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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1982
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards, limited documentation, acceptable for assessment, MTD not reached
Cross-reference
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
publication
Title:
Effects of 1,2-dichloroethane and 1,1,1-trichloroethane in drinking water on reproduction and development in mice
Author:
Lane RW, Riddle BL & Borzelleca JF
Year:
1982
Bibliographic source:
Toxicol. Appl. Pharmacol. 63: 409-421

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Deviations:
yes
Principles of method if other than guideline:
Limitations included
- Dosing: 35 d premating dosing only. No exposure during pregnancy and lactation. No MTD reached: No toxic effect noted at any of the doses used. - Examination: Necropsy performed on pups, but no pathology and histopathology documented. No sperm parameters reported.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material: 1,2-dichloroethane
- Source: Aldrich Chemical Co., Milwaukee, Wisc., USA
- Purity: >99 %

Test animals

Species:
mouse
Strain:
ICR
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Flow Laboratories, Dublin, VA, USA
- Age: 7 weeks old
- Housing: On sawdust bedding in polycarbonate cages
- Diet: Purina Rodent Laboratory Chow 501, ad libitum
- Water: drinking solution, ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature: 22-23 degree C
- Humidity: 40-60 %
- Photoperiod: 12 hours dark / 12 hours light

Males were housed singly; females were kept three per cage, except during parturition and lactation, when they were housed one per cage. Males and females were co-housed (1:3, respectively) for 7 days at each mating. Litters were weaned at 21 days of age.

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
other: 1% solution of Emulphor EL-620
Details on exposure:
The test substance was administered with the drinking water containing 1 % Emulphor EL-620 at 0.03, 0.09, and 0.29 mg/mL, designed to yield doses of 5, 15, or 50 mg/kg bw/d. No aversion to the vehicle or the test substance was observed. Fresh drinking water solutions were prepared twice daily. The highest dose was chosen to provide approx. 1/10 of the LD50.
Details on mating procedure:
Matings between siblings were avoided. Males and females were co-housed (1:3, respectively) for 7 days at each mating.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data on analytical verification of doses.
Duration of treatment / exposure:
Exposure period: none during pregnancy and lactation
Premating exposure period (males): 5 weeks (F0); 11 weeks (F1)
Premating exposure period (females): 5 weeks (F0); 11 weeks (F1)
Duration of test: 25 wk and 24 wk in F0 and F1B animals, resp.
Frequency of treatment:
daily
Details on study schedule:
After 35 days of treatment, F0-generation was mated to produce an F1A generation (10 males, 30 females). Two weeks after weaning of the offspring, the same adults were mated again to produce an F1B generation and subsequently an F1C generation applying the same mating regimen. The F1A generation was subjected to necropsy on postnatal day 21, i.e. after weaning, while F1B mice were mated after weaning (three wk) and a further 11 wk of treatment to produce F2A and, two wk after weaning of the F2A generation, F2B. The F2A generation was autopsied on postnatal day 21.
Doses / concentrations
Remarks:
Doses / Concentrations:
ca. 0, 5, 15 or 50 mg/kg bw/d (30, 90 or 290 mg/L)
Basis:
nominal in water
No. of animals per sex per dose:
F0: 10 males and 30 females
F1: 10 males and 30 females
Control animals:
yes, concurrent no treatment
Details on study design:
no further details given
Positive control:
none

Examinations

Parental animals: Observations and examinations:
Weekly body weight and twice-weekly fluid consumption data were collected for the F0 and F1B adult mice throughout the study. Mean body weights were analysed similarly. Adult percentage mortality was calculated at the termination of each generation (25 weeks of dosing for the F0; 24 for the F1B). Mice found moribund or sacrificed at the end of the study were necropsied.
Oestrous cyclicity (parental animals):
Weights of rats showing vaginal smears were recorded on days 0, 6, 14, and 21 of gestation. 
Sperm parameters (parental animals):
not investigated
Litter observations:
Twenty-one-day survival studies were performed on litters from F1 and F2 matings. Litter size was recorded on Days 0, 4, 7, 14, and 21. Litters were randomly culled to 10 pups each on day 4. Offspring were weighed collectively on days 7 and 14 and individually on day 21. All pups from each litter were sacrificed and necropsied at the conclusion of each 21-day survival study.
Postmortem examinations (parental animals):
Mice found moribund or sacrificed at the end of the study were necropsied.
Postmortem examinations (offspring):
All pups from each litter were sacrificed and necropsied at the conclusion of each 21-day survival study.
Statistics:
Group differences in body weight and fluid uptake were evaluated by Duncan's multiple range test. Adult reproductive performance was evaluated by fertility and gestation indices. Evaluation of litter data included Kruskal-Wallis test and Dunn's test. Level of significance chosen was always p<0.05.
Reproductive indices:
Adult reproductive performance was evaluated by calculation of fertility and gestation indices.
Offspring viability indices:
Viability and lactation indices were calculated.

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
no effects observed
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:
not specified
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
not examined
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed

Details on results (P0)

Adult mice (F0 and F1B) showed no significant changes in water consumption, body weight or fertility index and gestation index (number of females with live litters/number of females pregnant). Mortalities were seen only in the F0 animals (2/10 m, 3/30 f) at the lowest dose, e.g. effect was not dose related. At scheduled necropsy (after week 24  or 25 of dosing), neither chemical- nor dose-related gross pathology was observed in either generation.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
ca. 50 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: No adverse reproduction effects up to highest dose used in the study.

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings:
not examined

Details on results (F1)

Among the offspring of F0 and F1B animals (F1A, F1B, F2A), no significant changes were seen in mean litter size, mean post-natal body weights (measured on days 7, 14 and 21), or survival (measured on days 4 and 21). There was no evidence of dose-dependent gross pathology or congenital external,  visceral or skeletal malformations although no details or data were given.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
ca. 50 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: No adverse reproduction effects up to highest dose used in the study.

Results: F2 generation

Effect levels (F2)

Dose descriptor:
NOAEL
Generation:
F2
Effect level:
ca. 50 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: No adverse reproduction effects up to highest dose used in the study.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Dominant lethal screening:

Statistically significant effects in the ratio of dead to live fetuses were observed in both generations. However, these effects, which were both increases and decreases compared to controls, did not appear to be dose related.

Teratogenicity screening:

Maternal ingestion of the test compound produced no apparent adverse reproductive effects or increased incidence of fetal visceral or skeletal anomalies.

Applicant's summary and conclusion

Conclusions:
There appeared to be no dose-dependent effects on fertility, gestation, viability, or lactation indices. Pup survival and weight gain were not adversely affected. 1,2 -dichlororethane failed to produce significant dominant lethal mutations or teratogenic effects in either of the two generations tested.
Executive summary:

A multigeneration reproduction study was modified to include screening for lethal and teratogenic effects of 1,2 -dichloroethane in drinking solution (Emulphor: deionized water, 1:99, v/v). Male and female (10 and 30/dose level, respectively) ICR Swiss mice received 1,2 -dichloroethane at concentrations of 0, 0.03, 0.09 or 0.29 mg/mL. These concentrations were designed to yield daily doses of 0, 5, 15 or 50 mg/kg bw/d. No taste aversion was evident. There appeared to be no dose-dependent effects on fertility, gestation, viability, or lactation indices. Pup survival and weight gain were not adversely affected. 1,2 -dichlororethane failed to produce significant dominant lethal mutations or terata in either of the two generations tested.