Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No toxicity to reproduction studies were available investigating the effects of Hexachlorocyclopentadiene to the fertility. It was possible to obtain information on the effects of the substance to reproductive organs from repeated-dose toxicity studies performed on the substance.

 

Information on effects to reproductive organs following an oral exposure were obtained during a subchronic toxicity study performed on rats according to a method similar to the OECD Testing Guideline 408 (non GLP). Rats received up to 150 mg/kg bw/d of Hexachlorocyclopentadiene by gavage once a day, 5 days per week, for 13 weeks. The protocol was determined to mimic the exposure of workers. Seminal vesicles, prostate and testes or mammary glands, ovaries and uterus were examined at the end of the study. No significant treatment related effects were reported on reproductive organs.

 

Information on effects to reproductive organs following an inhalation exposure were obtained during a subchronic toxicity study performed on rats according to a method similar to the OECD Testing Guideline 413. Rats were exposed at concentrations up to 2 ppm of Hexachlorocyclopentadiene in air (equivalent to 22.28 mg/m3) for 6 hours per day, 5 days per week, for 13 weeks. Adrenal gland, epididymis, mammary gland, ovary, pituitary gland, prostate gland, testis, and uterus were examined at the end of the study. No significant treatment related effects were reported on reproductive organs.

 

An ovarian inflammation was observed in mice exposed to Hexachlorocyclopentadiene by inhalation for two years during a study performed by the US NTP (1994). Considering that this effect was not identified in the subchronic study performed on mice by the US NTP (1994) nor in the 15-month interim group included in this chronic study, it can be concluded that this effect occurred after 15 months of exposure to the substance. According to Gosden et al. (1983) the fertility is already low or inexistent in 15-month-old mice or older, therefore this effect is not considered to affect the fertility.

 

Reference

Gosden R, Laing S, Felicio L, Nelson J, Finch C (1983) Imminent oocyte exhaustion and reduced follicular recruitment mark the transition to acyclicity in aging C57BL/6J mice. Biol Reprod., 28(2):255-60.

Link to relevant study records

Referenceopen allclose all

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
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
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
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.
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
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
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: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
not examined
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.
Remarks on result:
other: see 'subchronic repeated dose toxicity: oral_key study' for details on the results
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: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
not examined
Remarks on result:
not measured/tested
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
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Remarks on result:
not measured/tested
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
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Remarks on result:
not measured/tested
Reproductive effects observed:
no
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.

Endpoint:
fertility, other
Remarks:
Information on reproductive organs were obtained during a subchronic toxicity study by inhalation on rats performed according to the OECD Testing Guideline 413.
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 25 October 1983 to 27 January 1984
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to
Guideline:
other: OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Version / remarks:
Information on reproductive organs were obtained during a subchronic toxicity study by inhalation on rats performed according to the OECD Testing Guideline 413.
Deviations:
yes
Remarks:
No FOB and ophthalmological examination were performed
Principles of method if other than guideline:
Information on reproductive organs were obtained during a subchronic toxicity study by inhalation on rats performed according to the OECD Testing Guideline 413.
GLP compliance:
yes
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Frederick Cancer Research Facility
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 6 weeks
- Weight at study initiation: Females: 101 to 108g / Males: 118 to 127g
- Housing: individually in stainless steel cages (Hazleton Systems)
- Diet (e.g. ad libitum): NIH-07 pelleted rodent diet ad libitum
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20°C-21°C
- Humidity (%): 35%-65%
- Air changes (per hr): 20 changes/h
- Photoperiod (hrs dark / hrs light): 12h/12h
Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
air
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Stainless steel whole-body inhalation chamber (Hazleton Systems)
- Source and rate of air: fresh air
- System of generating particulates/aerosols: Vaporizer. Gardner Type CN condensation nuclei detector
used to ensure the generation of vapour and not of aerosol.

TEST ATMOSPHERE
- Brief description of analytical method used: On-line gas chromatograph with electron capture detector.
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations
Details on mating procedure:
not applicable
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
A gas chromatograph with an electron capture detector was used. The system was a 3% OV-225 coating on a 100/120 mesh Gas Chrom Q column and an argon/methane (9O:lO) carrier gas at a flow rate of 30 mL/minute. Column was maintained isothermally at 125°C.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 hours per day, 5 days per week
Dose / conc.:
0 ppm (nominal)
Remarks:
Equivalent to 0 mg/m3.
Dose / conc.:
0.04 ppm (nominal)
Remarks:
Equivalent to 0.45 mg/m3.
Dose / conc.:
0.15 ppm (nominal)
Remarks:
Equivalent to 1.67 mg/m3.
Dose / conc.:
0.4 ppm (nominal)
Remarks:
Equivalent to 4.46 mg/m3.
Dose / conc.:
1 ppm (nominal)
Remarks:
Equivalent to 11.14 mg/m3.
Dose / conc.:
2 ppm (nominal)
Remarks:
Equivalent to 22.28 mg/m3.
No. of animals per sex per dose:
10 animals/sex/dose.
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Not specified
Positive control:
No
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: At beginning, 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: No

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

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Days 4, 16, 46 and 93
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals: All animals

