available

Route of administration:

oral: unspecified

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: not specified

DIET PREPARATION - not specified

VEHICLE - not specified

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

not applicable, as already pregnant mice were used

Duration of treatment / exposure:

10 days (from day 6 to day 15 of gestation)

Frequency of treatment:

once daily

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

6.95 mg/kg bw/day (nominal)

Dose / conc.:

32.5 mg/kg bw/day (nominal)

Dose / conc.:

150 mg/kg bw/day (nominal)

Dose / conc.:

695 mg/kg bw/day (nominal)

No. of animals per sex per dose:

not specified

Control animals:

yes

Statistics:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not examined

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:

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 specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

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:

not specified

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): not specified

Changes in number of pregnant:

not specified

Other effects:

not specified

Dose descriptor:

NOAEL

Effect level:

> 695 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: not specified

Fetal body weight changes:

not specified

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified

Reduction in number of live offspring:

not specified

Changes in sex ratio:

not specified

Changes in litter size and weights:

not specified

Changes in postnatal survival:

not specified

External malformations:

not specified

Skeletal malformations:

not specified

Visceral malformations:

not specified

Other effects:

not examined

Dose descriptor:

NOAEL

Effect level:

> 695 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: not specified

Developmental effects observed:

no

Conclusions:

In summary, these negative data on the teratogenicity of glucono-delta-lactone, together with the natural occurrence of gluconic acid in the human metabolism sufficiently support the lack of developmental toxicity for all the gluconates of the category.

Executive summary:

Glucono-delta-lactone was administered to CD-1 mice for 10 days (from day 6 - 15 of gestation) at doses of 0, 6.95, 32.5, 150, 695 mg/kg dw/day. A NOAEL of > 695 mg/kg bw/day for maternal and developmental toxicity (teratogenicity) was determined.

Cross-reference 11

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:

other: Acceptable well documented peer-reviewed report.

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

Principles of method if other than guideline:

Two studies conducted in 1978 to assess the potential teratogenicity of GDL on rats (Fukuhara, K. 1978b) and mice (Fukuhara, K. 1978c) reported that GDL was not teratogenic when given orally at doses > 4000 mg/kgbw.

GLP compliance:

not specified

Limit test:

no

Species:

mouse

Strain:

ICR

Details on test animals or test system and environmental conditions:

no data available

Route of administration:

oral: unspecified

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: not specified

DIET PREPARATION - not specified

VEHICLE - not specified

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

not applicable, as already pregnant mice were used

Duration of treatment / exposure:

10 days (from day 6 to day 15 of gestation)

Frequency of treatment:

once daily

Duration of test:

until postnatal day 21

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

1 000 mg/kg bw/day (nominal)

Dose / conc.:

4 000 mg/kg bw/day (nominal)

No. of animals per sex per dose:

not specified

Control animals:

yes

Maternal examinations:

general condition, body weight change or food consumption

Fetal examinations:

Some of the fetuses were observed by laparotomy on pregnancy day 18.
Several dams in each group were allowed to deliver spontaneously, and the offspring were observed until postnatal day 21.

Statistics:

not specified

Clinical signs:

no effects observed

Description (incidence and severity):

During pregnancy, no abnormalities were observed in the general condition, body weight change or food consumption in any of the dose groups, nor were any death.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

There were no death.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

During pregnancy, no abnormalities were observed in the body weight change in any of the dose groups.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

During pregnancy, no abnormalities were observed in the food consumption in any of the dose groups.

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 specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Details on results:

During pregnancy, no abnormalities were observed in the general condition, body weight change or food consumption in any of the dose groups, nor were any death. In observation of dams after laparotomy, no abnormalities were detected in the number of implantations, dead foetuses, live offspring or mean body weight of offspring, nor was there any influence of the drug on the external appearance, organs, or skeletons of the foetuses. Observation of the dams allowed to deliver spontaneously, protraction of the duration of pregnancy or abnormalities at birth were not observed, nor any influence of the drug detected in the mortality rate, body weight gain, behavior, external appearance or visceral abnormalities of the offspring during the period of nursing.

Number of abortions:

no effects observed

Description (incidence and severity):

no abnormalities were detected in the number of implantations, dead foetuses, live offspring or mean body weight of offspring.

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

no abnormalities were detected in the number of implantations, dead foetuses, live offspring or mean body weight of offspring.

Total litter losses by resorption:

no effects observed

Description (incidence and severity):

no abnormalities were detected in the number of implantations, dead foetuses, live offspring or mean body weight of offspring.

Early or late resorptions:

no effects observed

Description (incidence and severity):

no abnormalities were detected in the number of implantations, dead foetuses, live offspring or mean body weight of offspring.

Dead fetuses:

no effects observed

Description (incidence and severity):

no abnormalities were detected in the number of implantations, dead foetuses, live offspring or mean body weight of offspring.

Changes in pregnancy duration:

no effects observed

Description (incidence and severity):

no abnormalities were detected in the number of implantations, dead foetuses, live offspring or mean body weight of offspring.
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): no abnormalities were detected in the number of implantations, dead foetuses, live offspring or mean body weight of offspring.

Changes in number of pregnant:

no effects observed

Description (incidence and severity):

no abnormalities were detected in the number of implantations, dead foetuses, live offspring or mean body weight of offspring.

Other effects:

not examined

Details on maternal toxic effects:

In observation of dams after laparotomy, no abnormalities were detected in the number of implantations, dead foetuses, live offspring or mean body weight of offspring, nor was there any influence of the drug on the external appearance, organs, or skeletons of the foetuses. Observation of the dams allowed to deliver spontaneously, protraction of the duration of pregnancy or abnormalities at birth were not observed, nor any influence of the drug detected in the mortality rate, body weight gain, behavior, external appearance or visceral abnormalities of the offspring during the period of nursing.

Dose descriptor:

NOAEL

Effect level:

> 4 000 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

clinical signs

dead fetuses

food consumption and compound intake

mortality

pre and post implantation loss

Abnormalities:

no effects observed

Fetal body weight changes:

no effects observed

Description (incidence and severity):

Observation of the dams allowed to deliver spontaneously, protraction of the duration of pregnancy or abnormalities at birth were not observed, nor any influence of the drug detected in the mortality rate, body weight gain, behavior, external appearance or visceral abnormalities of the offspring during the period of nursing.
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): Observation of the dams allowed to deliver spontaneously, protraction of the duration of pregnancy or abnormalities at birth were not observed, nor any influence of the drug detected in the mortality rate, body weight gain, behavior, external appearance or visceral abnormalities of the offspring during the period of nursing.

Reduction in number of live offspring:

no effects observed

Description (incidence and severity):

Observation of the dams allowed to deliver spontaneously, protraction of the duration of pregnancy or abnormalities at birth were not observed, nor any influence of the drug detected in the mortality rate, body weight gain, behavior, external appearance or visceral abnormalities of the offspring during the period of nursing.

Changes in sex ratio:

not specified

Changes in litter size and weights:

no effects observed

Description (incidence and severity):

Observation of the dams allowed to deliver spontaneously, protraction of the duration of pregnancy or abnormalities at birth were not observed, nor any influence of the drug detected in the mortality rate, body weight gain, behavior, external appearance or visceral abnormalities of the offspring during the period of nursing.

Changes in postnatal survival:

no effects observed

Description (incidence and severity):

Observation of the dams allowed to deliver spontaneously, protraction of the duration of pregnancy or abnormalities at birth were not observed, nor any influence of the drug detected in the mortality rate, body weight gain, behavior, external appearance or visceral abnormalities of the offspring during the period of nursing.

External malformations:

no effects observed

Description (incidence and severity):

There was no influence of the drug on the external appearance, organs, or skeletons of the foetuses.

Skeletal malformations:

no effects observed

Description (incidence and severity):

There was no influence of the drug on the external appearance, organs, or skeletons of the foetuses.

Visceral malformations:

no effects observed

Description (incidence and severity):

There was no influence of the drug on the external appearance, organs, or skeletons of the foetuses.

Other effects:

not examined

Details on embryotoxic / teratogenic effects:

Observation of the dams allowed to deliver spontaneously, protraction of the duration of pregnancy or abnormalities at birth were not observed, nor any influence of the drug detected in the mortality rate, body weight gain, behavior, external appearance or visceral abnormalities of the offspring during the period of nursing.

Dose descriptor:

NOAEL

Effect level:

> 4 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reduction in number of live offspring

fetal/pup body weight changes

changes in litter size and weights

changes in postnatal survival

external malformations

skeletal malformations

visceral malformations

Abnormalities:

no effects observed

Developmental effects observed:

no

During pregnancy, no abnormalities were observed in the general condition, body weight change or food consumption in any of the dose groups, nor were any death. In observation of dams after laparotomy, no abnormalities were detected in the number of implantations, dead foetuses, live offspring or mean body weight of offspring, nor was there any influence of the drug on the external appearance, organs, or skeletons of the foetuses. Observation of the dams allowed to deliver spontaneously, protraction of the duration of pregnancy or abnormalities at birth were not observed, nor any influence of the drug detected in the mortality rate, body weight gain, behavior, external appearance or visceral abnormalities of the offspring during the period of nursing.

Conclusions:

In summary, these negative data on the teratogenicity of glucono-delta-lactone, together with the natural occurrence of gluconic acid in the human metabolism sufficiently support the lack of developmental toxicity for all the gluconates of the category.

Executive summary:

In the experiments glucono-delta-lactone was administered orally to female nulliparous mice for 10 days and the fetuses were observed by laparotomy on pregnancy day 18. Several dams in each group were allowed to deliver spontaneously, and the offspring were observed until postnatal day 21. The report does not contain specific information on the method used. During pregnancy, no abnormalities were observed in the general condition, body weight change or food consumption in any of the dose groups, nor were any death. In observation of dams after laparotomy, no abnormalities were detected in the number of implantations, dead foetuses, live offspring or mean body weight of offspring, nor was there any influence of the drug on the external appearance, organs, or skeletons of the foetuses. Observation of the dams allowed to deliver spontaneously, protraction of the duration of pregnancy or abnormalities at birth were not observed, nor any influence of the drug detected in the mortality rate, body weight gain, behavior, external appearance or visceral abnormalities of the offspring during the period of nursing.

A NOAEL of > 4000 mg/kg bw/day was established for mice.

Cross-reference 12

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:

other: Acceptable well documented peer-reviewed report.

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

Principles of method if other than guideline:

The only available studies reported on the developmental toxicity for the gluconates of the category are for glucono-delta-lactone. These studies (unpublished) investigated teratogenicity following oral daily dosing of glucono-delta-lactone in in the rat, mouse, hamster and rabbit (Food & Drug Research Laboratories - Unpublished data (1973).

GLP compliance:

not specified

Limit test:

no

Species:

rabbit

Strain:

Dutch

Details on test animals or test system and environmental conditions:

no data available

Route of administration:

oral: unspecified

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: not specified

DIET PREPARATION - not specified

VEHICLE - not specified

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

not applicable, as already pregnant rabbits were used

Duration of treatment / exposure:

13 days (from day 6 to day 18 of gestation)

Frequency of treatment:

once daily

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

7.8 mg/kg bw/day (nominal)

Dose / conc.:

36.2 mg/kg bw/day (nominal)

Dose / conc.:

168.5 mg/kg bw/day (nominal)

Dose / conc.:

780 mg/kg bw/day (nominal)

No. of animals per sex per dose:

not specified

Control animals:

yes

Statistics:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not examined

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:

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 specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

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:

not specified

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): not specified

Changes in number of pregnant:

not specified

Other effects:

not specified

Dose descriptor:

NOAEL

Effect level:

> 780 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: not specified

Fetal body weight changes:

not specified

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified

Reduction in number of live offspring:

not specified

Changes in sex ratio:

not specified

Changes in litter size and weights:

not specified

Changes in postnatal survival:

not specified

External malformations:

not specified

Skeletal malformations:

not specified

Visceral malformations:

not specified

Other effects:

not examined

Dose descriptor:

NOAEL

Effect level:

> 780 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: not specified

Abnormalities:

no effects observed

Developmental effects observed:

no

Conclusions:

In summary, these negative data on the teratogenicity of glucono-delta-lactone, together with the natural occurrence of gluconic acid in the human metabolism sufficiently support the lack of developmental toxicity for all the gluconates of the category.

Executive summary:

Glucono-delta-lactone was administered to Dutch rabbits for 13 days (from day 6 - 18 of gestation) at doses of 0, 7.80, 36.2, 168.5, 780.0 mg/kg.. A NOAEL of > 780 mg/kg bw for maternal and developmental toxicity (teratogenicity) was determined.

Cross-reference 13

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:

other: Acceptable well documented peer-reviewed report.

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

Principles of method if other than guideline:

The only available studies reported on the developmental toxicity for the gluconates of the category are for glucono-delta-lactone. These studies (unpublished) investigated teratogenicity following oral daily dosing of glucono-delta-lactone in in the rat, mouse, hamster and rabbit (Food & Drug Research Laboratories - Unpublished data (1973).

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

no data available

Route of administration:

oral: unspecified

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: not specified

DIET PREPARATION - not specified

VEHICLE - not specified

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

not applicable, as already pregnant rats were used

Duration of treatment / exposure:

10 days (from day 6 to day 15 of gestation)

Frequency of treatment:

once daily

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

5.94 mg/kg bw/day (nominal)

Dose / conc.:

27.6 mg/kg bw/day (nominal)

Dose / conc.:

128 mg/kg bw/day (nominal)

Dose / conc.:

594 mg/kg bw/day (nominal)

No. of animals per sex per dose:

not specified

Control animals:

yes

Statistics:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not examined

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:

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 specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

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:

not specified

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): not specified

Changes in number of pregnant:

not specified

Other effects:

not specified

Dose descriptor:

NOAEL

Effect level:

> 594 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: not specified

Fetal body weight changes:

not specified

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified

Reduction in number of live offspring:

not specified

Changes in sex ratio:

not specified

Changes in litter size and weights:

not specified

Changes in postnatal survival:

not specified

External malformations:

not specified

Skeletal malformations:

not specified

Visceral malformations:

not specified

Other effects:

not examined

Dose descriptor:

NOAEL

Effect level:

> 594 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: not specified

Developmental effects observed:

no

Conclusions:

In summary, these negative data on the teratogenicity of glucono-delta-lactone, together with the natural occurrence of gluconic acid in the human metabolism sufficiently support the lack of developmental toxicity for all the gluconates of the category.

