Hexachlorocyclopentadiene

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1978

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1978

Report date:

1978

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

The highest dose did not induce maternal toxicity. Exposure limited to the organogenesis period.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Hexachlorocyclopentadiene

EC Number:

201-029-3

EC Name:

Hexachlorocyclopentadiene

Cas Number:

77-47-4

Molecular formula:

C5Cl6

IUPAC Name:

hexachlorocyclopentadiene

Test material form:

liquid

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: approximately 3 months old at the time of mating
- Weight at study initiation:
- Housing: Individually in wire mesh cages
- Diet (e.g. ad libitum): Purina Laboratory Chow ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: Two weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): controlled
- Humidity (%): controlled
- Air changes (per hr): controlled
- Photoperiod (hrs dark / hrs light):

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

VEHICLE
- Amount of vehicle (if gavage): 10 ml/kg/day

Details on mating procedure:

- Impregnation procedure: cohoused
- M/F ratio per cage: 1/1
- Length of cohabitation: not specified
- Proof of pregnancy: vaginal plug or sperm in vaginal smear] referred to as day 0 of pregnancy

Duration of treatment / exposure:

From Day 6 through Day 15 of gestation

Frequency of treatment:

Once a day

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

3 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

10 mg/kg bw/day (nominal)

Doses / concentrations 4

Dose / conc.:

30 mg/kg bw/day (nominal)

No. of animals per sex per dose:

25 female animals / dose

Control animals:

yes, concurrent vehicle

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: on Days 0, 6, 9, 12, 16 and 20 of gestation

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No

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

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes / No / No data
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: 1/3 per litter
- Skeletal examinations: Yes: 2/3 per litter
- Head examinations: No data

Statistics:

All statistical analyses compared the treatment groups with the control group, with a level of significance at p<0.05. Male to female fetal sex ratio, and number of litters with anomalies were compared using the Chi-square test criterion with Yates correction and/or Fisher's exact probability test, as described by Siegel, to judge significance of differences.
The percentage of early resorbed fetuses, and post implantation losses were compared by the Mann-Whitney U-test as described by Siegel and Weil to judge significance of differences.
Mean number of corpora lutea, total implantations, and viable fetuses were compared by analysis of variance, Bartlett's test for homogeneity of variances and the appropriate t-test as described by Steel and Torrie, using Dunnett's multiple comparison table, to judge significance of differences.
Fetal body weights were compared by analysis of variance and t-test, as described by Steel and Torrie, using Dunnett's multiple comparison table, to judge significance of differences.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

no effects observed

Description (incidence and severity):

There were no differences in appearance or behaviour in any of the rats attributable to treatment with Hexachlorocyclopentadiene at 3 or 10 mg/kg bw per day when compared to the rats in the control group. Staining of the anogenital area was seen in all treated groups, however, it was of longer duration in the rats in the 30 mg/kg bw dosage group.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

Survival was 100% for all groups.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Mean maternal body weights were comparable for rats in the treated groups and the control group.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Maternal developmental toxicity

Number of abortions:

not specified

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

There were no biological meaningful differences in the mean number of implantation losses between the treated groups and the control group.

Total litter losses by resorption:

no effects observed

Description (incidence and severity):

There were no biological meaningful differences in the mean number of resorptions between the treated groups and the control group.

Early or late resorptions:

no effects observed

Description (incidence and severity):

There were no biological meaningful differences in the mean number of resorptions between the treated groups and the control group.

Dead fetuses:

no effects observed

Description (incidence and severity):

There were no biological meaningful differences in the mean number of dead foetuses between the treated groups and the control group.

Changes in pregnancy duration:

not examined

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined

Changes in number of pregnant:

not examined

Details on maternal toxic effects:

There were no biological meaningful differences in the mean number of implantations, corpora lutea, live foetuses, and post implantation losses between the treated groups and the control group. No maternal toxicity was observed.

Effect levels (maternal animals)

Key result

Dose descriptor:

NOAEL

Effect level:

> 30 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

body weight and weight gain

clinical signs

dead fetuses

early or late resorptions

maternal abnormalities

mortality

pre and post implantation loss

total litter losses by resorption

Maternal abnormalities

Key result

Abnormalities:

no effects observed

Results (fetuses)

Fetal body weight changes:

no effects observed

Description (incidence and severity):

There were no biological meaningful differences in the mean foetal body weights between the treated groups and the control group.

Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined

Reduction in number of live offspring:

no effects observed

Description (incidence and severity):

There were no biological meaningful differences in the mean number of live foetuses between the treated groups and the control group.

Changes in sex ratio:

no effects observed

Description (incidence and severity):

There were no biological meaningful differences in the male to female sex ratio between the treated groups and the control group.

Changes in litter size and weights:

not specified

Changes in postnatal survival:

not examined

External malformations:

no effects observed

Description (incidence and severity):

There were no biological meaningful differences in the mean number of litters with malformations between the treated groups and the control group.

Skeletal malformations:

no effects observed

Description (incidence and severity):

There were no biological meaningful differences in the mean number of litters with malformations between the treated groups and the control group.

Visceral malformations:

no effects observed

Description (incidence and severity):

There were no biological meaningful differences in the mean number of litters with malformations between the treated groups and the control group.

Details on embryotoxic / teratogenic effects:

There were no biological meaningful differences in the mean number of live foetuses, mean foetal body weights, male to female sex ratio and the number of litters with malformations between the treated groups and the control group.

Effect levels (fetuses)

Key result

Dose descriptor:

NOAEL

Effect level:

> 30 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reduction in number of live offspring

changes in sex ratio

external malformations

skeletal malformations

visceral malformations

Fetal abnormalities

Key result

Abnormalities:

no effects observed

Overall developmental toxicity

Key result

Developmental effects observed:

no

Applicant's summary and conclusion

Conclusions:

No signs of maternal or developmental toxicity was observed at up to 30 mg/kg bw/day.

Executive summary:

The developmental toxicity / teratogenicity of Hexachlorocyclopentadiene was evaluated during a study performed according to a method similar to the OECD Testing Guideline 414 (non-GLP).

The substance was administrated by gavage to CD rats at dosage levels of 3, 10 and 30 mg/kg bw/day from Day 6 through 15 of gestation. A control group received the vehicle - corn oil - at 10 ml/kg bw/day. During gestation the females were observed for clinical signs, mortality and changes in body weight. Cesarean sections were performed on Day 20 of gestation. The numbers of viable and non-viable fetuses, early and late resorptions, corpora lutea and total implantations were recorded. The fetuses were weighted and sexed. Examinations for external, soft tissue and skeletal anomalies and variations were performed.

There were no differences in appearance or behaviour in any of the rats attributable to treatment with Hexachlorocyclopentadiene at 3 or 10 mg/kg bw per day when compared to the rats in the control group. Staining of the anogenital area was seen in all treated groups, however, it was of longer duration in the rats in the 30 mg/kg bw dosage group. Survival was 100% for all groups. Mean maternal body weights were comparable for rats in the treated groups and the control group. There were no biological meaningful differences in the mean number of implantations, corpora lutea, live foetuses, post implantations losses, mean foetal body weights, male to female sex ratio and the number of litters with malformations between the treated groups and the control group. Developmental variations were comparable for the treated groups and the control group.

A NOAEL above 30 mg/kg bw/day can be derived for both maternal toxicity and developmental toxicity.