Iron digluconate

Endpoint summary

Description of key information

Via study data and read across Iron Gluconate is not classified as toxic
Justification for using read across for the actute toxicity via the dermal route is attached.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study without detailed documentation

Qualifier:

no guideline available

Principles of method if other than guideline:

No guideline available

GLP compliance:

not specified

Remarks:

GLP compliance of the report used to produce results not given in the publication

Test type:

other: no guideline available

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Blue Spruce Farms
- Weight at study initiation: 200-250 g
- Fasting period before study: 12 hours
- Water (e.g. ad libitum): Yes

Route of administration:

oral: gavage

Vehicle:

other: Tris buffer

Details on oral exposure:

VEHICLE
- Amount of vehicle (if gavage): 1-3 ml

Control animals:

not specified

Details on study design:

There are no details on the study design

Statistics:

Weil method

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

>= 2 237 mg/kg bw

Based on:

not specified

Mortality:

No data

Clinical signs:

other: Diarrhea seen at sub-lethal and lethal doses.

Gross pathology:

At doses higher or equal to the LD50 - stomach and small intestine were dilated and filled with dark fluid and occasionally blood. Stomach and small intestine mucosa were covered with grey-green granular material. Ceacum and large intestine containied black liquid faeces.
At sub-lethal doses - occasional dilation of upper gastrointestinal tract with fluid. Small hamorrhages were seen in stomach or small intestine. Black liquid faeces was reported.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

LD50 (rat) is 2237 mg/kg

Iron Gluconate is not classified as hazardous

Executive summary:

Iron Gluconate is not classified as hazardous

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 237 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

The test is waived as per column 2 in Annex VIII

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

2009

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

housing of the animals was in individual cages, drinking water analysis was performed in September instead of August, dosing of males occurred one week prior to the completion of the female study

Principles of method if other than guideline:

housing of the animals was in individual cages, drinking water analysis was performed in September instead of August, dosing of males occurred
one week prior to the completion of the female study

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories France, Domaine des Oncins, 69592 L'Arbresle Cedex, France.
- Weight at study initiation: 223.9 to 243.6 g for females, and 257.6 to 296.4 g for males
- Fasting period before study: None
- Housing: Individually caged in standard cages with sawdust bedding
- Diet (e.g. ad libitum): RM1 (E)-SQC/DIETEX feed ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period:Minimum 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 45-65
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 hrs dark/ 12 hrs light

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: Dorsal area of the rat
- % coverage: at least 10%
- Type of wrap if used: Piece of absorbant gauze which was protected by a pad and covered with an adhesive tape. Held in place for 24 hours.


REMOVAL OF TEST SUBSTANCE
- Washing (if done): Not done



TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg body weight
- Concentration (if solution): undiluted
- Constant volume or concentration used: yes

Duration of exposure:

24 hours

Doses:

2000 mg/kg body weight

No. of animals per sex per dose:

5 animals per sex

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were examined clinically before the first treatment, twice on the day of treatment, and thereafter, daily. Animals were weighed on day 1, 7, 14 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: Skin lesion evaluation was done daily, and full clinical examinations were done on days 2, 7, and 14. At necropsy their organs were examined macroscopically.

As the test item was expected to be non-toxic by the dermal route, a single group of 5 females was dosed at the maximum limit dose of 2000 mg/kg body weight followed by a group of 5 males dosed at the same dose level to establish that animals of this sex are not markedly more sensitive to Gluconic Acid.

Scoring system of skin lesions

Erythema and Eschar formation
No erythema 0
Very slight erythema (barely perceptible) 1
Well-defined erythema 2
Moderate to marked erythema 3
Severe erythema (beet redness) to slight eschar formation preventing the grading of the erythema 4

Formation of oedema
No oedema 0
Very slight oedema (barely perceptible) 1
Slight oedema (edges of area well-defined by definited raising) 2
Moderate oedema (raised approximately 1 mm) 3
Severe oedema (raised more than 1 mm) extending beyond the area of exposure) 4

Statistics:

Not reported; however, not required for acute toxicity.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

No mortality occurred during the study in male and female Sprague-Dawley rats.

Clinical signs:

other: No clinical signs were observed during the course of the study.

Gross pathology:

No organ or tissue gross findings were seen at necropsy.

Other findings:

No dermal reactions were observed during the course of the study.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: other: CLP (EC 1278/2008)

Conclusions:

D-Gluconic Acid is not toxic

Executive summary:

D-Gluconic Acid is not classified as toxic

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Additional information

Justification for selection of acute toxicity – oral endpoint
Iron Gluconate is classified as non-hazardous for this end point

Justification for selection of acute toxicity – inhalation endpoint
The test is waived as per column 2 in Annex VIII

Justification for selection of acute toxicity – dermal endpoint
There are no acute dermal toxicity studies on ferrous gluconate. Results of a study conducted with a structurally similar compound, D-gluconic acid, are reported and used for read across. From this read across ferrous gluconate is not classified as toxic.

Via read across Iron Gluconate is classified as non-hazardous for this end point

Justification for classification or non-classification

Via study data (acute toxicity: oral) and read across (acute toxicity: dermal) Iron Gluconate is not classified as toxic.

Iron Gluconate can be read across to D-Gluconic acid due to the comparable structures, similar minimal levels of dermal absorption and similar phys/chem properties relevant for determining dermal toxicity.

The pKa of most gluconic acid salts, including iron gluconate is 3.7 (OECD SIDS 2004). Henderson-Hasselbad modelling predicts that at the skin pH of 5, the majority of the iron gluconate will be present as the dissociated Fe++ ion and gluconate and, as a result, will be poorly absorbed (Wikipedia 2014). The read across material, d-gluconic acid has a similar pKa (3.86) and is also poorly absorbed for the same reason. However, once absorbed the gluconate will undergo the same fate and make the same contributions to systemic effects regardless of whether it comes from the iron gluconate or from the read across material, the gluconic acid.  

 

The absorbed iron portion of the molecule will likewise be minimal but that which is absorbed will have similar distribution, metabolism and systemic effects as dietary sources of iron. Mammalian systems have numerous homeostatic mechanism for maintaining appropriate systemic iron levels (Andrews and Schmidt 2007). The minor amounts absorbed dermally from iron gluconate are not likely to overwhelm those mechanisms. 

 

Full justification for using read across for the actute toxicity via the dermal route is attached.