Executive summary:

Glucono-delta-lactone was administered to Wistar rats for 10 days (from day 6 - 15 of gestation) at doses of 0, 5.94, 27.6, 128.0, 594.0 mg/kg bw/day. A NOAEL of > 594 mg/kg bw/day for maternal and developmental toxicity (teratogenicity) was determined.

Cross-reference 14

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:

other: Acceptable well documented peer-reviewed report.

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

Principles of method if other than guideline:

Two studies conducted in 1978 to assess the potential teratogenicity of GDL on rats (Fukuhara, K. 1978b) and mice (Fukuhara, K. 1978c) reported that GDL was not teratogenic when given orally at doses > 4000 mg/kgbw.

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

no data available

Route of administration:

oral: unspecified

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: not specified

DIET PREPARATION - not specified

VEHICLE - not specified

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

not applicable, as already pregnant rats were used

Duration of treatment / exposure:

10 days (from day 6 to day 15 of gestation)

Frequency of treatment:

once daily

Duration of test:

until postnatal day 21

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

1 000 mg/kg bw/day (nominal)

Dose / conc.:

4 000 mg/kg bw/day (nominal)

No. of animals per sex per dose:

not specified

Control animals:

yes

Maternal examinations:

general condition, body weight change or food consumption

Fetal examinations:

Some of the fetuses were observed by laparotomy on pregnancy day 21.
Several dams in each group were allowed to deliver spontaneously, and the offspring were observed until postnatal day 21.

Statistics:

not specified

Clinical signs:

no effects observed

Description (incidence and severity):

During pregnancy, no abnormalities were observed in the general condition, body weight change or food consumption in any of the dose groups, nor were any death.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

There were no death.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

During pregnancy, no abnormalities were observed in the body weight change in any of the dose groups.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

During pregnancy, no abnormalities were observed in the food consumption in any of the dose groups.

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 specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Details on results:

During pregnancy, no abnormalities were observed in the general condition, body weight change or food consumption in any of the dose groups, nor were any death. In observation of dams after laparotomy, no abnormalities were detected in the number of implantations, dead fetuses, live offspring or mean body weight of offspring, nor was there any influence of the drug on the external appearance, organs, or skeletons of the fetuses. Observation of the dams allowed to deliver spontaneously, protraction of the duration of pregnancy or abnormalities at birth were not observed, nor any influence of the drug detected in the mortality rate, body weight gain, behavior, external appearance or visceral abnormalities of the offspring during the period of nursing.

Number of abortions:

no effects observed

Description (incidence and severity):

no abnormalities were detected in the number of implantations, dead foetuses, live offspring or mean body weight of offspring.

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

no abnormalities were detected in the number of implantations, dead foetuses, live offspring or mean body weight of offspring.

Total litter losses by resorption:

no effects observed

Description (incidence and severity):

no abnormalities were detected in the number of implantations, dead foetuses, live offspring or mean body weight of offspring.

Early or late resorptions:

no effects observed

Description (incidence and severity):

no abnormalities were detected in the number of implantations, dead foetuses, live offspring or mean body weight of offspring.

Dead fetuses:

no effects observed

Description (incidence and severity):

no abnormalities were detected in the number of implantations, dead foetuses, live offspring or mean body weight of offspring.

Changes in pregnancy duration:

no effects observed

Description (incidence and severity):

no abnormalities were detected in the number of implantations, dead foetuses, live offspring or mean body weight of offspring.
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): no abnormalities were detected in the number of implantations, dead foetuses, live offspring or mean body weight of offspring.

Changes in number of pregnant:

no effects observed

Description (incidence and severity):

no abnormalities were detected in the number of implantations, dead foetuses, live offspring or mean body weight of offspring.

Other effects:

not examined

Details on maternal toxic effects:

In observation of dams after laparotomy, no abnormalities were detected in the number of implantations, dead foetuses, live offspring or mean body weight of offspring, nor was there any influence of the drug on the external appearance, organs, or skeletons of the foetuses. Observation of the dams allowed to deliver spontaneously, protraction of the duration of pregnancy or abnormalities at birth were not observed, nor any influence of the drug detected in the mortality rate, body weight gain, behavior, external appearance or visceral abnormalities of the offspring during the period of nursing.

Dose descriptor:

NOAEL

Effect level:

> 4 000 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

body weight and weight gain

changes in pregnancy duration

clinical signs

dead fetuses

early or late resorptions

effects on pregnancy duration

food consumption and compound intake

mortality

number of abortions

pre and post implantation loss

Abnormalities:

no effects observed

Fetal body weight changes:

no effects observed

Description (incidence and severity):

Observation of the dams allowed to deliver spontaneously, protraction of the duration of pregnancy or abnormalities at birth were not observed, nor any influence of the drug detected in the mortality rate, body weight gain, behavior, external appearance or visceral abnormalities of the offspring during the period of nursing.
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): Observation of the dams allowed to deliver spontaneously, protraction of the duration of pregnancy or abnormalities at birth were not observed, nor any influence of the drug detected in the mortality rate, body weight gain, behavior, external appearance or visceral abnormalities of the offspring during the period of nursing.

Reduction in number of live offspring:

no effects observed

Description (incidence and severity):

Observation of the dams allowed to deliver spontaneously, protraction of the duration of pregnancy or abnormalities at birth were not observed, nor any influence of the drug detected in the mortality rate, body weight gain, behavior, external appearance or visceral abnormalities of the offspring during the period of nursing.

Changes in sex ratio:

not specified

Changes in litter size and weights:

no effects observed

Description (incidence and severity):

Observation of the dams allowed to deliver spontaneously, protraction of the duration of pregnancy or abnormalities at birth were not observed, nor any influence of the drug detected in the mortality rate, body weight gain, behavior, external appearance or visceral abnormalities of the offspring during the period of nursing.

Changes in postnatal survival:

no effects observed

Description (incidence and severity):

Observation of the dams allowed to deliver spontaneously, protraction of the duration of pregnancy or abnormalities at birth were not observed, nor any influence of the drug detected in the mortality rate, body weight gain, behavior, external appearance or visceral abnormalities of the offspring during the period of nursing.

External malformations:

no effects observed

Description (incidence and severity):

There was no influence of the drug on the external appearance, organs, or skeletons of the foetuses.

Skeletal malformations:

no effects observed

Description (incidence and severity):

There was no influence of the drug on the external appearance, organs, or skeletons of the foetuses.

Visceral malformations:

no effects observed

Description (incidence and severity):

There was no influence of the drug on the external appearance, organs, or skeletons of the foetuses.

Other effects:

not examined

Details on embryotoxic / teratogenic effects:

Observation of the dams allowed to deliver spontaneously, protraction of the duration of pregnancy or abnormalities at birth were not observed, nor any influence of the drug detected in the mortality rate, body weight gain, behavior, external appearance or visceral abnormalities of the offspring during the period of nursing.

Dose descriptor:

NOAEL

Effect level:

> 4 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reduction in number of live offspring

fetal/pup body weight changes

changes in litter size and weights

changes in postnatal survival

external malformations

skeletal malformations

visceral malformations

Abnormalities:

no effects observed

Developmental effects observed:

no

During pregnancy, no abnormalities were observed in the general condition, body weight change or food consumption in any of the dose groups, nor were any death. In observation of dams after laparotomy, no abnormalities were detected in the number of implantations, dead foetuses, live offspring or mean body weight of offspring, nor was there any influence of the drug on the external appearance, organs, or skeletons of the foetuses. Observation of the dams allowed to deliver spontaneously, protraction of the duration of pregnancy or abnormalities at birth were not observed, nor any influence of the drug detected in the mortality rate, body weight gain, behavior, external appearance or visceral abnormalities of the offspring during the period of nursing.

Conclusions:

In summary, these negative data on the teratogenicity of glucono-delta-lactone, together with the natural occurrence of gluconic acid in the human metabolism sufficiently support the lack of developmental toxicity for all the gluconates of the category.

Executive summary:

In the experiments glucono-delta-lactone was administered orally to female nulliparous rats for 10 days and the fetuses were observed by laparotomy on pregnancy day 21. Several dams in each group were allowed to deliver spontaneously, and the offspring was observed until postnatal day 21. The report does not contain specific information on the method used. During pregnancy, no abnormalities were observed in the general condition, body weight change or food consumption in any of the dose groups, nor were any death. In observation of dams after laparotomy, no abnormalities were detected in the number of implantations, dead foetuses, live offspring or mean body weight of offspring, nor was there any influence of the drug on the external appearance, organs, or skeletons of the foetuses. Observation of the dams allowed to deliver spontaneously, protraction of the duration of pregnancy or abnormalities at birth were not observed, nor any influence of the drug detected in the mortality rate, body weight gain, behavior, external appearance or visceral abnormalities of the offspring during the period of nursing.

A NOAEL of > 4000 mg/kg bw/day was established for rats.

Cross-reference 15

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

in vitro gene mutation study in bacteria

Remarks:

Type of genotoxicity: other: summary of available in vitro and in vivo genetic toxicity data

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well documented peer-reviewed report.

Reason / purpose for cross-reference:

reference to same study

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reference to same study

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Qualifier:

according to guideline

Guideline:

OECD Guideline 471 (Bacterial Reverse Mutation Assay)

Deviations:

yes

Remarks:

The study was made on one yeast strain : Saccharomyces cerevisiae, strain D4 and 3 bacteria strains: S. typhimuriumTA1535, TA1537 and TA 1538. Positive controls are different from those in the OECD 471; only 3 concentration tested.

Principles of method if other than guideline:

Summary of genetic toxicity data on glucono-delta-lactone, sodium or calcium gluconate

GLP compliance:

not specified

Type of assay:

bacterial reverse mutation assay

Target gene:

his-

Species / strain / cell type:

other: S.typhimurium TA 1535, TA 1537, TA 1538

Species / strain / cell type:

Saccharomyces cerevisiae

Details on mammalian cell type (if applicable):

strain D4

Metabolic activation:

with and without

Metabolic activation system:

The tissue homogenates and supernatants (9000 g) were prepared from tissues of mouse (ICR random bred adult males); rat (Sprague-Dawnley adult males) and monkey (Macaca mulatta adult males).

Test concentrations with justification for top dose:

Sodium gluconate: 0.06, 0.012, 0.024 µg/mL (Salmonella typhimurium); 12.5, 25 and 50 µg/mL (yeast);
Glucono-delta-lactone: 2.5, 5 (5 µg/mL plate test; Salmonella typhimurium); 12.5 and 25 µg/mL (yeast);
Calcium gluconate: 12.5, 25 and 50 µg/mL (Salmonella typhimurium); 7.5, 15 and 30 µg/mL (yeast).

Vehicle / solvent:

- Solvent used: 0.067 M phosphate buffer, pH 7.4

Untreated negative controls:

yes

Remarks:

solvent control

Negative solvent / vehicle controls:

yes

Remarks:

vehicle control

True negative controls:

no

Positive controls:

yes

Remarks:

without S9

Positive control substance:

2-nitrofluorene

ethylmethanesulphonate

other: Quinacrine or quinacrinemustard (QM)

Untreated negative controls:

yes

Remarks:

solvent control

Negative solvent / vehicle controls:

yes

Remarks:

vehicle control

True negative controls:

no

Positive controls:

yes

Remarks:

with S9

Positive control substance:

2-acetylaminofluorene

N-dimethylnitrosamine

Details on test system and experimental conditions:

METHOD OF APPLICATION: in agar (plate incorporation) and in suspension

DURATION
- Glucono-delta-lactone: 4 days: bacteria and yeasts (plate test); 4 hours (yeasts) and 1 hour (bacteria) in suspension test.
- Sodium gluconate: 48 to 72 hours bacteria and yeasts (plate test); 4 hours (yeasts) and 1 hour (bacteria) in suspension test.
- Calcium gluconate: 4 days: bacteria and yeasts (plate test); 4 hours (yeasts) and 1 hour (bacteria) in suspension test.

DETERMINATION OF CYTOTOXICITY
- Glucono-delta-lactone: 50% survival in bacteria calculated was at 1% (10 μg/mL) test substance and 5% (50 μg/mL) for yeast;
- Sodium gluconate: 50% survival in bacteria calculated was at 0.0024 % test substance and 5% for yeast;
- Calcium gluconate: 50% survival in bacteria calculated was at 5.00 % test substance and 3.00% for yeast.

Tests in suspension without S9 mix: Bacterial plates were scored after incubation for 48 hours at 37°C. The yeast plates were incubated at 30°C for 3-5 days before scoring.

Species / strain:

S. typhimurium, other: TA 1535; TA 1537 and TA 1538

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

cytotoxicity

Vehicle controls validity:

valid

Untreated negative controls validity:

valid

Positive controls validity:

valid

Remarks on result:

other: all strains/cell types tested

Remarks:

Migrated from field 'Test system'.

Cytotoxic concentration (50% survival) (μg/ml):

Sodium gluconate: 0.024 (bacteria), 50 (yeast);

Glucono-delta-lactone: 10 (bacteria), 50 (yeast);

Caclium gluconate: 50 (bacteria), 30 (yeast).

Conclusions:

The available in vitro mutagenicity data with glucono-delta-lactone, sodium or calcium gluconate were negative.

Executive summary:

Sodium gluconate, glucono-delta-lactone and calcium gluconate were tested on Saccharomyces cerevisiae and Salmonella typhimurium with and without metabolic activation. OECD Guideline 471 was deviated for the number of strains tested and the choice of positive controls. The substances were tested on Saccharomyces cerevisiae (strain D4) and Salmonella typhimurium (3 strains) with and without metabolic activation. Only 3 concentrations were tested where OECD guideline recommends at least 5 concentrations. None of the test substances showed mutagenicity on the strains tested.

Cross-reference 16

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well documented peer-reviewed report.

Reason / purpose for cross-reference:

reference to same study

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reference to same study

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Principles of method if other than guideline:

Repeated toxicity studies were also performed on Beagle dogs with sodium gluconate administered orally for 4 weeks at 500, 1000, 2000 mg/kg bw doses.

