1,2,3-Propanetricarboxylic acid, 2-hydroxy-, chromium(3+) salt (1:1)

Repeated dose toxicity: oral

Administrative data

Endpoint:

repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

90 days and 2 year

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Justification for type of information:

As with all inorganic salts, the significance for toxicity or environmental assessment is the presence of specific ions that will form when in solution or when in biological systems.In the case of Cr III salts, the counter ion will have an effect on solubility and this is itself dependant on the type of media being used and in particular the pH of that media. It is generally accepted that in the case of metal salts, testing with salts that are soluble in the respective test media will ensure maximum exposure of the metal ions. This will include chlorides and nitrates as being more soluble and will indeed have relevance when dissolved in acid media, such as if ingested.Read-across to other chromium III salts is therefore considered valid as long as the exposure in the test system is greater than wold be expected for the substance under review for registration.

Data source

Reference

Reference Type:

publication

Title:

Absence of Toxic and Carcinogenic Effects after Administration of High Doses of Chromic Oxide Pigment in Subacute and Long-term Feeding Experiments in Rats

Author:

Ivankovic, S. & Preussmann, R.

Year:

1975

Bibliographic source:

Cosmetic Toxicology, 13, 347-351

Materials and methods

Test guideline

Test guideline 1

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Version / remarks:

Feeding

Test guideline 2

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 452 (Chronic Toxicity Studies)

Version / remarks:

Feeding

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Chromoium oxide

IUPAC Name:

Chromoium oxide

Details on test material:

Chromium oxide was obtained by reduction of chromate at about 600C. the product was washed until all soluble components, particularly chromate, had disappeared, was a fine green powder of pure Cr2O3, insoluble in water, alkali and mineral acids. The product was in a non-hydrated form. Analysis of the preparation gave a maximum content of 3 ppm Cr3+. The preparation was free from chromate (detection limit 1 µg Cr2O4.

Test animals

Species:

rat

Strain:

other: BD

Details on species / strain selection:

Inbred DB Strain

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS- Age at study initiation:about 100 days old - Weight at study initiation: Average about 200 g- Housing: Groups of 4 in Makrolon cages- Diet: Untreated controls were fed Altromin, while the test pigment was administered in bread which was made twice weekly by incormporating 1, 2 or 5% Cr2O3 into bread.- Water: Tap water ad libitumENVIRONMENTAL CONDITIONSNo data

Administration / exposure

Route of administration:

oral: feed

Details on route of administration:

Administered as bread

Details on oral exposure:

Cr2O3 was incorporated into a dough made from 2835g flour, 150g milk powder, 150g mixed salts (NaCl, CaHPO4, and Cu, Zn, Mn and K), 150g cooking oil, 150g cod liver oil, 300g malt extract, 600 g sugar, 80 g yeast and 900 ml water and subsequently baked. Uneaten bread was weighed in order to determine the amount consumed. There were only small losses from crtumbs.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

90 day study and 2 year study

Frequency of treatment:

5 days/week. Control diet with a vegetable supplement given at weekends.

Doses / concentrations

Doses / concentrations 1

Remarks:

1, 2 or 5% in diet

Doses / concentrations 2

Dose / conc.:

1 200 mg/kg bw/day (nominal)

Remarks:

Expressed as Cr3+

No. of animals per sex per dose:

90 day study: two groups, one group of 14 males and 5 females receiving 2% in the feed and a second group of 5 males and 10 females receiving 5% in the diet. 2 year study: groups of 60 male and female rats

Control animals:

yes, plain diet

Details on study design:

Based on the reported food consumption, these chromium(III) oxide levels corresponded to a Cr3+ uptake of 568 mg/kg bw per day for males and 547 mg/kg bw per day for females in the 2% group and 1368 mg/kg bw per day for males and 1216 mg/kg bw per day for females in the 5% group

Examinations

Observations and examinations performed and frequency:

90 DAY TESTBODY WEIGHT: Bodyweight was determined fortnightlyFOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Uptake of food was determined weeklyHAEMATOLOGY: The blood picture was determined before the beginning of the experiment and monthly during feeding. At the end of the feeding period animals were fasted for 24 hrs then blood was taken from the retrobulbar plexus for determinations of blood sugar, serum protein and serum bilirubin, and from the tail for counts of erythrocytes, total and specific leucocytes and haemoglobin estimation. URINALYSIS: Random samples were taken during the course of the study and from all animals in the last week for determination of protein, sugar, bilirubin, blood and sedimentOTHER: during the the last 30days of treatment males and females from the smae group were paired to test fertility and the number of young ine ach litter recorded. 2 YEAR STUDYBODY WEIGHT: Bodyweight was determined monthlyFOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Uptake of food was determined weeklyAt the end of the study surviving animals were maintained on the control diet until they either died or became moribund.

Sacrifice and pathology:

90 DAY STUDYAnimals were killed with ether and autopsied. Liver, kidney and spleen were weighed in all animals and brain and ovaries in random samples. Samples fo these organs and of lung, heart, pancreas, stomach, small intestine and bladder were fixed and stained. 2 YEAR STUDYaninals either died or were killed with ether if they were moribund. At autopy all the important organs were fixed and examined histologically.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

In the 90 day study a dose dependent reduction was seen in the organ weights of liver and spleen. However no pathological changes were seen, either macroscopic or histological and the toxicologica significance could not be determiend without further investigation. In the 2 year study doses of 1, 2 or 5% were tolerated without signs of chronic toxicity. No significant differences in body weights or survival times were observed. No macroscopic or histological post-mortem findings could be attributed to Cr2O3 treatment. The type and frequency of tumours appearing in experimental and control animals were comparable.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

5 other: nominal % in diet

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

2

Key result

Dose descriptor:

NOAEL

Effect level:

> 1 200 mg/kg bw/day (nominal)

Based on:

element

Remarks:

Cr3+

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Target system / organ toxicity

Key result

Critical effects observed:

no

Applicant's summary and conclusion

Conclusions:

Administration of up to 5% (ca 1200 mg/kg/day) Cr2O3 in the diets of rats for up to two years showed no significant toxic effects or evidence of carcinogenicity.

Executive summary:

Administration of 2 or 5% in the feed for 90 days produced no signs of significant toxic effects and no detectable differences from untreated controls. Fertility of the animals was normal during treatment, and the young showed no malformations.

Feeding of 1, 2 or 5% Cr₂O₃in the feed for 2 yr was well tolerated. The animals were observed throughout life and there was no reduction in the average life expectancy of the experimental animals. Even with the very high oral doses of Cr₂O₃given, no carcinogenic action was detected.