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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
fertility, other
Remarks:
Information on reproductive organs were obtained during a subchronic toxicity study by the oral route on rats performed according to the OECD Testing Guideline 408
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1981
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:
1981
Report Date:
1981

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Version / remarks:
Information on reproductive organs were obtained during a subchronic toxicity study by the oral route on rats performed according to the OECD Testing Guideline 408
Deviations:
yes
Remarks:
Exposure 5 days per week
Principles of method if other than guideline:
Information on reproductive organs were obtained during a subchronic toxicity study by the oral route on rats performed according to the OECD Testing Guideline 408.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratory
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 52 days
- Weight at study initiation: Females: 99 - 135 g. Males: 130 - 170 g.
- Housing: Five animals per cage in polycarbonate cages.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 20 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 72°F to 78°F (22°C to 25°C)
- Humidity (%): 23% to 58%
- Air changes (per hr): 15 changes per hour
- Photoperiod (hrs dark / hrs light): 12h/12h

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
VEHICLE
- Lot/batch no.: 1-13-82A
- Amount of vehicle (if gavage): 0.5ml/100g
- Purity: 100%
Details on mating procedure:
not applicable
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dosage analysis for concentration verification was performed in duplicate on each dose level from the first set of mixings and a set approximately midway through the study.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Once a day, 5 days per week. The frequency was selected to mimic the exposure of workers.
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
10 mg/kg bw/day (nominal)
Dose / conc.:
19 mg/kg bw/day (nominal)
Dose / conc.:
38 mg/kg bw/day (nominal)
Dose / conc.:
75 mg/kg bw/day (nominal)
Dose / conc.:
150 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10 animals/sex/dose
Control animals:
yes, concurrent vehicle
Details on study design:
not specified

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: Initially, weekly, and at termination

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: Not specified

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

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No
Oestrous cyclicity (parental animals):
Not included
Sperm parameters (parental animals):
Not included
Litter observations:
Not applicable
Postmortem examinations (parental animals):
GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes. Histopathological examination of seminal vesicles, prostate and testes or mammary glands, ovaries and uterus was performed at dose levels of 0, 75 and 150 mg/kg.
Postmortem examinations (offspring):
Not applicable
Statistics:
Not specified
Reproductive indices:
Not applicable
Offspring viability indices:
Not applicable

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Animals treated at 150 mg/kg bw/day displayed a ruffled fur and a slight inactivity that were considered treatment-related. Other clinical observations were attributed to the housing of animals collectively or were not considered as significant due to their low incidence.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, treatment-related
Description (incidence):
6/10 male rats receiving 150 mg/kg bw/day died as a result of the treatment. 1/10 female rats receiving 75 mg/kg bw/day died as a result of the treatment. Other deaths occurred in male and female rats at different doses that were attributed to improper gavage technique.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
A significant reduction of the bodyweight was observed in male rats receiving 38 mg/kg bw/day or above. A reduction was also observed in male rats receiving 10 and 19 mg/kg bw/day.
A significant reduction of the bodyweight was observed in female rats receiving 75 mg/kg bw/day or above. A reduction was also observed in male rats receiving 10, 19 and 75 mg/kg bw/day.
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:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Animals exposed to 38 mg/kg bw/day and above exhibited acute kidney tubular necrosis characterised by vacuolisation, cytomegaly, karyomegaly, anisokaryosis, and tubular dilation.
In male rats receiving 38 mg/kg bw/day or above and female rats receiving 19 mg/kg bw/day, significant proliferation and inflammatory changes of the epithelia in the stomach were observed.

No relevant treatment related effects were reported on seminal vesicles, prostate and testes or mammary glands, ovaries and uterus.
Histopathological findings: neoplastic:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
not examined

Details on results (P0)

No relevant treatment related effects were reported on seminal vesicles, prostate and testes or mammary glands, ovaries and uterus during the subchronic toxicity study by oral route on rats.

Effect levels (P0)

Remarks on result:
other: see 'subchronic repeated dose toxicity: oral_key study' for details on the results

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:
not examined
Dermal irritation (if dermal study):
not examined
Mortality:
not examined
Body weight and weight changes:
not examined
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

Reproductive function / performance (P1)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
not examined

Effect levels (P1)

Remarks on result:
not measured/tested

Results: F1 generation

General toxicity (F1)

Clinical signs:
not examined
Dermal irritation (if dermal study):
not examined
Mortality / viability:
not examined
Body weight and weight changes:
not examined
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
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined
Other effects:
not examined

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined

Effect levels (F1)

Remarks on result:
not measured/tested

Results: F2 generation

General toxicity (F2)

Clinical signs:
not examined
Dermal irritation (if dermal study):
not examined
Mortality / viability:
not examined
Body weight and weight changes:
not examined
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
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined

Developmental neurotoxicity (F2)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F2)

Developmental immunotoxicity:
not examined

Effect levels (F2)

Remarks on result:
not measured/tested

Overall reproductive toxicity

Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
No effects were identified on reproductive organs during a subchronic toxicity study by oral route performed on rats at up to 150 mg/kg bw.
Executive summary:

Information on reproductive organs were obtained during a subchronic toxicity study by the oral route on rats performed according to a method similar to the OECD Testing Guideline 408 (non GLP).

Rats received doses of 0, 10, 19, 38, 75 and 150 of Hexachlorocyclopentadiene by gavage once a day, 5 days per week, for 13 weeks. The protocol was determined to mimic the exposure of workers. Mortality, clinical signs and body weight were recorded. At the end of the study, surviving animals were subjected to gross necropsy and histopathology. Histopathological examination of seminal vesicles, prostate and testes or mammary glands, ovaries and uterus was performed at dose levels of 0, 75 and 150 mg/kg bw.

No relevant treatment related effects were reported on seminal vesicles, prostate and testes or mammary glands, ovaries and uterus during the subchronic toxicity study by oral route on rats.