GLP compliance:

not specified

Limit test:

no

Species:

dog

Strain:

Beagle

Sex:

not specified

Route of administration:

oral: unspecified

Details on route of administration:

oral administration

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

4 weeks

Frequency of treatment:

not specified (adminstered orally)

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

500 mg/kg bw/day (nominal)

Dose / conc.:

1 000 mg/kg bw/day (nominal)

Dose / conc.:

2 000 mg/kg bw/day (nominal)

No. of animals per sex per dose:

4/sex/group

Control animals:

yes

Details on study design:

- Dose selection rationale: not specified
- Rationale for animal assignment (if not random): not specified
- Rationale for selecting satellite groups: not applicable
- Post-exposure recovery period in satellite groups: not applicable
- Section schedule rationale (if not random): not specified

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Not specified

BODY WEIGHT: Yes / No / Not specified

FOOD EFFICIENCY:
Not specified

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Not specified

CLINICAL CHEMISTRY: Not specified

URINALYSIS: Not specified


NEUROBEHAVIOURAL EXAMINATION: Not specified

IMMUNOLOGY: Not specified

OTHER:

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Other examinations:

not specified

Statistics:

no data

Clinical signs:

no effects observed

Description (incidence and severity):

Increased frequency of vomiting and loose or watery stools were observed in the 1000 and 2000 mg/kg bw dose groups, as compared to controls.

Mortality:

no mortality observed

Description (incidence):

None of the animals died during the period of treatment in any dose group

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No significantly toxicologically changes were detected in the body weight

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No significantly toxicologically changes were detected in the food intake

Food efficiency:

not specified

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

no effects observed

Description (incidence and severity):

No significantly toxicologically changes were detected in the water intake

Ophthalmological findings:

no effects observed

Description (incidence and severity):

No significantly toxicologically changes were detected in the ophthalmologic test

Haematological findings:

no effects observed

Description (incidence and severity):

No significantly toxicologically changes were detected in the haematological test

Clinical biochemistry findings:

not specified

Description (incidence and severity):

No significantly toxicologically changes were detected in the blood chemistry analysis

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

No significantly toxicologically changes were detected in the urinalysis

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 significantly toxicologically changes were detected in the organ weight examination.

Gross pathological findings:

not specified

Description (incidence and severity):

No significantly toxicologically changes were detected in the autopsy examination.

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No significantly toxicologically changes were detected in histopathological examination.

Histopathological findings: neoplastic:

not specified

Other effects:

no effects observed

Description (incidence and severity):

No significantly toxicologically changes were detected in the electrocardiography examination.

Details on results:

Repeated toxicity studies were also performed on Beagle dogs with sodium gluconate administered orally for 4 weeks at 500, 1000, 2000 mg/kg bw. doses. None of the animals died during the period of treatment in any dose group and no significantly toxicologically changes were detected in the body weight, food intake, water intake, urinalysis, haematological test, blood chemistry analysis, ophthalmologic test, electrocardiography, autopsy and organ weight or in histopathological examination. However, increased frequency of vomiting and loose or watery stools were observed in the 1000 and 2000 mg/kg bw. dose groups, as compared to controls.

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical signs

gross pathology

histopathology: non-neoplastic

mortality

ophthalmological examination

organ weights and organ / body weight ratios

urinalysis

water consumption and compound intake

Critical effects observed:

no

Repeated toxicity studies were also performed on Beagle dogs with sodium gluconate administered orally for 4 weeks at 500, 1000, 2000 mg/kg bw doses. None of the animals died during the period of treatment in any dose group and no significantly toxicologically changes were detected in the body weight, food intake, water intake, urinalysis, haematological test, blood chemistry analysis, ophthalmologic test, electrocardiography, autopsy and organ weight or in histopathological examination. However, increased frequency of vomiting and loose or watery stools were observed in the 1000 and 2000 mg/kg bw dose groups, as compared to controls.

On the basis of these results, the non-toxic dose was estimated to be 500 mg/kg bw / day. However, the toxicological effects observed (vomiting, passage of loose or watery stools) were considered extremely slight since other tests did not show the same changes (Okamoto, M. Bozo Research Center, 1995a).

Conclusions:

None of the repeated dose toxicity studies of any duration (4 weeks, 6 months, or 24 months) showed any significant toxicological effects of gluconates. Potential side effects were attributed to high doses of cation intake, evidenced by results from assays designed for the gluconate anion effect specifically. On the basis of these data and considering that gluconates are used as food additives permitted in the EU following the Quantum Satis principle (no maximum level specified), further chronic toxicity tests are considered unnecessary.

Executive summary:

Repeated toxicity studies were also performed on Beagle dogs with sodium gluconate administered orally for 4 weeks at 500, 1000, 2000 mg/kg bw doses. None of the animals died during the period of treatment in any dose group and no significantly toxicologically changes were detected in the body weight, food intake, water intake, urinalysis, haematological test, blood chemistry analysis, ophthalmologic test, electrocardiography, autopsy and organ weight or in histopathological examination. However, increased frequency of vomiting and loose or watery stools were observed in the 1000 and 2000 mg/kg bw dose groups, as compared to controls.

On the basis of these results, the non-toxic dose was estimated to be 500 mg/kg bw / day. However, the toxicological effects observed (vomiting, passage of loose or watery stools) were considered extremely slight since other tests did not show the same changes (Okamoto, M. Bozo Research Center, 1995a).

Cross-reference 17

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well documented peer-reviewed report.

Reason / purpose for cross-reference:

reference to same study

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Principles of method if other than guideline:

Wistar rats were fed for 24 months with a diet containing 2.5% and 10% of glucono-delta-lactone (the total intake of the drug: 1240-1350 mg/kgbw in 2.5% GDL group and 4920-5760 mg/kgbw in the 10 % GDL group).

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

oral: feed

Vehicle:

not specified

Details on oral exposure:

a diet containing 2.5% and 10% of glucono-delta-lactone (the total intake of the drug: 1240-1350 mg/kgbw in 2.5% GDL group and 4920-5760 mg/kgbw in the 10 % GDL group)

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

24 months

Frequency of treatment:

continously

Dose / conc.:

0 mg/kg bw/day (actual dose received)

Dose / conc.:

1 240 mg/kg bw/day (nominal)

Remarks:

1240-1350 mg/kgbw in 2.5% GDL group

Dose / conc.:

4 920 mg/kg bw/day (nominal)

Remarks:

4920-5760 mg/kgbw in the 10 % GDL group

No. of animals per sex per dose:

not specified

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale: not specified
- Rationale for animal assignment (if not random): not specified
- Rationale for selecting satellite groups: not applicable
- Post-exposure recovery period in satellite groups: not applicable
- Section schedule rationale (if not random): not specified

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Not specified

BODY WEIGHT: Not specified

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Not specified

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Not specified

CLINICAL CHEMISTRY: Not specified

URINALYSIS: Not specified

NEUROBEHAVIOURAL EXAMINATION: Not specified

IMMUNOLOGY: Not specified

OTHER:

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Other examinations:

not specified

Statistics:

no data

Clinical signs:

no effects observed

Description (incidence and severity):

no changes were observed in the general condition throughout the period of testing

Mortality:

no mortality observed

Description (incidence):

There was no statistically significant difference in the number and time of deaths between the treated and control groups.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

weight gain tended to be slightly reduced 2-3 months after the initiation of the test feeding in 10% GDL group

Food consumption and compound intake (if feeding study):

not examined

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 specified

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

Histopathological changes accompanying aging were observed in all groups including the controls, but no specific changes likely to be associated with the test substance were detected (Fukuhara K, 1978a).

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Details on results:

In Wistar rats fed for 24 months with a diet containing 2.5% and 10% of glucono-delta-lactone (the total intake of the drug: 1240-1350 mg/kgbw in 2.5% GDL group and 4920-5760 mg/kgbw in the 10 % GDL group), no changes were observed in the general condition throughout the period of testing, but weight gain tended to be slightly reduced 2-3 months after the initiation of the test feeding in 10% GDL group. There was no statistically significant difference in the number and time of deaths between the treated and control groups. Histopathological changes accompanying aging were observed in all groups including the controls, but no specific changes likely to be associated with the test substance were detected (Fukuhara K, 1978a).

Dose descriptor:

NOAEL

Remarks on result:

not determinable

Critical effects observed:

no

In Wistar rats fed for 24 months with a diet containing 2.5% and 10% of glucono-delta-lactone (the total intake of the drug: 1240-1350 mg/kgbw in 2.5% GDL group and 4920-5760 mg/kgbw in the 10 % GDL group), no changes were observed in the general condition throughout the period of testing, but weight gain tended to be slightly reduced 2-3 months after the initiation of the test feeding in 10% GDL group. There was no statistically significant difference in the number and time of deaths between the treated and control groups. Histopathological changes accompanying aging were observed in all groups including the controls, but no specific changes likely to be associated with the test substance were detected (Fukuhara K, 1978a).

Conclusions:

None of the repeated dose toxicity studies of any duration (4 weeks, 6 months, or 24 months) showed any significant toxicological effects of gluconates. Potential side effects were attributed to high doses of cation intake, evidenced by results from assays designed for the gluconate anion effect specifically. The NOAEL of sodium gluconate determined from the 28 days studies on rats was equal to 1000 mg/kg bw for males and 2000 mg/kg bw for females. On the basis of these data and considering that gluconates are used as food additives permitted in the EU following the Quantum Satis principle (no maximum level specified), further chronic toxicity tests are considered unnecessary.

Executive summary:

In Wistar rats fed for 24 months with a diet containing 2.5% and 10% of glucono-delta-lactone (the total intake of the drug: 1240-1350 mg/kgbw in 2.5% GDL group and 4920-5760 mg/kgbw in the 10 % GDL group), no changes were observed in the general condition throughout the period of testing, but weight gain tended to be slightly reduced 2-3 months after the initiation of the test feeding in 10% GDL group. There was no statistically significant difference in the number and time of deaths between the treated and control groups. Histopathological changes accompanying aging were observed in all groups including the controls, but no specific changes likely to be associated with the test substance were detected (Fukuhara K, 1978a).

Cross-reference 18

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well documented peer-reviewed report.

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

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:

equivalent or similar to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Principles of method if other than guideline:

A 28-day oral feeding study was conducted rats with sodium gluconate at doses of 0, 1000, 2000 and 4100 mg/kg bw.

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: feed

Details on route of administration:

oral feeding

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

28 days

Frequency of treatment:

once daily

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

1 000 mg/kg bw/day (nominal)

Dose / conc.:

2 000 mg/kg bw/day (nominal)

Dose / conc.:

4 100 mg/kg bw/day (nominal)

No. of animals per sex per dose:

10/sex/group

Control animals:

yes

Details on study design:

- Dose selection rationale: not specified
- Rationale for animal assignment (if not random): not specified
- Rationale for selecting satellite groups: not applicable
- Post-exposure recovery period in satellite groups: not applicable
- Section schedule rationale (if not random): not specified

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Not specified

BODY WEIGHT: Not specified

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Not specified

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Not specified

CLINICAL CHEMISTRY: Not specified

URINALYSIS: Not specified

NEUROBEHAVIOURAL EXAMINATION: Not specified

IMMUNOLOGY: Not specified

OTHER:

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Other examinations:

not specified

Statistics:

no data

Clinical signs:

no effects observed

Description (incidence and severity):

No revisions in the general condition were observed in the animals over the study period.

Mortality:

no mortality observed

Description (incidence):

No deaths occurred during the study period.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No revisions in the body weight were observed in the animals over the study period.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No revisions in the food intake were observed in the animals over the study period.

Food efficiency:

not specified

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

no effects observed

Description (incidence and severity):

No revisions in the water intake were observed in the animals over the study period.

Ophthalmological findings:

no effects observed

Description (incidence and severity):

No changes were observed in the investigated ophthalmologic tests

Haematological findings:

no effects observed

Description (incidence and severity):

No changes were observed in the investigated hematology

Clinical biochemistry findings:

not specified

Description (incidence and severity):

No changes were observed in the investigated blood chemistry

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

Statistically significant differences in some urinary parameters reported in animals receiving 2.5 or 5% sodium gluconate were comparable to those observed in the NaCl control group, and were interpreted as related to the high sodium concentration of the diet.

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 specified

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Histopathological examination indicated no adverse effects as a result of the treatment regime

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Details on results:

No deaths occurred during the study period. No revisions in the general condition, body weight, or food and water intake were observed in the animals over the study period. No changes were observed in the investigated ophthalmologic tests, urinalysis, hematology and blood chemistry over the study period. In addition, histopathological examination indicated no adverse effects as a result of the treatment regime. Statistically significant differences in some urinary parameters reported in animals receiving 2.5 or 5% sodium gluconate were comparable to those observed in the NaCl control group, and were interpreted as related to the high sodium concentration of the diet.

Dose descriptor:

NOAEL

Effect level:

4 100 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

clinical signs

gross pathology

histopathology: non-neoplastic

mortality

ophthalmological examination

organ weights and organ / body weight ratios

urinalysis

water consumption and compound intake

Remarks on result:

other: 5% w/w sodium gluconate (max. 4100 mg/kg bw for males and 4400 mg/kg bw for females)

Dose descriptor:

NOAEL

Effect level:

4 400 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

body weight and weight gain

clinical signs

gross pathology

histopathology: non-neoplastic

mortality

ophthalmological examination

organ weights and organ / body weight ratios

urinalysis

water consumption and compound intake

Remarks on result:

other: 5% w/w sodium gluconate (max. 4100 mg/kg bw for males and 4400 mg/kg bw for females)

Critical effects observed:

no

A 28-day toxicity study in rats fed with a diet containing up to 5% w/w sodium gluconate (max. 4100 mg/kg bw for males and 4400 mg/kg bw for females) was conducted using a control group receiving equivalent concentration of sodium in the form of NaCl in order to differentiate the potential effects of high doses of sodium intake. No deaths occurred during the study period. No revisions in the general condition, body weight, or food and water intake were observed in the animals over the study period. No changes were observed in the investigated ophthalmologic tests, urinalysis, hematology and blood chemistry over the study period. In addition, histopathological examination indicated no adverse effects as a result of the treatment regime. Statistically significant differences in some urinary parameters reported in animals receiving 2.5 or 5% sodium gluconate were comparable to those observed in the NaCl control group, and were interpreted as related to the high sodium concentration of the diet.

The authors concluded that the NOAEL was 5% (equal to 4100 mg/kg bw per day). However, The JECFA committee who evaluated this report has concluded that the study was not suitable for identifying a NOAEL because of the small group sizes and the positive findings in the qualitative analysis, even if they have acknowledged that the effects shown in the qualitative urine analyses were related to the high sodium intake (Mochizuki, M. Bozo Research Center, 1997). Nonetheless, this study demonstrates the lack of effects of the gluconate anion even in large doses as the urinary effects were attributed to the high sodium intake and was therefore considered as critical for this endpoint.

