Registration Dossier

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

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 guidelineopen allclose all
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Version / remarks:
Feeding
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 452 (Chronic Toxicity Studies)
Version / remarks:
Feeding
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
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 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 / concentrationsopen allclose all
Remarks:
1, 2 or 5% in diet
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

open allclose all
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
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.


Route: .live1