Methylcyclopentadiene

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well conducted, GLP compliant, study according to internationally recognised test methods

Data source

Reference

Reference Type:

other: USEPA High Production Volume Information System (HPVIS)

Title:

Unnamed

Year:

2003

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Methylcyclopentadiene

EC Number:

247-724-5

EC Name:

Methylcyclopentadiene

Cas Number:

26472-00-4

Molecular formula:

not applicable, UVCB substance

IUPAC Name:

3a,4,7,7a-tetrahydro-1H-4,7-methanoindene

Test material form:

liquid

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on mating procedure:

- M/F ratio per cage: No data
- Length of cohabitation: 2 weeks

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Females - Approximately 2 weeks pre-mating, a cohabitation (mating) period of approximately 2 weeks, a gestation period of approximately 3 weeks and a lactation period of approximately 4 days.
Males - Total of 31 days

Frequency of treatment:

Daily, 7 days / week

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 20, 100 and 300 mg/kg/day
Basis:
nominal conc.

No. of animals per sex per dose:

12 male / 12 female

Control animals:

yes, concurrent vehicle

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of [...] pups/litter ([...]/sex/litter as nearly as possible); excess pups were killed and discarded - No data.

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals - after 31 days of treatment
- Maternal animals: All surviving animals - Day 4 post-partum

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring were sacrificed at 4 days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination)

Statistics:

Group means and standard deviations were calculated for all measured parameters.

Jonckheere-Terpstra trend test - Body weight, weight gain, food consumption and organ weights
One-way analysis of variance followed with Dunnett’s test - Food efficiency
Cochran-Armitage trend test - Clinical observations, mating index, fertility index and gestation index
Jonckheere-Terpstra trend test - Gestation time, implantation site numbers, implantation efficiency, mean number of pups/litter, % live pups, day 0-4 viability of pups, viability index, number of corpora lutea , sex ratio, pre-implantation loss and post-implantation loss.
linear contrast of the least square means - Mean pup weights

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Reproductive function / performance (P0)

Reproductive performance:

effects observed, treatment-related

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
Increased incidences of salivation, stained and/or wet fur were observed in males and females dosed at 100 and 300 mg/kg/day. Salivation was observed in males and females dosed at 20 mg/kg/day.

BODY WEIGHT (PARENTAL ANIMALS)
In females, there were no treatment related effects on body weight or weight gain in animals dosed at 300 mg/kg/day during the pre-mating period. By the end of the gestation period (day 21), body weight was 5% lower than controls and for the interval of gestation (days 0-21) weight gain was 13% lower than control values. There were no effects on body weight or weight gain at any dose level during the lactation period.

In males, a treatment related decrease in body weight and/or weight gain was observed in animals dosed at 300 mg/kg/day. On test day 28, body weight of males was 7.5% lower than controls. Body weight gain in males over the period of test days 1-28 was 19% lower than controls. Instances of decreased body weight and/or weight gain were also noted in animals dosed at 100 mg/kg/day.

FOOD CONSUMPTION (PARENTAL ANIMALS)
In females, statistically significant decreases in food consumption and/or food efficiency occurred in animals dosed at 300 mg/kg/day during the gestation period. Food consumption and food efficiency were decreased by 7.5% and 7.3%, respectively during gestation (days 0-21).

In males, transient changes in food consumption and/or food efficiency were observed in males dosed at 100 or 300 mg/kg/day.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
No treatment related effects or statistically significant differences in mating index, fertility index, gestation length, number of implantation sites, implantation efficiency, pre-implantation loss, post-implantation loss, or number of corpora lutea were observed.

HISTOPATHOLOGY (PARENTAL ANIMALS)
There were no treatment related effects on morphology of the reproductive tract in either males or females.

Effect levels (P0)

Dose descriptor:

NOEL

Effect level:

300 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Fertility

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Details on results (F1)

VIABILITY (OFFSPRING)
No effects

BODY WEIGHT (OFFSPRING)
Decreased mean pup weight was observed in pups from females dosed at both at 100 and 300 mg/kg/day.

GROSS PATHOLOGY (OFFSPRING)
No effects

Effect levels (F1)

1

Dose descriptor:

NOEL

Generation:

F1

Effect level:

20 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Developmental toxicity

2

Dose descriptor:

LOEL

Generation:

F1

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Developmental toxicity

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Repeated administration of the test substance to male and female Sprague Dawley rats at dose levels of 0, 20, 100 or 300 mg/kg/day produced no evidence of teratogenicity. Pups born from females treated at 100 and 300 mg/kg/day showed decreased body weight. Based on these findings the no-observed­effect level (NOEL) for developmental toxicity in pups was considered to be 20 mg/kg/day.

There was no evidence of adverse effects on any measures of reproductive function. A no-observed-effect level (NOEL) for reproductive toxicity (fertility) was considered to be 300 mg/kg/day based on these findings.

Executive summary:

Repeated administration of the test substance to male and female Sprague Dawley rats at dose levels of 0, 20, 100 or 300 mg/kg/day produced no evidence of teratogenicity. Pups born from females treated at 100 and 300 mg/kg/day showed decreased body weight. Based on these findings the no-observed­effect level (NOEL) for developmental toxicity in pups was considered to be 20 mg/kg/day.

 

There was no evidence of adverse effects on any measures of reproductive function. A no-observed-effect level (NOEL) for reproductive toxicity (fertility) was considered to be 300 mg/kg/day based on these findings.