Conclusions:

None of the repeated dose toxicity studies of any duration (4 weeks, 6 months, or 24 months) showed any significant toxicological effects of gluconates. Potential side effects were attributed to high doses of cation intake, evidenced by results from assays designed for the gluconate anion effect specifically. On the basis of these data and considering that gluconates are used as food additives permitted in the EU following the Quantum Satis principle (no maximum level specified), further chronic toxicity tests are considered unnecessary.

Executive summary:

Another 28-day toxicity study in rats fed with a diet containing up to 5% w/w sodium gluconate (max. 4100 mg/kg bw for males and 4400 mg/kg bw for females) was conducted using a control group receiving equivalent concentration of sodium in the form of NaCl in order to differentiate the potential effects of high doses of sodium intake. No deaths occurred during the study period. No revisions in the general condition, body weight, or food and water intake were observed in the animals over the study period. No changes were observed in the investigated ophthalmologic tests, urinalysis, hematology and blood chemistry over the study period. In addition, histopathological examination indicated no adverse effects as a result of the treatment regime. Statistically significant differences in some urinary parameters reported in animals receiving 2.5 or 5% sodium gluconate were comparable to those observed in the NaCl control group, and were interpreted as related to the high sodium concentration of the diet.

The authors concluded that the NOAEL was 5% (equal to 4100 mg/kg bw per day). However, the JECFA committee who evaluated this report has concluded that the study was not suitable for identifying a NOAEL because of the small group sizes and the positive findings in the qualitative analysis, even if they have acknowledged that the effects shown in the qualitative urine analyses were related to the high sodium intake (Mochizuki, M. Bozo Research Center, 1997). Nonetheless, this study demonstrates the lack of effects of the gluconate anion even in large doses as the urinary effects were attributed to the high sodium intake and was therefore considered as critical for this endpoint.

Cross-reference 19

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well documented peer-reviewed report.

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

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Principles of method if other than guideline:

A 28-day study was conducted by feeding rats by gavage with sodium gluconate at doses of 0, 500, 1000, 2000 mg/kg bw in water at a volume of 1 ml/ 100g bw.

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Route of administration:

oral: gavage

Details on route of administration:

feeding by gavage in water at a volume of 1 mL/ 100g bw.

Vehicle:

water

Details on oral exposure:

feeding by gavage in water at a volume of 1 mL/ 100g bw.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

28 days

Frequency of treatment:

once daily

Dose / conc.:

0 mg/kg bw/day (actual dose received)

Dose / conc.:

500 mg/kg bw/day (actual dose received)

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

Dose / conc.:

2 000 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

12/sex/group

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale: not specified
- Rationale for animal assignment (if not random): not specified
- Rationale for selecting satellite groups: not applicable
- Post-exposure recovery period in satellite groups: not applicable
- Section schedule rationale (if not random): not specified

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Not specified

BODY WEIGHT: Not specified

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Not specified

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Not specified

CLINICAL CHEMISTRY: Not specified

URINALYSIS: Not specified

NEUROBEHAVIOURAL EXAMINATION: Not specified

IMMUNOLOGY: Not specified

OTHER:

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Other examinations:

not specified

Statistics:

no data

Clinical signs:

no effects observed

Description (incidence and severity):

No death or clinical signs of abnormality were observed in any of the groups.

Mortality:

no mortality observed

Description (incidence):

No death or clinical signs of abnormality were observed in any of the groups.

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not specified

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

no effects 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:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

Histopathological examination showed a thickening of the limiting ridge of the stomach in 5 out of 12 males at 2000 mg/kg bw per day dose. No toxic changes associated with the test article were detected. As the limiting ridge is a tissue specific to rodents, this lesion is not toxicologically relevant for humans. Other lesions occurred incidentally and were not treatment-related.

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

clinical signs

histopathology: non-neoplastic

mortality

Dose descriptor:

NOAEL

Effect level:

2 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

clinical signs

histopathology: non-neoplastic

mortality

Critical effects observed:

no

A 28-day study was conducted by feeding rats by gavage with sodium gluconate at doses of 0, 500, 1000, 2000 mg/kg bw in water at a volume of 1 mL/ 100g bw. No death or clinical signs of abnormality were observed in any of the groups. Histopathological examination showed a thickening of the limiting ridge of the stomach in 5 out of 12 males at 2000 mg/kg bw per day dose. No toxic changes associated with the test article were detected. As the limiting ridge is a tissue specific to rodents, this lesion is not toxicologically relevant for humans. Other lesions occurred incidentally and were not treatment -related.

The NOAEL was estimated to be 1000 mg/kg bw/day for males and 2000 mg/kg bw/day for female (Mochizuki, M, Bozo Research Center, 1995a).

Conclusions:

None of the repeated dose toxicity studies of any duration (4 weeks, 6 months, or 24 months) showed any significant toxicological effects of gluconates. Potential side effects were attributed to high doses of cation intake, evidenced by results from assays designed for the gluconate anion effect specifically. The NOAEL of sodium gluconate determined from the 28 days studies on rats was equal to 1000 mg/kg bw for males and 2000 mg/kg bw for females. On the basis of these data and considering that gluconates are used as food additives permitted in the EU following the Quantum Satis principle (no maximum level specified), further chronic toxicity tests are considered unnecessary.

Executive summary:

A 28-day study was conducted by feeding rats by gavage with sodium gluconate at doses of 0, 500, 1000, 2000 mg/kg bw in water at a volume of 1 mL/ 100g bw. No death or clinical signs of abnormality were observed in any of the groups. Histopathological examination showed a thickening of the limiting ridge of the stomach in 5 out of 12 males at 2000 mg/kg bw per day dose. No toxic changes associated with the test article were detected. As the limiting ridge is a tissue specific to rodents, this lesion is not toxicologically relevant for humans. Other lesions occurred incidentally and were not treatment -related. The NOAEL was estimated to be 1000 mg/kg bw/day for males and 2000 mg/kg bw/day for female (Mochizuki, M, Bozo Research Center, 1995a).

Cross-reference 20

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well documented peer-reviewed report.

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

Principles of method if other than guideline:

Glucono-delta-lactone (250, 500, 1000, 2000 and 4000 mg/kgbw for 6 months) was orally administered to Sprague-Dawley rats.

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: unspecified

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

6 months

Frequency of treatment:

not specified

Dose / conc.:

0 mg/kg bw/day (actual dose received)

Dose / conc.:

250 mg/kg bw/day (nominal)

Dose / conc.:

500 mg/kg bw/day (nominal)

Dose / conc.:

1 000 mg/kg bw/day (nominal)

Dose / conc.:

2 000 mg/kg bw/day (nominal)

Dose / conc.:

4 000 mg/kg bw/day (nominal)

No. of animals per sex per dose:

not specified

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale: not specified
- Rationale for animal assignment (if not random): not specified
- Rationale for selecting satellite groups: not applicable
- Post-exposure recovery period in satellite groups: not applicable
- Section schedule rationale (if not random): not specified

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Not specified

BODY WEIGHT: Not specified

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Not specified

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Not specified

CLINICAL CHEMISTRY: Not specified

URINALYSIS: Not specified

NEUROBEHAVIOURAL EXAMINATION: Not specified

IMMUNOLOGY: Not specified

OTHER:

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Other examinations:

not specified

Statistics:

no data

Clinical signs:

no effects observed

Description (incidence and severity):

No deaths or other abnormalities were detected

Mortality:

no mortality observed

Description (incidence):

No deaths or other abnormalities were detected

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not examined

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 specified

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

In all dose groups, thickening of the stratified squamous epithelium was detected at the anterior stomach, particularly the transitional area continuous with the pyloric stomach; the frequency and severity of this thickening increased with the dose. In high dose groups, submucosal inflammatory cell infiltration was also detected, but this change was not statistically significant.

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Details on results:

In all dose groups, thickening of the stratified squamous epithelium was detected at the anterior stomach, particularly the transitional area continuous with the pyloric stomach; the frequency and severity of this thickening increased with the dose. In high dose groups, submucosal inflammatory cell infiltration was also detected, but this change was not statistically significant. No deaths or other abnormalities were detected (Fukuhara K, 1978).

Dose descriptor:

NOAEL

Remarks on result:

not determinable due to absence of adverse toxic effects

Critical effects observed:

no

Glucono-delta-lactone (250, 500, 1000, 2000 and 4000 mg/kgbw for 6 months) was orally administered to Sprague-Dawley rats. In all dose groups, thickening of the stratified squamous epithelium was detected at the anterior stomach, particularly the transitional area continuous with the pyloric stomach; the frequency and severity of this thickening increased with the dose. In high dose groups, submucosal inflammatory cell infiltration was also detected, but this change was not statistically significant. No deaths or other abnormalities were detected (Fukuhara K, 1978). In Wistar rats fed for 24 months with a diet containing 2.5% and 10% of glucono-delta-lactone (the total intake of the drug: 1240-1350 mg/kgbw in 2.5% GDL group and 4920-5760 mg/kgbw in the 10 % GDL group), no changes were observed in the general condition throughout the period of testing, but weight gain tended to be slightly reduced 2-3 months after the initiation of the test feeding in 10% GDL group. There was no statistically significant difference in the number and time of deaths between the treated and control groups. Histopathological changes accompanying aging were observed in all groups including the controls, but no specific changes likely to be associated with the test substance were detected (Fukuhara K, 1978a).

Conclusions:

None of the repeated dose toxicity studies of any duration (4 weeks, 6 months, or 24 months) showed any significant toxicological effects of gluconates. Potential side effects were attributed to high doses of cation intake, evidenced by results from assays designed for the gluconate anion effect specifically. The NOAEL of sodium gluconate determined from the 28 days studies on rats was equal to 1000 mg/kg bw for males and 2000 mg/kg bw for females. On the basis of these data and considering that gluconates are used as food additives permitted in the EU following the Quantum Satis principle (no maximum level specified), further chronic toxicity tests are considered unnecessary.

Executive summary:

Glucono-delta-lactone (250, 500, 1000, 2000 and 4000 mg/kgbw. for 6 months) was orally administered to Sprague-Dawley rats. In all dose groups, thickening of the stratified squamous epithelium was detected at the anterior stomach, particularly the transitional area continuous with the pyloric stomach; the frequency and severity of this thickening increased with the dose. In high dose groups, submucosal inflammatory cell infiltration was also detected, but this change was not statistically significant. No deaths or other abnormalities were detected (Fukuhara K, 1978). In Wistar rats fed for 24 months with a diet containing 2.5% and 10% of glucono-delta-lactone (the total intake of the drug : 1240-1350 mg/kgbw in 2.5% GDL group and 4920-5760 mg/kgbw in the 10 % GDL group), no changes were observed in the general condition throughout the period of testing, but weight gain tended to be slightly reduced 2-3 months after the initiation of the test feeding in 10% GDL group. There was no statistically significant difference in the number and time of deaths between the treated and control groups. Histopathological changes accompanying aging were observed in all groups including the controls, but no specific changes likely to be associated with the test substance were detected (Fukuhara K, 1978a).

Cross-reference 21

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

short-term toxicity to aquatic invertebrates

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: OECD guideline study; GLP compliance; read-across

Qualifier:

according to guideline

Guideline:

OECD Guideline 202 (Daphnia sp. Acute Immobilisation Test)

Deviations:

no

GLP compliance:

not specified

Remarks:

The study reviewed in this report was stated to be GLP-compliant.

Specific details on test material used for the study:

Details on properties of test surrogate or analogue material (migrated information):
No details on properties are given.

Analytical monitoring:

yes

Details on sampling:

No details given.

Vehicle:

not specified

Details on test solutions:

Dilution water source: OECD M4 medium.

Test organisms (species):

Daphnia magna

Details on test organisms:

TEST ORGANISM
- Source: GSF Institute of Ecological Chemistry, Germany
- Age at study initiation (mean and range, SD): juveniles within 24 hours old

Test type:

static

Water media type:

freshwater

Limit test:

no

Total exposure duration:

48 h

Post exposure observation period:

Not reported.

Hardness:

247 mg/L as CaCO3

Test temperature:

21 ±0.5°C

pH:

5.92 – 8.41

Dissolved oxygen:

84–99 %

Salinity:

Not applicable.

Nominal and measured concentrations:

Measured concentrations were 3.93, 7.14, 14.0, 24.2, 44.7 and 83.6 mg/L (Nominal concentrations at 3, 6, 12, 23, 45 and 90 mg/L).

Details on test conditions:

TEST SYSTEM
- No. of organisms per vessel: 10
- No. of replicates: 3 replicates per 10 organisms were used

OTHER TEST CONDITIONS
- Adjustment of pH: no (The pH of test solutions remained neutral due to the buffering action of M4 medium.)
- Photoperiod: 16/8 (light/dark)
- Light intensity: 620 – 630 Lux

TEST CONCENTRATIONS
- Test concentrations: 0 (control), 3, 6, 12, 23, 45, 90 mg/L (nominal concentrations)

Reference substance (positive control):

not required

Duration:

48 h

Dose descriptor:

EC50

Effect conc.:

19 mg/L

Nominal / measured:

not specified

Conc. based on:

test mat.

Basis for effect:

mobility

Remarks on result:

other: EC50 value with 95 % confidence limit was 15 – 25 mg/L.

Details on results:

No details given.

Results with reference substance (positive control):

Not applicable.

Reported statistics and error estimates:

EC50 value and 95 % confidence limit were calculated by Probit method (EPA/600/4-85/13, 1985).

Table 1. The results of cumulative immobilization data for Daphnia magna

Nominal concentrations (mg/L)	Measured concentrations (mg/L)	Number of organisms tested	Cumulative number of organisms immobilized
			24 hrs	48 hrs
Control	Control	30	0	0
3	3.93	30	0	4
6	7.14	30	0	5
12	14.0	30	0	11
23	24.2	30	0	13
45	44.7	30	12	23
90	83.6	30	30	30

Table 2. pH of test condition

Nominal concentrations (mg/L)	Measured Concentrations (mg/L)	0 hr	48 hrs
Control	Control	8.41	7.93
3	3.93	7.78	7.98
6	7.14	7.50	7.98
12	14.0	7.09	7.93
23	24.2	6.68	7.79
45 90	44.7 83.6	6.24 5.92	7.30

Validity criteria fulfilled:

yes

Remarks:

no immobilisation in control group; Dissolved oxygen concentration 84–99 %

Conclusions:

EC50 (48 h) = 19 mg FeCl2/L

Executive summary:

The acute toxicity of the read-across substance Iron dichloride (CAS 7758-94-3) towards Daphnia magna was determined according to OECD Guideline 202 in compliance with GLP. The following test concentrations have been used: 0 (control), 3, 6, 12, 23, 45 and 90 mg/L (based on nominal concentrations). Measured concentrations were 3.93, 7.14, 14.0, 24.2, 44.7 and 83.6 mg/L (Method applied: ICP-AES). The test organisms (3 replicates/concentration, 10 daphnids/vessel) were exposed for 48 h to the test substance. The EC50 (48 h) value based on mobility was determined to be 19 mg/L. EC50 (48 h) with 95 % confidence limit was 15 – 25 mg/L. EC50 value and 95 % confidence limit were calculated by Probit method (EPA/600/4-85/13, 1985).

