Reaction mass of heptachromium tricarbide and trichromium dicarbide

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Read-across to chromium(III) oxide. The release of chromium from chromium carbide is very similar to the release from chromium metal and chromium(III) oxide and therefore the results obtained with these substances can readily be used in the assessment of trichromium dicarbide. Acceptable, well-documented study report.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

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. and R. Preussman

Year:

1975

Bibliographic source:

Food Cosmet Toxicol.13(3): 347-51.

Materials and methods

Principles of method if other than guideline:

Chromium(III) oxide was baked into bread at concentrations of 2% and 5% and this bread was fed to animals 5 days/week for a period of 90 days.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Chromium(III) oxide

IUPAC Name:

Chromium(III) oxide

Details on test material:

- Name of test material (as cited in study report): Chromium oxide green (Schultz no 1451; Colour Index no. 77288; pigment green 17)
- Molecular formula (if other than submission substance): Cr2O3
- Molecular weight (if other than submission substance): 152
- Substance type: pure substance (non-hydrated from)
- Physical state: fine green powder
- Analytical purity: maximum content of 3 ppm Cr(III)
- Impurities (identity and concentrations): free from chromate CrO4(2-). With respect to heavy-metal impurities the product compiled with the specifications of the Deutsche Forschungsgemeinschaft, Farbstoff-Kommission (1959)
- Composition of test material, percentage of components: pure Cr2O3 (no data on %)
- Isomers composition: no data
- Purity test date: no data
- Lot/batch No.: no data
- Expiration date of the lot/batch: no data
- Stability under test conditions: no data
- Storage condition of test material: no data
- Other:

Test animals

Species:

rat

Strain:

other: BD rats

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: inbread BD rats, no data on source
- Age at study initiation: about 100 days
- Weight at study initiation: about 200 g
- Fasting period before study: no data
- Housing: in groups of four rats in Makrolon cages
- Diet (e.g. ad libitum): Altromin standard diet ad libitum for controls. Bread (2835 g flour, 150 g milk powder, 150 g mixed salts (NaCl, CaHPO4 and Cu, Zn, Co, Mn and K), 150 g cooking oil, 150 g cod-liver oil, 300 g malt extract, 600 g sugar, 80 g yeast and 900 ml water) containing 2% or 5% of the test substance for test groups (ad libitum). At weekends the treatment groups received the control diet with a vegetable supplement.
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data


IN-LIFE DATES: From: day 90 To: day 91

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: bread

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: no solutions


DIET PREPARATION
- Rate of preparation of diet (frequency): twice weekly
- Mixing appropriate amounts with (Type of food): Incorporationg 2% or 5% of the test substance into a dough made from 2835 g flour, 150 g milk powder, 150 g mixed salts (NaCl, CaHPO4 and Cu, Zn, Co, Mn and K), 150 g cooking oil, 150 g cod-liver oil, 300 g malt extract, 600 g sugar, 80 g yeast and 900 ml water, and subsequently baked
- Storage temperature of food: no data


VEHICLE
- Justification for use and choice of vehicle (if other than water): bread
- Concentration in vehicle: 2% and 5%

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The bread given to the rats was weighed, and the uneaten bread was weighed in order to determined the amount consumed. There were only small losses from crumbs. The estimated uptake of Cr(III) based on the Cr2O3 concentrations in the bread consumed was 568 mg/kg/day for males and 547 mg/kg/day for males in the 2% group, and 1368 mg/kg/day for males and 1216 mg/kg/day for females in the 5% group.

Duration of treatment / exposure:

90 days

Frequency of treatment:

5 days/week

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
568 or 1368 mg Cr(III)/kg/day for males; 547 or 1216 mg Cr(III)/kg/day for females
Basis:
actual ingested

Doses / concentrations 2

Remarks:

Doses / Concentrations:
2 or 5 %
Basis:
nominal in diet

No. of animals per sex per dose:

2% dose: 14 males and 5 females
5% dose: 5 males and 10 females
controls: 6 males and 6 females

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: The doses were selected to be higher than the 1% in feed recommended by national (Deutsche Forschungsgemenschaft) and international (WHO) authorities
- Rationale for animal assignment (if not random): no data
- Rationale for selecting satellite groups: no satellite groups

Positive control:

No

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data


DETAILED CLINICAL OBSERVATIONS: No data


BODY WEIGHT: Yes
- Time schedule for examinations: every second week


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes (4 animals per cage, average food consumption per animal)
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data


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: No data


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data


OPHTHALMOSCOPIC EXAMINATION: No data


HAEMATOLOGY: Yes
- Time schedule for collection of blood: The blood picture was determined before the beginning of the experiment and monthly during feeding. At the end of the study, the animals were fasted for 24 hours, after which blood samples were taken from retrobulbar plexus and from the tail vein.
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals: All
- Parameters checked in table 1 were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At the end of the feeding period animals were fasted for 24 h, after which blood samples were taken from the retrobulbar plexus.
- Animals fasted: Yes
- How many animals: All animals
- Parameters checked in table 2 were examined.


URINALYSIS: Yes
- Time schedule for collection of urine: Random samples were taken during the course of the study and from all animals in the last week of the experiment
- Metabolism cages used for collection of urine: No data
- Animals fasted: No
- Parameters checked in table 3 were examined.


NEUROBEHAVIOURAL EXAMINATION: No data



OTHER: During the last 30 days of treatment, males and females (altogether 9 pairs) from the same treatment group, were paired to test fertility. The number of young in each litter was recorded.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see table 4)
HISTOPATHOLOGY: Yes (see table 5)

Statistics:

No data given on statistical analysis methods used.

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:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

ORGAN WEIGHTS: Dose-dependent decreases in the absolute weights of liver and spleen were observed, but did not correlate with any pathological findings of the microscopic examinations, and therefore these effects were not considered as toxic.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

ca. 1 368 mg/kg bw/day (actual dose received)

Sex:

male

Basis for effect level:

other: No signs of toxicity observed among male rats eating bread containing 5% Cr = ca 1368 mg/kg/day

2

Dose descriptor:

NOAEL

Effect level:

ca. 1 216 mg/kg bw/day (actual dose received)

Sex:

female

Basis for effect level:

other: No signs of toxicity observed among female rats eating bread containing 5% Cr = ca 1216 mg/kg/day

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Although the doses of chromium oxide used in this study were relatively high (Cr(III) intake for males ca 1368 mg/kg/day and 1216 mg/kg/day for females), no signs of toxicity were observed, which can obviously be explained by the water-insolubility and poor bioavailability of chromium(III)oxide.

Executive summary:

The toxic potential of chromium(III) oxide was studied in rats, which were fed bread containing chromium oxide at concentration levels of 2% and 5% during a period of 90 days (5 days/week). In the 2% group, the intake of chromium(III) (as calculated from the estimated chromium(III) oxide intake, based on the food consumption) corresponded to 568 mg/kg/day for male rats and 547 mg/kg/day for females. In the 5% group, the intake was 1368 mg/kg/day for males and 1216 mg/kg/day for females. No clinical signs of toxicity occurred during the study period. No effects on body weight, food intake, blood or urinary samples were observed either. Dose-dependent decreases in the absolute weights of liver and spleen were observed, but did not correlate with any pathological findings of the microscopic examinations, and therefore these effects were not considered as toxic. Although the doses of chromium oxide used in this study were relatively high, no signs of toxicity were observed, which can obviously be explained by the water-insolubility and poor bioavailability of chromium(III) oxide.