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Days 4, 16, 46 and 93
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals: All animals
URINALYSIS: Yes
- Time schedule for collection of urine: Days 3, 15, 45, 92
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Not specified
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 adrenal gland, epididymis, mammary gland, ovary, pituitary gland, prostate gland, testis, and uterus.
Postmortem examinations (offspring):
Not applicable
Statistics:
Statistical analyses for possible dose-related effects on survival used Cox’s (1972) method for testing two groups for equality and Tarone’s (1975) life table test to identify dose-related trends.
Reproductive indices:
Not applicable
Offspring viability indices:
Not applicable
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Listlessness was observed in rats exposed to 0.4, 1 and 2 ppm. Respiratory distress was observed in rats exposed to 1 and 2 ppm.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, treatment-related
Description (incidence):
All rats exposed to 1 or 2 ppm of test substance died in the first 4 weeks of exposure. All rats exposed to lower concentrations survived.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Final mean body weight and mean body weight gain of male rats exposed to 0.4 ppm were significantly lower than those of the control animals.
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:
effects observed, non-treatment-related
Description (incidence and severity):
Statistically significant differences in haematology parameters were observed but were not attributed to the test substance as they were not persistent nor dose-related.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
Statistically significant differences in clinical biochemistry parameters were observed but were not attributed to the test substance as they were not persistent nor dose-related.
Urinalysis findings:
effects observed, non-treatment-related
Description (incidence and severity):
Statistically significant differences in urinalysis parameters were observed but were not attributed to the test substance as they were not persistent nor dose-related.
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):
In rats exposed to 1 and 2 ppm of test substance, acute and subacute inflammation was observed consisting of vascular congestion, edema, accumulation of fibrin, and infiltrates of neutrophils and mononuclear cells. In some animals fibrinosuppurative exudate and suppurative alveolar inflammation were observed.
In rats exposed to 0.4 ppm, focal or multifocal suppurative inflammation of the nose or lung was observe d (especially in male rats). Focal squamous metaplasia was observed in some male rats exposed to 0.4 ppm and some male and female rats exposed to 1 and 2 ppm.

No relevant treatment related effects were reported on reproductive organs.
Histopathological findings: neoplastic:
no effects observed
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
not examined
Mortality was observed in rats exposed to 1 ppm and above. No relevant treatment related effects were reported on reproductive organs during the subchronic toxicity study by inhalation on rats.
Remarks on result:
other: other: see 'subchronic repeated dose toxicity: inhalation_key study' for details on the results
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: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
not examined
Remarks on result:
not measured/tested
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
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Remarks on result:
not measured/tested
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
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Remarks on result:
not measured/tested
Reproductive effects observed:
no
Conclusions:
Mortality was observed in rats exposed to 1 ppm and above. No relevant treatment related effects were reported on reproductive organs during the subchronic toxicity study by inhalation on rats at lower concentrations.
Executive summary:

Information on reproductive organs were obtained during a subchronic toxicity study by inhalation on rats performed according to a method similar to the OECD Testing Guideline 413.

Rats were exposed at concentrations of 0, 0.04, 0.15, 0.4, 1 and 2 ppm of Hexachlorocyclopentadiene in air(equivalent to 0, 0.45, 1.67, 4.46, 11.14 and 22.28 mg/m3) for 6 hours per day, 5 days per week, for 13 weeks. Mortality, clinical signs, body weight, and haematology, clinical biochemistry, and urinalysis parameters were recorded. At the end of the study, surviving animals were subjected to gross necropsy and histopathology. Histopathological examination of adrenal gland, epididymis, mammary gland, ovary, pituitary gland, prostate gland, testis, and uterus was performed.

Mortality was observed in rats exposed to 1 ppm and above. No relevant treatment related effects were reported on reproductive organs during the subchronic toxicity study by inhalation on rats at lower concentrations.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
150 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Information on effects on fertility 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).
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Dose descriptor:
NOAEC
4.46 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
Information on effects on fertility were obtained during a subchronic toxicity study by inhalation on rats performed according to a method similar to the OECD Testing Guideline 413.
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Description of key information

The developmental toxicity / teratogenicity of Hexachlorocyclopentadiene was investigated during non-GLP studies performed according to the OECD Testing Guideline 414 on rats, rabbits, and mice. The study performed on rats was considered as the key study.

 

The substance was administrated by gavage to CD rats at dosage levels of 3, 10 and 30 mg/kg bw/day from days 6 through 15 of gestation. 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 between the treated groups and the control group. Developmental variations were comparable for the treated groups and the control group. A NOAEL of 30 mg/kg bw/day can be derived for both maternal toxicity and developmental toxicity.

Link to relevant study records
Reference
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
Qualifier:
equivalent or similar to
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
Species:
rat
Strain:
Crj: CD(SD)
Details on test animals 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):

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
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
3 mg/kg bw/day (nominal)
Dose / conc.:
10 mg/kg bw/day (nominal)
Dose / conc.:
30 mg/kg bw/day (nominal)
No. of animals per sex per dose:
25 female animals / dose
Control animals:
yes, concurrent vehicle
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.
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
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.
Key result
Dose descriptor:
NOAEL
Effect level:
> 30 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
clinical signs
mortality
body weight and weight gain
maternal abnormalities
pre and post implantation loss
total litter losses by resorption
early or late resorptions
dead fetuses
Key result
Abnormalities:
no effects observed
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.
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
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
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.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
30 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
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) with non-significant deviations.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

No adverse were observed to reproductive organs during the subchronic repeated-dose toxicity studies performed on the substance by the oral and inhalation routes. The ovarian inflammation observed in female mice following an exposure to the substance for more than 15 months was not considered as affecting the fertility due to the time necessary for this effect to appear. No developmental effects was observed in the developmental toxicity studies performed on the substance apart from an increased frequency of foetuses with 13 ribs compared to control in the highest dose group in one study on rabbits. The normal number of ribs in rabbits is 12 or 13 so this effect is not considered as adverse. It is concluded that the substance does not meet the criteria for classification as toxic to reproduction according to Regulation (EC) No.1272/2008.