Cross-reference 22

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

short-term toxicity to aquatic invertebrates

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: study conducted according to OECD guidelines; quality assurance and GLP certificates; read-across

Qualifier:

according to guideline

Guideline:

OECD Guideline 202 (Daphnia sp. Acute Immobilisation Test)

Deviations:

no

GLP compliance:

not specified

Remarks:

Study was stated to be GLP-compliant in the review

Specific details on test material used for the study:

Details on properties of test surrogate or analogue material (migrated information):
No details given.

Analytical monitoring:

yes

Details on sampling:

No details given.

Vehicle:

not specified

Details on test solutions:

No details given.

Test organisms (species):

Daphnia magna

Details on test organisms:

TEST ORGANISM
- Source: National Institute for Environmental Studies, Japan
- Age and gender: female juvenile (less than 24 hours)

Test type:

static

Water media type:

freshwater

Limit test:

yes

Total exposure duration:

48 h

Post exposure observation period:

No details given.

Hardness:

No details given.

Test temperature:

20 +/- 1°C

pH:

No details given.

Dissolved oxygen:

≥ 60% of the saturation

Salinity:

Not applicable.

Nominal and measured concentrations:

Measured concentrations of the test substance in the test solution were within +/- 20% of the nominal concentration in all concentrations.

Details on test conditions:

TEST SYSTEM
- No. of vessels/concentration: 2 (range-finding test)
- Biomass loading rate: 10 daphnids/concentration (range-finding test)

OTHER TEST CONDITIONS
- Photoperiod: fluorescent light, 16 hours light (below 800 lux)/8 hours dark

TEST CONCENTRATIONS
- Range finding study
- Results used to determine the conditions for the definitive study: yes

TEST MEDIUM
- Dilution water (Elendt M4) recommended by OECD guidelines for testing of chemicals No. 211 was used.

Reference substance (positive control):

not required

Duration:

48 h

Dose descriptor:

NOEC

Effect conc.:

> 1 000 mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

not specified

Duration:

48 h

Dose descriptor:

EC100

Effect conc.:

> 1 000 mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

not specified

Duration:

48 h

Dose descriptor:

EC50

Effect conc.:

> 1 000 mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

not specified

Duration:

24 h

Dose descriptor:

NOEC

Effect conc.:

> 1 000 mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

not specified

Duration:

24 h

Dose descriptor:

EC100

Effect conc.:

> 1 000 mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

not specified

Duration:

24 h

Dose descriptor:

EC50

Effect conc.:

> 1 000 mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

not specified

Details on results:

No details given.

Results with reference substance (positive control):

Not applicable.

Reported statistics and error estimates:

No details given.

Validity criteria fulfilled:

not specified

Remarks:

immobilised daphnids in the control not reported

Conclusions:

EC50/NOEC (48 h) > 1000 mg/L (based on nominal concentration)

Executive summary:

The acute toxicity of the read-across substance Sodium gluconate (CAS 527-07-1) towards Daphnia magna has been determined according to OECD Guideline 202 in compliance with GLP. After the range-finding study (2 vessels/concentration, 10 daphnids/concentration), the definitive test was conducted with test concentrations of 0 (control) and 1000 mg/L (limit test). The measured concentrations of the test substance in the test solution were within +/- 20% of the nominal concentration in all concentrations (HPLC technique has been used).

The EC50/NOEC (48 h) value amounts to > 1000 mg/L based on the nominal test concentration.

Cross-reference 23

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

short-term toxicity to aquatic invertebrates

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: study conducted according to OECD guidelines; quality assurance and GLP certificates; read-across

Qualifier:

according to guideline

Guideline:

OECD Guideline 202 (Daphnia sp. Acute Immobilisation Test)

Deviations:

no

GLP compliance:

not specified

Remarks:

The study reviewed in the report was stated to be GLP-compliant.

Specific details on test material used for the study:

Details on properties of test surrogate or analogue material (migrated information):
No details given.

Analytical monitoring:

yes

Details on sampling:

No details given.

Vehicle:

not specified

Details on test solutions:

A limit test with 1000 mg/L was conducted: a solution of 100.5 mg in 100 mL or 1005 mg/L was prepared and distributed to 4 beakers.

Test organisms (species):

Daphnia magna

Details on test organisms:

TEST ORGANISM
- Strain and source: Daphnia magna Straus origin from a clone breeding of the German Federal Environmental Agency, department V 3.2. 
- Age at study initiation: 2-23 h; Before using, the new young Daphnia were held at 20°C for 2 hours to ensure that none of them was younger than 2 h.

Test type:

static

Water media type:

freshwater

Limit test:

yes

Total exposure duration:

48 h

Post exposure observation period:

No details given.

Hardness:

No details given.

Test temperature:

Temperature in the incubator was stable at 20°C during the test period.

pH:

pH difference between beginning and end of test = 0.2 units.

Dissolved oxygen:

Oxygen concentration was 95% of the start concentration. 

Salinity:

Not applicable.

Nominal and measured concentrations:

The stability of the investigated concentration of sodium D-gluconate during testing was also examined via enzymatic analysis.  The test concentration did not decrease during the test period.

Details on test conditions:

TEST SYSTEM
- Test vessel: beaker
- No. of organisms per vessel: 5

OTHER TEST CONDITIONS
- Light intensity: complete darkness for 48 hours

EFFECT PARAMETERS MEASURED (with observation intervals if applicable):
- After 24 and 48 h, the swimming capability of the daphnia was observed.  An animal not swimming within 15 seconds after gently moving the beaker was considered immobile. After 48 h, the oxygen concentration and the pH was measured.

TEST CONCENTRATIONS
- Test concentrations: 0 (control) and 1000 mg/L

Reference substance (positive control):

yes

Remarks:

Potassium dichromate

Duration:

48 h

Dose descriptor:

EC0

Effect conc.:

> 1 000 mg/L

Nominal / measured:

not specified

Conc. based on:

test mat.

Basis for effect:

mobility

Duration:

24 h

Dose descriptor:

EC0

Effect conc.:

> 1 000 mg/L

Nominal / measured:

not specified

Conc. based on:

test mat.

Basis for effect:

mobility

Details on results:

No details given.

Results with reference substance (positive control):

Quality Assurance takes place in regular intervals using a concentration range of Potassium dichromate.  Last quality check was January 2001 and EC50 was between 1.16and 2.32 mg/L (required: 0.6-2.4 mg/L).

Reported statistics and error estimates:

No details given.

At 1000 mg/L, all daphnia kept their swimming capability.

Validity criteria fulfilled:

not specified

Remarks:

immobilised daphnids in the control not reported

Conclusions:

EC0 (48 h) > 1000 mg/L

Executive summary:

The acute toxicity of the read-across substance Sodium gluconate (CAS 527-07-1) towards Daphnia magna was determined according to OECD Guideline 202 in compliance with GLP. A limit test with 1000 mg/L was conducted. The test organisms (5 daphnids/vessel) were exposed for 48 h to the test substance. The EC50 (48 h) value based on mobility was determined to be > 1000 mg/L. Toxic effects were not observed.

Cross-reference 24

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

short-term toxicity to fish

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: OECD guideline study; GLP compliance; read-across

Qualifier:

according to guideline

Guideline:

OECD Guideline 203 (Fish, Acute Toxicity Test)

Deviations:

no

GLP compliance:

not specified

Remarks:

the study reviewed in the report was stated to be GLP-compliant

Specific details on test material used for the study:

No details on properties are given.

Analytical monitoring:

yes

Details on sampling:

No details given.

Vehicle:

not specified

Details on test solutions:

No details given.

Test organisms (species):

Oryzias latipes

Details on test organisms:

TEST ORGANISM
- Age at study initiation (mean and range, SD): 4 months
- Length at study initiation (length definition, mean, range and SD): 2.9 ± 0.1 cm
- Weight at study initiation (mean and range, SD): 0.22 ± 0.03 g

ACCLIMATION
- Acclimation period: Fish were acclimated for 7 days before test. No food was fed before 1 day and during test.

Test type:

static

Water media type:

freshwater

Limit test:

no

Total exposure duration:

96 h

Post exposure observation period:

Not reported.

Hardness:

34 mg/L as CaCO3

Test temperature:

23.7 ± 0.3 °C

pH:

3.50 – 7.42

Dissolved oxygen:

65 – 97 %

Salinity:

Not applicable.

Nominal and measured concentrations:

Measured concentrations were 11.7, 16.5, 24.0, 34.4, 62.6 and 99.2 mg/L (nominal concentrations at 10, 15, 24, 39, 63 and 100 mg/L).

Details on test conditions:

TEST SYSTEM
- Test vessel: 8.7 L aquarium with 5 L test solution
- No. of organisms per vessel: 7


TEST MEDIUM / WATER PARAMETERS
- Source/preparation of dilution water: Tap water passed through activated carbon and membrane filter (1 μm)
- Alkalinity: 24 mg/L as CaCO3

OTHER TEST CONDITIONS
- Adjustment of pH: no
- Photoperiod: 16/8 (light/dark)
- Light intensity: 890 – 1,030 Lux

TEST CONCENTRATIONS
- Test concentrations: 10, 15, 24, 39, 63 and 100 mg/L

Reference substance (positive control):

not required

Duration:

96 h

Dose descriptor:

LC50

Effect conc.:

46.6 mg/L

Nominal / measured:

meas. (not specified)

Conc. based on:

test mat.

Basis for effect:

mortality (fish)

Remarks on result:

other: 95% CL: 36.1 – 61.5 mg/L

Details on results:

- Mortality of control: No dead fish.

Results with reference substance (positive control):

Not reported.

Reported statistics and error estimates:

LC50 value and 95 % confidence limit were calculated by Probit method (EPA/600/4-85/13, 1985).

Sublethal observations / clinical signs:

Table 1. Cumulative mortality of Oryzias latipes

Nominal concentrations (mg/L)	Measured concentrations (mg/L)	Number of organisms tested	Cumulative number of dead fish
			24 hrs	48 hrs	72 hrs	96 hrs
Control	Control	7	0	0	0	0
10	11.7	7	0	0	0	0
15	16.5	7	0	0	0	0
24	24.0	7	0	0	0	0
39	34.4	7	0	0	0	1
63	62.6	7	0	0	1	6
100	99.2	7	2	4	7	7

Table 2. pH of test solutions

Nominal concentrations (mg/L)	Measured concentrations (mg/L)	0 hr	24 hrs	48 hrs	72 hrs	96 hrs
Control	Control	7.42	7.15	7.17	7.25	7.27
10	11.7	6.75	7.00	7.07	7.09	7.17
15	16.5	6.58	6.82	6.97	7.01	7.07
24	24.0	6.36	6.49	6.65	6.67	6.80
39	34.4	6.11	5.89	5.34	4.11	4.19
63	62.6	5.93	5.61	4.72	3.65	3.50
100	99.2	5.71	5.53	4.21	-	-

Table 3. The results of acute toxicity test with pH adjustment

Nominal concentrations (mg/L)	pH	Number of organisms tested	Cumulative number of dead fish
			24 hrs	48 hrs	72 hrs	96 hrs
100	3.50	5	5	5	5	5
100	4.00	5	0	0	0	0
100	4.50	5	0	0	0	0
100	5.00	5	0	0	0	0
100	5.50	5	0	0	0	0
100	6.00	5	0	0	0	0

When iron dichloride was dissolved in water, the test solution became acidic. So, a preliminary test was conducted to evaluate the effect of pH on fish. 100 mg/L of iron dichloride was dissolved and pH of the test solutions were adjusted to 3.5, 4.0, 4.5, 5.0, 5.5 and 6.0. A group of 5 fish was used without duplication. The mortality was affected at pH 3.5 only. Therefore, mortality increase in 62.6 mg/L at 96 hours was due to the low pH.

Validity criteria fulfilled:

yes

Remarks:

Validity criteria (e.g. mortality in the control, constant conditions, dissolved oxygen concentration, concentration of the test substance) were met.

Conclusions:

LC50 (96 h) = 46.6 mg/L (based on measured concentration)

Executive summary:

The acute toxicity of the read-across substance Iron dichloride (CAS 7758-94-3) towards fish was determined according to OECD Guideline 203 in compliance with GLP. The following test concentrations have been used: 0 (control), 10, 15, 24, 39, 63 and 100 mg/L (based on nominal concentrations). Measured concentrations were 11.7, 16.5, 24.0, 34.4, 62.6 and 99.2 mg/L (Method applied: ICP-AES). Oryzias latipes was chosen as test organism which was exposed for 96 h to the test substance. 7 fish were tested for each concentration (incl. control). At 39 mg/L test concentration, one dead fish was observed after 96 hours. At 63 mg/L, 6 dead fish were observed after 96 hours. At 100 mg/L, all fish died after 96 hours.

When iron dichloride was dissolved in water, the test solution became acidic. The influence of the pH value on the mortality of the fish has, thus, been evaluated as well. The mortality was affected at pH 3.5 only. Therefore, mortality increase in 63 mg/L at 96 hours was due to the low pH. The LC50 (96 h) value was determined to be 46.6 mg/L (based on measured concentration). LC50 (96 h) with 95 % confidence limit was 36.1 – 61.5 mg/L.

Cross-reference 25

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

short-term toxicity to fish

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: study conducted according to OECD guidelines; quality assurance and GLP certificates; read-across

Qualifier:

according to guideline

Guideline:

OECD Guideline 203 (Fish, Acute Toxicity Test)

Deviations:

no

GLP compliance:

yes

Specific details on test material used for the study:

No details given.

Analytical monitoring:

yes

Details on sampling:

No details given.

Vehicle:

not specified

Details on test solutions:

No details given.

Test organisms (species):

Oryzias latipes

Details on test organisms:

No details given.

Test type:

semi-static

Water media type:

freshwater

Limit test:

yes

Total exposure duration:

96 h

Post exposure observation period:

No details provided.

Hardness:

No details provided.

