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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
fertility, other
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Read-acros from soluble chromates. Acceptabe study report which meets basic scientific principles.

Data source

Reference
Reference Type:
publication
Title:
Embryo- and fetotoxicity of chromium in pregestationally exposed mice.
Author:
Junaid, M., R. C. Murthy, et al.
Year:
1996
Bibliographic source:
Bull Environ Contam Toxicol.57(2): 327-34.

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The effect of pregestational exposure to chromium was studied in female mice. The mice were given potassium chromate in drinking water for 20 days, after which they were mated with unexposed males. Signs of general toxicity, and numbers of implantations, corpora lutea and pre-implantation losses were followed.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Potassium dichromate. No details presented.

Test animals

Species:
mouse
Strain:
Swiss
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Industrial Toxicology Research Centre
- Age at study initiation: (P) x 4 months
- Weight at study initiation: (P) ; Females: 30 ± 5 g
- Fasting period before study: no data
- Housing: individual cages until day 20 when matched with utreated males
- Diet (e.g. ad libitum): feed pellets from Lipton India ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-22°C
- Humidity (%): 50 ±5%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 h

Administration / exposure

Route of administration:
oral: drinking water
Details on exposure:
250, 500, or 750 ppm in drinking water for 20 days before mating
Details on mating procedure:
Females were checked for pregnancy the next morning after mating. The day that the vaginal plug was found was degnated at day 0 of gestation.
After becoming pregnant the females were kept individually in plastic cages.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Calculated from water consuption.
Duration of treatment / exposure:
20 days
Frequency of treatment:
Daily ad libitum in water
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 250, 500, 750 ppm
Basis:
nominal in water
Remarks:
Doses / Concentrations:
0, 63, 119, 174 mg Cr(VI)/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
15
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on an earlier study (Trivedi et al 1989), average Cr intake of humans in drinking water is ca 200 µg/day.

- Actual exposure calculated based on water intake: 0, 63, 119 and 174 mg Cr(VI)/kg/day.
Positive control:
No

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data


BODY WEIGHT: Yes


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: no data

OTHER:
Estrous cyclicity (parental animals):
No data
Sperm parameters (parental animals):
No
Litter observations:
10 pregnant animals/group were sacrificed on day 19 of gestation. Total implantations/litter, number of live/dead foetuses, crown-rump length, number of resoprtions, foetus and placenta weights were recorded.
Postmortem examinations (parental animals):
SACRIFICE
- Maternal animals: Day 19 of gestation.

GROSS NECROPSY
- No data

HISTOPATHOLOGY / ORGAN WEIGHTS: placentae
Postmortem examinations (offspring):
Foetuses were examined for gross external abnormalities. 1/3 of the foetuses were fixed in Bouin's fluid for examination of visceral abnormalities; 2/3 fixed in 95% ethanol and stained by the Alizarin red S method in order to enable examination skeletal deformities.
Statistics:
One-way Anova followed by Student's t-test; Fischer's Exact test.

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
3 mothers died in the highest dose group
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
increades placental weight
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: estrous cycle:
not specified
Reproductive function: sperm measures:
not examined
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
reduced number of implantations, increased numbers of pre-implantation losses

Details on results (P0)

General toxicity was observed as 3 mothers in the highest dose group died.
Fertility effects were observed in the highest dose group (174 mg Cr(VI)/kg/day, where no implantation were seen and the number of corpora lutea was significantly decreased. Also at the concentration 119 mg Cr(VI)/kg/day could reduced numbers of implantations and increases in pre-implantation losses be observed.

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Effect level:
119 other: mg Cr(VI)/kg/day
Sex:
female
Basis for effect level:
other: General toxicity for mothers
Dose descriptor:
NOAEL
Effect level:
63 other: mg Cr(VI)/kg/day
Sex:
female
Basis for effect level:
other: Female fertility effects

Results: F1 generation

General toxicity (F1)

Clinical signs:
effects observed, treatment-related
Mortality / viability:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
crown-rump length
Histopathological findings:
not specified

Details on results (F1)

Presented under 7.8.2 Developmental toxicity

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Pregestational exposure to potassium dichromate in drinking water caused general toxicity in the mothers (NOAEL 119 mg Cr(VI)/kg/day). Female fertility effects (decreased numbers of implantations and corpora lutaea, increases in pre-implantation losses) were significant, and NOAEL for these effects was 63 mg Cr(VI)/kg/day.
Executive summary:

The effect of pregestational exposure to chromium was studied in adult female Swiss albino mice(Junaid et al 1996b). Groups of 15 mice were administered daily 0, 250, 500 or 750 ppm heaxavalent chromium, as potassium dichromate in drinking water for 20 days, after which they were mated with unexposed males. On day 19 of gestation, 10 pregnant females from each group were randomly selected and sacrificed. Based on water intake and the reported body weight of 30 g, the chromium exposures of the rats can be calculated as 0, 63, 119 and 174 mg Cr(VI)/kg/day.

No clinical signs of toxicity could be detected in the treated mothers. At the highest dose level (174 mg Cr(VI)/kg/day ) 3 deaths occurred among the 15 mice in the group. Autopsy did not establish the cause of death, but as all cases were in the high exposure group, the deaths were likely to be connected to the exposure. No implantations (100% loss) were seen in the highest exposure group, and the number of corpora lutea was significantly decreased at this concentration. Pregestational treatment with 119 mg Cr(VI)/kg/day also reduced the number of implantations. At 119 mg/kg/day there was also a statistically significant increase in pre-implantation losses. A NOAEL of 119 mg Cr(VI)/kg/day can be identified for general toxicity. The NOAEL for female fertility effects appears to be 63 mg Cr(VI)/kg/day. Developmental effects of the foetuses are reported under "Developmental toxicity".