Test temperature:

24 +/- 1°C

pH:

min: 7.1 - max : 7.6

Dissolved oxygen:

Dissolved oxygen concentrations were over 60% of the saturation value (8.25 mg/L at 24.0°C)

Salinity:

Not applicable.

Nominal and measured concentrations:

Measured concentrations of the test substance were within +/- 20% of the nominal concentrations.

Details on test conditions:

TEST SYSTEM
- No. of organisms per vessel: 5 (range finding test)
- Biomass loading rate: 10 fish/concentration (definitive test)

OTHER TEST CONDITIONS
- Photoperiod: fluorescent light; 16 hours light/8 hours dark

EFFECT PARAMETERS MEASURED (with observation intervals if applicable): toxicological symptoms and deaths

TEST CONCENTRATIONS
- Range finding study
- Results used to determine the conditions for the definitive study: yes

Reference substance (positive control):

not required

Duration:

96 h

Dose descriptor:

NOEC

Effect conc.:

> 100 mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

other: mortality and toxicological symptoms

Duration:

96 h

Dose descriptor:

LC0

Effect conc.:

> 100 mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

other: mortality and toxicological symptoms

Details on results:

No details provided.

Results with reference substance (positive control):

No data.

Reported statistics and error estimates:

None reported.

Sublethal observations / clinical signs:

Measured concentrations of the test substance were within +/- 20% of the nominal concentrations. Results were based on the nominal concentrations.

No toxicological symptoms nor any death were observed at 100 mg/L (limit test).

Validity criteria fulfilled:

yes

Remarks:

Validity criteria (e.g. mortality in the control, constant conditions, dissolved oxygen concentration, concentration of the test substance) were met.

Conclusions:

NOEC/LC0 (96 h) > 100 mg/L

Executive summary:

The acute toxicity of the read-across substance Sodium gluconate (CAS 527-07-1) towards fish was determined according to OECD Guideline 203 in compliance with GLP. A range finding test (5 fish/vessel/concentration) was conducted before the definitive test. Based on the results of the range finding test, only two concentrations were tested in the definitive test: 0 and 100 mg/L (limit test). Oryzias latipes served as test organism.

10 fish/concentration were used for the definitive test. Neither toxicological symptoms nor any death were observed at 100 mg/L. Conclusively, the NOEC/LC0 (96 h) was set to > 100 mg/L based on the nominal concentration.

Cross-reference 26

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

toxicity to aquatic algae and cyanobacteria

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: OECD guideline study in compliance with GLP

Qualifier:

according to guideline

Guideline:

OECD Guideline 201 (Alga, Growth Inhibition Test)

Deviations:

no

GLP compliance:

not specified

Remarks:

reviewed study was stated to be GLP-compliant in the report

Specific details on test material used for the study:

No details given.

Analytical monitoring:

yes

Details on sampling:

Because of precipitation, the test solutions were mixed well before sampling.

Vehicle:

not specified

Details on test solutions:

No details reported.

Test organisms (species):

Pseudokirchneriella subcapitata (previous names: Raphidocelis subcapitata, Selenastrum capricornutum)

Details on test organisms:

TEST ORGANISM
- Strain: ATCC 22662
- Method of cultivation: sterilization

ACCLIMATION
- Culturing media and conditions (same as test or not): ATCC culture medium 625 Gorham’s medium

Test type:

static

Water media type:

freshwater

Limit test:

no

Total exposure duration:

72 h

Post exposure observation period:

No details reported.

Hardness:

No details reported.

Test temperature:

22 – 24 °C

pH:

pH 7.04 – 8.0 at the beginning and pH 4.74 – 7.64 at the end of tests.

Dissolved oxygen:

No details reported.

Salinity:

Not applicable.

Nominal and measured concentrations:

Measured concentrations = 1.1, 2.4, 5.1, 12, 22 and 44 mg/L (Nominal concentrations at 3, 6, 13, 25, 50 and 100 mg/L) were studied. The measured
concentrations were 75 – 85 % of nominal concentrations. So, measured concentration was used in this test instead of nominal concentration.

Details on test conditions:

TEST SYSTEM
- Initial cells density: 1 x 10E4 cells/mL
- No. of vessels per concentration (replicates): 3

OTHER TEST CONDITIONS
- Light intensity and quality: 7,940 – 8,318 Lux

TEST CONCENTRATIONS
- Test concentrations:Nominal concentrations at 3, 6, 13, 25, 50 and 100 mg/L

Reference substance (positive control):

not required

Duration:

72 h

Dose descriptor:

EC50

Effect conc.:

6.9 mg/L

Nominal / measured:

meas. (not specified)

Conc. based on:

test mat.

Basis for effect:

growth rate

Duration:

72 h

Dose descriptor:

EC50

Effect conc.:

3.8 mg/L

Nominal / measured:

meas. (not specified)

Conc. based on:

test mat.

Basis for effect:

biomass

Duration:

72 h

Dose descriptor:

NOEC

Effect conc.:

2.4 mg/L

Nominal / measured:

meas. (not specified)

Conc. based on:

test mat.

Basis for effect:

growth rate

Duration:

72 h

Dose descriptor:

NOEC

Effect conc.:

1.1 mg/L

Nominal / measured:

meas. (not specified)

Conc. based on:

test mat.

Basis for effect:

biomass

Duration:

72 h

Dose descriptor:

LOEC

Effect conc.:

5.1 mg/L

Nominal / measured:

meas. (not specified)

Conc. based on:

test mat.

Basis for effect:

growth rate

Duration:

72 h

Dose descriptor:

LOEC

Effect conc.:

2.4 mg/L

Nominal / measured:

meas. (not specified)

Conc. based on:

test mat.

Basis for effect:

biomass

Details on results:

None reported.

Results with reference substance (positive control):

Not applicable.

Reported statistics and error estimates:

EC50 value and NOECs were calculated by Comprehensive Toxicity Data Analysis, database Software (Version 5.0) and Dunnett’s test, respectively.

Table 1. Cell density of Selenastrum capricornutum (ATCC 22662) during the test

Nominal Concentrations (mg/L)	Measured Concentrations (mg/L)	Cell density (x 10^4cell/mL)
		0 hr	24 hrs	48 hrs	72 hrs
Control	Control	1.1	2.1	24	190
3	1.1	0.92	2.5	22	130
6	2.4	1.4	2.5	26	95
13	5.1	1.1	1.4	22	120
25	12	0.84	0.55	11	1.9
50	22	0.67	0.21	0.64	0.34
100	44	0.79	0.083	0.34	0.083

Table 2. Percent inhibition of growth rates per concentration.

Nominal Concentrations (mg/L)	Measured Concentrations (mg/L)	Growth rates
		Growth rate	Relative growth rates (%)	Relative inhibition (%)
Control	Control	0.072	-	-
3	1.1	0.068	95.5	4.5
6	2.4	0.065	91.1	8.9
13	5.1	0.058	81.0	19.0
25	12	0.012	16.3	83.7
50	22	-0.047	0	100
100	44	-0.088	0	100

Nominal Concentrations (mg/L)	Measured Concentrations (mg/L)	Areas under the curve
		Areas under the curve	Relative growth rates (%)	Relative inhibition (%)
Control	Control	28,708,000	-	-
3	1.1	23,680,000	82.5	17.5
6	2.4	19,268,000	67.1	32.9
13	5.1	17,488,000	61.0	39.0
25	12	761,200	2.7	97.3
50	22	-154,796	0	100
100	44	-365,192	0	100

Table 3. pH of test solutions

Nominal Concentrations (mg/L)	Measured Concentrations (mg/L)	0 hr	72 hrs
Control	Control	7.81	7.61
3	1.1	7.72	7.44
6	2.1	7.69	7.64
13	5.1	7.24	7.51
25	12	8.00	6.86
50	22	7.5	5.48
100	44	7.04	4.74

Precipitation of test substance was observed at 12 – 44 mg/L. The condition of test solutions of 12, 22 and 44 mg/L became acidic after 72 hours. The acidic condition of test solutions affected the growth of algae.

Validity criteria fulfilled:

not specified

Remarks:

Coefficient of variation of average specific growth rates in replicate control cultures are not reported.

Conclusions:

EbC50 (72 h) value = 3.8 mg/L; NOEbC (72 h) = 1.1 mg/L; ErC50 (72 h) = 6.9 mg/L; NOErC (72 h) = 2.4 mg/L

Executive summary:

The acute toxicity of the read-across substance Iron dichloride (CAS 7758-94-3) towards algae (Selenastrum capricornutum, Strain: ATCC 22662) was determined according to OECD Guideline 201 in compliance with GLP. The test organisms were exposed to nominal concentrations of the test substance at 3, 6, 13, 25, 50 and 100 mg/L for 72 hours. Iron concentrations in the test solutions were analysed with ICP-AES (measured substance was total iron (Fe) and measured total iron concentration was converted into iron dichloride concentration in the test solution). The measured concentrations were 75 – 85 % of nominal concentrations. So, measured concentrations were used in the test instead of nominal concentration. An initial cells density of 1 x 10E4 cells/mL was used. Based on biomass, an EC50 (72 h) value of 3.8 mg/L and a NOEC (72 h) of 1.1 mg/L were estimated. Based on growth rate, the EC50 (72 h) was 6.9 mg/L while the NOEC (72 h) was 2.4 mg/L.

Cross-reference 27

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

toxicity to aquatic algae and cyanobacteria

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The substance has only been tested at 100 and 1000 mg/L because this test has been made on the basis of an older test according to a German norm; The inhibition level was thus expectable and the test concentrations limited to 100 and 1000 mg/L; read-across

Qualifier:

according to guideline

Guideline:

OECD Guideline 201 (Alga, Growth Inhibition Test)

Deviations:

yes

Remarks:

The substance has only been tested at 100 and 1000 mg/L.

GLP compliance:

not specified

Remarks:

reviewed study was stated to be GLP-compliant in the report

Specific details on test material used for the study:

No details given.

Analytical monitoring:

yes

Details on sampling:

No details provided.

Vehicle:

not specified

Details on test solutions:

PREPARATION AND APPLICATION OF TEST SOLUTION
- Method: Sample preparation: stock solution in redistilled water.

Test organisms (species):

Desmodesmus subspicatus (previous name: Scenedesmus subspicatus)

Details on test organisms:

TEST ORGANISM
- Strain: CHODAT (strain No 86.81 SAG)

Test type:

static

Water media type:

freshwater

Limit test:

no

Total exposure duration:

72 h

Post exposure observation period:

No details reported.

Hardness:

No details reported.

Test temperature:

Test 1: 22.7-24.8°C 
Test 2: 23.4-27.9°C

pH:

pH maximal difference between 0 and 72 hours: 0.3

Dissolved oxygen:

No details reported.

Salinity:

Not applicable.

Nominal and measured concentrations:

No details reported.

Details on test conditions:

TEST SYSTEM
- Test vessel: flasks
- Type (delete if not applicable): For test 2, the procedure has been modified by covering the test vessels with glass petri dishes to prevent contamination by micro-organisms.
- Initial cells density: 10 x 10E4 algae/mL
- No. of vessels per concentration (replicates):Test 1: 3 flasks with test item and 6 flasks without test item were prepared. Test 2: 3 flasks with 100 mg/L, 3 flasks with 1000 mg/L and 6 flasks without test item.
- No. of vessels per control (replicates): 6

OTHER TEST CONDITIONS
- Photoperiod: illuminated with 4 parallel set universal white fluorescent tubes of approximately 65 cm above the level of the tested media
- Light intensity and quality: 8900-9300 lux

EFFECT PARAMETERS MEASURED (with observation intervals if applicable) :
- Determination of cell concentrations: counting chamber

TEST CONCENTRATIONS
- Test concentrations: Test 1: 1000 mg/L (invalid); Test 2: 100 and 1000 mg/L

Reference substance (positive control):

not required

Duration:

72 h

Dose descriptor:

NOEC

Effect conc.:

100 mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

growth rate

Duration:

72 h

Dose descriptor:

EC50

Effect conc.:

> 100 mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

growth rate

Details on results:

No details reported.

Results with reference substance (positive control):

Not applicable.

Reported statistics and error estimates:

No details reported.

Test 1 : 1000 mg/L
not valid -  a decrease of the test item concentration was observed and therefore the test could not meet the stability requirements.

Cell growth inhibition : 85%
Average specific growth rate inhibition: 55%
---------------------

Test 2 : 100 mg/L and 1000 mg/L
Cell growth inhibition : no inhibition at 100 mg/L; 70% inhibition at 1000 mg/L

Average specific growth rate inhibition: no inhibition at 100 mg/L

42% inhibition at 1000 mg/L
----------------------------------------

Cell concentration increase in controls: factor 65.9 after 72 h

Validity criteria fulfilled:

not specified

Remarks:

Details such as coefficient of variation (average specific growth rates) are not reported.

Conclusions:

As final results and based on growth rate, an EC50 (72 h) of > 100 mg/L and a NOEC (72 h) of 100 mg/L were derived.

Executive summary:

The toxicity of the read-across substance Sodium gluconate (CAS 527-07-1) towards algae has been determined according to OECD Guideline 201 in compliance with GLP. Two tests have been performed. In the first test, 1000 mg/L of the test item have been tested. However, a decrease of the test item concentration was observed and therefore the test could not meet the stability requirements. Conclusively, a second test with 100 and 1000 mg/L test concentration was performed. Desmodesmus subspicatus CHODAT (strain No 86.81 SAG) was used as test organism. An initial cell density of 10 x 10E4 algae/mL was applied. For the second test, 3 flasks with 100 mg/L, 3 flasks with 1000 mg/L and 6 flasks without test item were used. The common OECD procedure has been modified by covering the test vessels with glass petri dishes to prevent contamination by micro-organisms. After 24, 48 and 72 hours, cell concentration was determined using a microscope with a counter chamber (8 fields counted). No cell growth inhibition at 100 mg/L was determined. At 1000 mg/L, 70% cell growth inhibition was observed. For the average specific growth rate, no inhibition at 100 mg/L but 42% inhibition at 1000 mg/L was determined. The cell concentrations in controls increased by a factor of 65.9 after 72 h. As final results and based on growth rate, an EC50 (72 h) of > 100 mg/L and a NOEC (72 h) of 100 mg/L were derived.

Cross-reference 28

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

toxicity to aquatic algae and cyanobacteria

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: study conducted according to OECD guidelines; quality assurance and GLP certificates; read-across

Qualifier:

according to guideline

Guideline:

OECD Guideline 201 (Alga, Growth Inhibition Test)

Deviations:

no

GLP compliance:

not specified

Remarks:

reviewed study was stated to be GLP-compliant in the report

Specific details on test material used for the study:

Details on properties of test surrogate or analogue material (migrated information):
No details given.

Analytical monitoring:

yes

Details on sampling:

No details given.

Vehicle:

no

Details on test solutions:

No details given.

Test organisms (species):

Pseudokirchneriella subcapitata (previous names: Raphidocelis subcapitata, Selenastrum capricornutum)

Details on test organisms:

No details given.

Test type:

static

Water media type:

freshwater

Limit test:

no

Total exposure duration:

72 h

Post exposure observation period:

No details reported.

Hardness:

No details reported.

Test temperature:

23+/- 2°C

pH:

No details reported.

Dissolved oxygen:

No details reported.

Salinity:

not applicable

Nominal and measured concentrations:

Measured concentrations of the test substance in the test solutions at the beginning of exposure were +/-20 % of the nominal concentrations.

Details on test conditions:

TEST SYSTEM
- Biomass loading: 1 x 10 E04 cells/mL

OTHER TEST CONDITIONS
- Photoperiod: continuous (+/- 20% at the surface of the test solutions)
- Light intensity and quality: 4000 lux

TEST CONCENTRATIONS
- Range finding study: yes
- Test concentrations: 0 (control), 100, 180, 320, 560, 1000 mg/L (nominal concentrations)
- Results used to determine the conditions for the definitive study: A range-finding test was conducted before the definitive test to enable the above-mentioned concentration range in the definitive test.

Reference substance (positive control):

not required

Duration:

72 h

Dose descriptor:

NOEC

Effect conc.:

560 mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

growth rate

Duration:

72 h

Dose descriptor:

EC50

Effect conc.:

> 1 000 mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

growth rate

Details on results:

No details reported.

Results with reference substance (positive control):

Not applicable.

Reported statistics and error estimates:

No details reported.

Cell growth inhibition at 1000 mg/L = 25.4 %

Growth rate inhibition (24-48 h) at 1000 mg/L = 7.6%

Growth rate inhibition (24-72 h) at 1000 mg/L = 9.0 %

50% growth inhibition concentration by comparison of areas
under the growth curves:

EbC50 (O-72 h): > 1000 mg/L
NOECb (0-72 h): 560 mg/L
----------------------------------------------------
50% growth inhibition concentration by comparison of growth
rates:

ErC50 (24 -48 h): > 1000 mg/L 
ErC50 (24-72 h): > 1000 mg/L
NOECr (24-72h) : 560 mg/L
NOECr (24-48h) : 560 mg/L

Color of the test solutions were observed with naked eye and the cell shapes of algae were observed through the microscope.  The test solutions were green at 24 hours after the start of exposure. Afterwards, the color of the test solutions showed a tendency to get more greenish with the passage of time.

No unusual cell shapes of algae and no agglutination were observed at the end of exposure and the algae looked normal compared to the control.

Validity criteria fulfilled:

not specified

Remarks:

Increase of biomass in control unknown.

Conclusions:

EC50 (72 h) > 1000 mg/L (based on growth rate; nominal concentration)
NOEC (72 h) = 560 mg/L (based on growth rate; nominal concentration)

Executive summary:

The acute toxicity of the read-across substance Sodium gluconate (CAS 527-07-1) towards algae was determined according to OECD Guideline 201 in compliance with GLP.

A range-finding test was conducted prior to the definitive test to enable the following concentrations in the definitive test: 0 (control), 100, 180, 320, 560, 1000 mg/L (nominal concentrations). Measured concentrations of the test substance in the test solutions at the beginning of exposure were +/-20 % of the nominal concentrations. As test organism, Pseudokirchnerella subcapitata has been used (Biomass loading: 1 x 10 E04 cells/mL).

As final results, the EC50 (72 h) was determined to be > 1000 mg/L while the NOEC (72 h) was set to 560 mg/L based on the growth rate (nominal concentration).

Cross-reference 29

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

toxicity to microorganisms, other

Remarks:

DIN 38412, part 8 (Pseudomonas Zellvermehrungshemm-Test)

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: basic scientific principles are met; read-across

Qualifier:

according to guideline

Guideline:

DIN 38412-8 (Pseudomonas Zellvermehrungshemmtest)

Deviations:

not specified

GLP compliance:

not specified

Specific details on test material used for the study:

No details provided.

Analytical monitoring:

not specified

Details on sampling:

No details provided.

Vehicle:

not specified

Details on test solutions:

No details provided.

Test organisms (species):

Pseudomonas putida

Details on inoculum:

No details provided.

Test type:

static

Water media type:

freshwater

Limit test:

no

Total exposure duration:

16 h

Post exposure observation period:

No details reported.

Hardness:

No details provided.

Test temperature:

21°C

pH:

No details provided.

Dissolved oxygen:

No details provided.

Salinity:

Not applicable.

Nominal and measured concentrations:

No details provided.

Details on test conditions:

TEST CONCENTRATIONS
- Test concentrations: 3 range of concentration tested: 0-40 mg/L; 80-5000 mg/L; > 5000 mg/L

Reference substance (positive control):

not specified

Duration:

16 h

Dose descriptor:

EC0

Effect conc.:

> 5 000 mg/L

Nominal / measured:

not specified

Conc. based on:

test mat.

Basis for effect:

growth inhibition

Details on results:

0-40 mg/L: no effect
80-5000 mg/L: stimulation of growth
> 5000 mg/L: no stimulation of growth but not toxic

Results with reference substance (positive control):

No details given.

Reported statistics and error estimates:

No details given.

Validity criteria fulfilled:

not specified

Remarks:

Only limited information available.

Conclusions:

EC0 (16 h) > 5000 mg/L

Executive summary:

The toxicity of the read-across substance Sodium gluconate (CAS 527-07-1) was tested according to the German standard procedure DIN 38412, part 8 (Pseudomonas Zellvermehrungshemm-Test). As test organism, Pseudomonas putida has been used. Three different concentration ranges were tested: 0 -40 mg/L, 80 -5000 mg/L and > 5000 mg/L. It was reported that in the 0 -40 mg/L concentration range, no effect were observed. In the 80 -5000 mg/L concentration range, growth was stimulated. For the range of > 5000 mg/L, neither stimulation of growth nor toxic effects were observed. As final result, the EC0 (16 h) amounts to > 5000 mg/L.

Cross-reference 30

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

reproductive toxicity, other

Remarks:

results of the histopathology and pathology examinations of a repeated dose study (4-weeks, oral feed) in dogs

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well documented peer-reviewed report.

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:

No reproduction toxicity study was available for any of the gluconates of the category. However, negative results in the histopathology of the reproductive organs in repeat dose studies on sodium gluconate and negative data on the teratogenicity of glucono-delta-lactone (Food & Drug Laboratories, 1973) support the lack of reproductive toxicity for all the gluconates of the category.
The repeat dose studies of sodium gluconate were in detail:
A 28-day study was conducted by feeding rats by gavage with sodium gluconate at doses of 0, 500, 1000, 2000 mg/kg bw in water at a volume of 1 mL/ 100g bw.
A 28-day oral feeding study was conducted rats with sodium gluconate at doses of 0, 1000, 2000 and 4100 mg/kg bw.
Repeated toxicity studies in Beagle dogs were conducted with sodium gluconate administered orally for 4 weeks at 500, 1000, 2000 mg/kg bw doses.

GLP compliance:

no

Limit test:

no

Species:

other: dog

Strain:

other: Beagle

Sex:

not specified

Route of administration:

oral: unspecified

Vehicle:

not specified

Details on mating procedure:

not applicable

Duration of treatment / exposure:

4 weeks

Frequency of treatment:

not specified

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

500 mg/kg bw/day (nominal)

Dose / conc.:

1 000 mg/kg bw/day (nominal)

Dose / conc.:

2 000 mg/kg bw/day (nominal)

No. of animals per sex per dose:

12/sex/group

Control animals:

yes

Details on study design:

- Dose selection rationale: not specified
- Rationale for animal assignment (if not random): not specified
- Rationale for selecting satellite groups: not applicable
- Post-exposure recovery period in satellite groups: not applicable
- Section schedule rationale (if not random): not specified

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Not specified

BODY WEIGHT: Not specified

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Not specified

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Not specified

CLINICAL CHEMISTRY: Not specified.

URINALYSIS: Not specified

NEUROBEHAVIOURAL EXAMINATION: Not specified
IMMUNOLOGY: Not specified

Oestrous cyclicity (parental animals):

not specified

Sperm parameters (parental animals):

not specified

Litter observations:

not applicable as no offsprings were generated

Postmortem examinations (parental animals):

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Postmortem examinations (offspring):

not applicable as no offsprings were generated

Statistics:

no data

Reproductive indices:

not examined

Offspring viability indices:

not examined

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Increased frequency of vomiting and loose or watery stools were observed in the 1000 and 2000 mg/kg bw dose groups, as compared to controls.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

None of the animals died during the period of treatment in any dose group.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No significantly toxicologically changes were detected in the body weight, food intake, water intake, urinalysis, haematological test, blood chemistry analysis, ophthalmologic test, electrocardiography, autopsy and organ weight or in histopathological examination.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No significantly toxicologically changes were detected in the body weight, food intake, water intake, urinalysis, haematological test, blood chemistry analysis, ophthalmologic test, electrocardiography, autopsy and organ weight or in histopathological examination.

Food efficiency:

not examined

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

no effects observed

Description (incidence and severity):

No significantly toxicologically changes were detected in the body weight, food intake, water intake, urinalysis, haematological test, blood chemistry analysis, ophthalmologic test, electrocardiography, autopsy and organ weight or in histopathological examination.

Ophthalmological findings:

no effects observed

Description (incidence and severity):

No significantly toxicologically changes were detected in the body weight, food intake, water intake, urinalysis, haematological test, blood chemistry analysis, ophthalmologic test, electrocardiography, autopsy and organ weight or in histopathological examination.

Haematological findings:

no effects observed

Description (incidence and severity):

No significantly toxicologically changes were detected in the body weight, food intake, water intake, urinalysis, haematological test, blood chemistry analysis, ophthalmologic test, electrocardiography, autopsy and organ weight or in histopathological examination.

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

No significantly toxicologically changes were detected in the body weight, food intake, water intake, urinalysis, haematological test, blood chemistry analysis, ophthalmologic test, electrocardiography, autopsy and organ weight or in histopathological examination.

Urinalysis findings:

no effects observed

Description (incidence and severity):

No significantly toxicologically changes were detected in the body weight, food intake, water intake, urinalysis, haematological test, blood chemistry analysis, ophthalmologic test, electrocardiography, autopsy and organ weight or in histopathological examination.

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No significantly toxicologically changes were detected in the body weight, food intake, water intake, urinalysis, haematological test, blood chemistry analysis, ophthalmologic test, electrocardiography, autopsy and organ weight or in histopathological examination.

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

not examined

Repeated toxicity studies were also performed on Beagle dogs with sodium gluconate administered orally for 4 weeks at 500, 1000, 2000 mg/kg bw doses. None of the animals died during the period of treatment in any dose group and no significantly toxicologically changes were detected in the body weight, food intake, water intake, urinalysis, haematological test, blood chemistry analysis, ophthalmologic test, electrocardiography, autopsy and organ weight or in histopathological examination. However, increased frequency of vomiting and loose or watery stools were observed in the 1000 and 2000 mg/kg bw dose groups, as compared to controls.
On the basis of these results, the non-toxic dose was estimated to be 500 mg/kg bw/day. However, the toxicological effects observed (vomiting, passage of loose or watery stools) were considered extremely slight since other tests did not show the same changes (Okamoto, M. Bozo Research Center, 1995a).

Remarks on result:

not determinable due to absence of adverse toxic effects

Critical effects observed:

no

Remarks on result:

not measured/tested

Reproductive effects observed:

no

Repeated toxicity studies were also performed on Beagle dogs with sodium gluconate administered orally for 4 weeks at 500, 1000, 2000 mg/kg bw doses. None of the animals died during the period of treatment in any dose group and no significantly toxicologically changes were detected in the body weight, food intake, water intake, urinalysis, haematological test, blood chemistry analysis, ophthalmologic test, electrocardiography, autopsy and organ weight or in histopathological examination. However, increased frequency of vomiting and loose or watery stools were observed in the 1000 and 2000 mg/kg bw dose groups, as compared to controls.

On the basis of these results, the non-toxic dose was estimated to be 500 mg/kg bw/day. However, the toxicological effects observed (vomiting, passage of loose or watery stools) were considered extremely slight since other tests did not show the same changes (Okamoto, M. Bozo Research Center, 1995a).

Conclusions:

SIDS testing requirements regarding reproductive toxicity were satisfied with histopathology of the reproductive organs in repeated dose studies on sodium gluconate and with developmental toxicity studies on glucono-delta-lactone.

Executive summary:

No reproduction toxicity study was available for any of the gluconates of the category. However, negative results in the histopathology of the reproductive organs in repeat dose studies on sodium gluconate and negative data on the teratogenicity of glucono-delta-lactone (Food & Drug Laboratories, 1973) support the lack of reproductive toxicity for all the gluconates of the category. On the basis of these data showing a lack of toxicity and considering that gluconates have been recognized direct food additives, no further tests are considered necessary.

Cross-reference 31

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

reproductive toxicity, other

Remarks:

results of the histopathology and pathology examinations of a repeated dose study (4-weeks, oral feed) in rats

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well documented peer-reviewed report.

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

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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

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:

equivalent or similar to guideline

Guideline:

other: OECD 407 (Repeated Dose 28-day Oral Toxicity in Rodents)

Principles of method if other than guideline:

No reproduction toxicity study was available for any of the gluconates of the category. However, negative results in the histopathology of the reproductive organs in repeated dose studies on sodium gluconate and negative data on the teratogenicity of glucono-delta-lactone (Food & Drug Laboratories, 1973) support the lack of reproductive toxicity for all the gluconates of the category.
The repeated dose studies of sodium gluconate were in detail:
A 28-day study was conducted by feeding rats by gavage with sodium gluconate at doses of 0, 500, 1000, 2000 mg/kg bw in water at a volume of 1 ml/ 100g bw.
A 28-day oral feeding study was conducted rats with sodium gluconate at doses of 0, 1000, 2000 and 4100 mg/kg bw.
Repeated toxicity studies in Beagle dogs were conducted with sodium gluconate administered orally for 4 weeks at 500, 1000, 2000 mg/kg bw doses.

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: feed

Vehicle:

not specified

Details on exposure:

oral feeding

Duration of treatment / exposure:

28 days

Frequency of treatment:

once daily

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

1 000 mg/kg bw/day (nominal)

Dose / conc.:

2 000 mg/kg bw/day (nominal)

Dose / conc.:

4 000 mg/kg bw/day (nominal)

No. of animals per sex per dose:

10/sex/group

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale: not specified
- Rationale for animal assignment (if not random): not specified
- Rationale for selecting satellite groups: not applicable
- Post-exposure recovery period in satellite groups: not applicable
- Section schedule rationale (if not random): not specified

Parental animals: Observations and examinations:

Repeated dose toxicity study with young adult unmated rats of both sexes
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Not specified

BODY WEIGHT: Not specified

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Not specified

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Not specified

CLINICAL CHEMISTRY: Not specified

URINALYSIS: Not specified

NEUROBEHAVIOURAL EXAMINATION: Not specified

IMMUNOLOGY: Not specified

Oestrous cyclicity (parental animals):

not specified

Sperm parameters (parental animals):

not specified

Litter observations:

not applicable as no offsprings were generated

Postmortem examinations (parental animals):

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Postmortem examinations (offspring):

not applicable as no offsprings were generated

Statistics:

no data

Reproductive indices:

not examined

Offspring viability indices:

not examined

Clinical signs:

no effects observed

Description (incidence and severity):

No revisions in the general condition.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

No deaths occurred during the study period.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No revisions in the body weight, or food and water intake were observed in the animals over the study period.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No revisions in the body weight, or food and water intake were observed in the animals over the study period.

Food efficiency:

not examined

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

no effects observed

Description (incidence and severity):

No revisions in the body weight, or food and water intake were observed in the animals over the study period.

Ophthalmological findings:

no effects observed

Description (incidence and severity):

No changes were observed in the investigated ophthalmologic tests, urinalysis, hematology and blood chemistry over the study period.

Haematological findings:

no effects observed

Description (incidence and severity):

No changes were observed in the investigated ophthalmologic tests, urinalysis, hematology and blood chemistry over the study period.

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

No changes were observed in the investigated ophthalmologic tests, urinalysis, hematology and blood chemistry over the study period.

Urinalysis findings:

no effects observed

Description (incidence and severity):

No changes were observed in the investigated ophthalmologic tests, urinalysis, hematology and blood chemistry over the study period. Statistically significant differences in some urinary parameters reported in animals receiving 2.5 or 5% sodium gluconate were comparable to those observed in the NaCl control group, and were interpreted as related to the high sodium concentration of the diet.

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

In addition, histopathological examination indicated no adverse effects as a result of the treatment regime.

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

not examined

Another 28-day toxicity study in rats fed with a diet containing up to 5% w/w sodium gluconate (max. 4100 mg/kg bw for males and 4400 mg/kg bw for females) was conducted using a control group receiving equivalent concentration of sodium in the form of NaCl in order to differentiate the potential effects of high doses of sodium intake. No deaths occurred during the study period. No revisions in the general condition, body weight, or food and water intake were observed in the animals over the study period. No changes were observed in the investigated ophthalmologic tests, urinalysis, hematology and blood chemistry over the study period. In addition, histopathological examination indicated no adverse effects as a result of the treatment regime. Statistically significant differences in some urinary parameters reported in animals receiving 2.5 or 5% sodium gluconate were comparable to those observed in the NaCl control group, and were interpreted as related to the high sodium concentration of the diet.
The authors concluded that the NOAEL was 5% (equal to 4100 mg/kg bw per day). However, The JECFA committee who evaluated this report has concluded that the study was not suitable for identifying a NOAEL because of the small group sizes and the positive findings in the qualitative analysis, even if they have acknowledged that the effects shown in the qualitative urine analyses were related to the high sodium intake (Mochizuki, M. Bozo Research Center, 1997). Nonetheless, this study demonstrates the lack of effects of the gluconate anion even in large doses as the urinary effects were attributed to the high sodium intake and was therefore considered as critical for this endpoint.

Dose descriptor:

NOAEL

Effect level:

4 100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

mortality

body weight and weight gain

food consumption and compound intake

water consumption and compound intake

ophthalmological examination

haematology

clinical biochemistry

urinalysis

organ weights and organ / body weight ratios

gross pathology

histopathology: non-neoplastic

Critical effects observed:

no

Remarks on result:

not measured/tested

Reproductive effects observed:

no

Another 28-day toxicity study in rats fed with a diet containing up to 5% w/w sodium gluconate (max. 4100 mg/kg bw for males and 4400 mg/kg bw for females) was conducted using a control group receiving equivalent concentration of sodium in the form of NaCl in order to differentiate the potential effects of high doses of sodium intake. No deaths occurred during the study period. No revisions in the general condition, body weight, or food and water intake were observed in the animals over the study period. No changes were observed in the investigated ophthalmologic tests, urinalysis, hematology and blood chemistry over the study period. In addition, histopathological examination indicated no adverse effects as a result of the treatment regime. Statistically significant differences in some urinary parameters reported in animals receiving 2.5 or 5% sodium gluconate were comparable to those observed in the NaCl control group, and were interpreted as related to the high sodium concentration of the diet.

The authors concluded that the NOAEL was 5% (equal to 4100 mg/kg bw per day). However, The JECFA committee who evaluated this report has concluded that the study was not suitable for identifying a NOAEL because of the small group sizes and the positive findings in the qualitative analysis, even if they have acknowledged that the effects shown in the qualitative urine analyses were related to the high sodium intake (Mochizuki, M. Bozo Research Center, 1997). Nonetheless, this study demonstrates the lack of effects of the gluconate anion even in large doses as the urinary effects were attributed to the high sodium intake and was therefore considered as critical for this endpoint.

Conclusions:

SIDS testing requirements regarding reproductive toxicity were satisfied with histopathology of the reproductive organs in repeated dose studies on sodium gluconate and with developmental toxicity studies on glucono-delta-lactone.

Executive summary:

No reproduction toxicity study was available for any of the gluconates of the category. However, negative results in the histopathology of the reproductive organs in repeat dose studies on sodium gluconate and negative data on the teratogenicity of glucono-delta-lactone (Food & Drug Laboratories, 1973) support the lack of reproductive toxicity for all the gluconates of the category. On the basis of these data showing a lack of toxicity and considering that gluconates have been recognized direct food additives, no further tests are considered necessary.

Cross-reference 32

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

reproductive toxicity, other

Remarks:

results of the histopathology and pathology examinations of a repeated dose study (4-weeks, oral gavage) in rats

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well documented peer-reviewed report.

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:

No reproduction toxicity study was available for any of the gluconates of the category. However, negative results in the histopathology of the reproductive organs in repeated dose studies on sodium gluconate and negative data on the teratogenicity of glucono-delta-lactone (Food & Drug Laboratories, 1973) support the lack of reproductive toxicity for all the gluconates of the category.
The repeated dose studies of sodium gluconate were in detail:
A 28-day study was conducted by feeding rats by gavage with sodium gluconate at doses of 0, 500, 1000, 2000 mg/kg bw in water at a volume of 1 ml/ 100g bw.
A 28-day oral feeding study was conducted rats with sodium gluconate at doses of 0, 1000, 2000 and 4100 mg/kg bw.
Repeated toxicity studies in Beagle dogs were conducted with sodium gluconate administered orally for 4 weeks at 500, 1000, 2000 mg/kg bw doses.

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Route of administration:

oral: gavage

Details on exposure:

feeding by gavage in water at a volume of 1 mL/100g bw.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

28 days

Frequency of treatment:

once daily

Dose / conc.:

0 mg/kg bw/day (actual dose received)

Dose / conc.:

500 mg/kg bw/day (actual dose received)

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

Dose / conc.:

2 000 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

12/sex/group

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale: not specified
- Rationale for animal assignment (if not random): not specified
- Rationale for selecting satellite groups: not applicable
- Post-exposure recovery period in satellite groups: not applicable
- Section schedule rationale (if not random): not specified

Parental animals: Observations and examinations:

Repeated dose toxicity study with young adult unmated rats of both sexes
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Not specified

BODY WEIGHT: Not specified

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Not specified

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Not specified
- Anaesthetic used for blood collection: Not specified

CLINICAL CHEMISTRY: Not specified

URINALYSIS: Not specified
- Metabolism cages used for collection of urine: Not specified

NEUROBEHAVIOURAL EXAMINATION: Not specified

IMMUNOLOGY: Not specified

Oestrous cyclicity (parental animals):

not specified

Sperm parameters (parental animals):

not specified

Litter observations:

not applicable as no offsprings were generated

Postmortem examinations (parental animals):

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Postmortem examinations (offspring):

not applicable as no offsprings were generated

Statistics:

no data

Reproductive indices:

not examined

Offspring viability indices:

not examined

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

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 examined

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Histopathological examination showed a thickening of the limiting ridge of the stomach in 5 out of 12 males at 2000 mg/kg bw per day dose. No toxic changes associated with the test article were detected. As the limiting ridge is a tissue specific to rodents, this lesion is not toxicologically relevant for humans. Other lesions occurred incidentally and were not treatment-related.

Histopathological findings: neoplastic:

no effects observed

Other effects:

not specified

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

not examined

A 28-day study was conducted by feeding rats by gavage with sodium gluconate at doses of 0, 500, 1000, 2000 mg/kg bw in water at a volume of 1 mL/100g bw. No death or clinical signs of abnormality were observed in any of the groups. Histopathological examination showed a thickening of the limiting ridge of the stomach in 5 out of 12 males at 2000 mg/kg bw per day dose. No toxic changes associated with the test article were detected. As the limiting ridge is a tissue specific to rodents, this lesion is not toxicologically relevant for humans. Other lesions occurred incidentally and were not treatment-related.
The NOAEL was estimated to be 1000 mg/kg bw/day for males and 2000 mg/kg bw/day for female (Mochizuki, M, Bozo Research Center, 1995a).

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

clinical signs

mortality

organ weights and organ / body weight ratios

gross pathology

histopathology: non-neoplastic

Dose descriptor:

NOAEL

Effect level:

2 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

clinical signs

mortality

organ weights and organ / body weight ratios

gross pathology

histopathology: non-neoplastic

Critical effects observed:

no

Remarks on result:

not measured/tested

Reproductive effects observed:

no

A 28-day study was conducted by feeding rats by gavage with sodium gluconate at doses of 0, 500, 1000, 2000 mg/kg bw in water at a volume of 1 mL/ 100g bw. No death or clinical signs of abnormality were observed in any of the groups. Histopathological examination showed a thickening of the limiting ridge of the stomach in 5 out of 12 males at 2000 mg/kg bw per day dose. No toxic changes associated with the test article were detected. As the limiting ridge is a tissue specific to rodents, this lesion is not toxicologically relevant for humans. Other lesions occurred incidentally and were not treatment -related. The NOAEL was estimated to be 1000 mg/kg bw/day for males and 2000 mg/kg bw/day for female (Mochizuki, M, Bozo Research Center, 1995a).

Conclusions:

SIDS testing requirements regarding reproductive toxicity were satisfied with histopathology of the reproductive organs in repeated dose studies on sodium gluconate and with developmental toxicity studies on glucono-delta-lactone.

Executive summary:

No reproduction toxicity study was available for any of the gluconates of the category. However, negative results in the histopathology of the reproductive organs in repeated dose studies on sodium gluconate and negative data on the teratogenicity of glucono-delta-lactone (Food & Drug Laboratories, 1973) support the lack of reproductive toxicity for all the gluconates of the category. On the basis of these data showing a lack of toxicity and considering that gluconates have been recognized direct food additives, no further tests are considered necessary.

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Safety Assessment of Monosaccharides, Disaccharides, and Related Ingredients as Used in Cosmetics

Author:

CIR (Cosmetic Ingredient Review)

Year:

2014

Bibliographic source:

Cosmetic Ingredient Review; Final Report Release Date: April 4, 2014; Panel Meeting Date: March 17-18, 2014

Reference 2

Reference Type:

publication

Title:

Unnamed

Year:

2004

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Summary of sensitization study results (non-human and human) conducted with monosaccharides, disaccharides, and related Ingredients as used in cosmetics.

GLP compliance:

not specified

Type of study:

patch test

Justification for non-LLNA method:

The REACH Regulation, Annex VII, paragraph 8.3 states "The Murine Local Lymph Node Assay (LLNA) is the first-choice method for in vivo testing. Only in exceptional circumstances should another test be used. Justification for the use of another test shall be provided." These non-human and human sensitisation study results are already available and their use is considered in the view of its relevance for the toxicological evaluation of iron glucoheptonate.

Test material

Test material information

Constituent 1

Reference substance name:

mono- and disaccharides, gluconic acid and its derivatives

IUPAC Name:

mono- and disaccharides, gluconic acid and its derivatives

Test material form:

other: cosmetic formulations

Results and discussion

In vivo (non-LLNA)

Results

Reading:

other: Mono- and disaccharides did not produce hypersensitivity skin reactions when tested in animals and In human repeated insult patch tests (HRIPTs).

Remarks on result:

other: Reading: other: Mono- and disaccharides did not produce hypersensitivity skin reactions when tested in animals and In human repeated insult patch tests (HRIPTs)..

Any other information on results incl. tables

A face and neck formulation containing 2.48% lactose did not produce irritation or hypersensitivity in a 4-wk safety-in use ophthalmological evaluation. Thirty-one subjects participated in the study.

In non-human studies, a 50% aq. solution of gluconic acid was not a dermal irritant and lactitol was not an irritant or sensitizer in rabbits. In human repeated insult patch tests (HRIPTs), formulations containing 10% rhamnose, up to 8% glucose, 5% mannose, 2.48% lactose, and less than 1% isomalt, kefiran, lactitol, sucralose, and xylobiose were not irritants or sensitizers. A formulation containing 10% rhamnose did induce a significant irritation reaction in one subject, and irritation was observed in 16% of the subjects during induction in an HRIPT of a rinse-off hair product containing 29% sucrose (tested as a 50% dilution); no sensitization reactions were reported for this product.

Applicant's summary and conclusion

Interpretation of results:

not sensitising

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

Calcium gluconate and gluconic acid, structurally similar anlogues to glucoheptonates, have been assessed by the Panel as non-sensitizers in cosmetic formulations.

Executive summary:

"The Panel acknowledged that sucrose and glucose are used in cosmetics at relatively high concentrations, and that data from irritation and sensitization studies at maximum use concentrations of these ingredients (i.e. calcium gluconate and gluconic acid) are lacking; however, based on the clinical experience of the Panel, there is little concern that these ingredients are irritants or sensitizers".