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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Remarks:
based on generations indicated in Effect levels (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP study, guideline study, available as published report and summary information sheet (provided by Japan Chemical Industry Ecology-Toxicology and Information Center (JETOC)), minor restrictions in design and/or reporting but otherwise adequate for assessment.

Data source

Referenceopen allclose all

Reference Type:
other: Information sheet
Title:
Unnamed
Year:
1998
Report Date:
1998
Reference Type:
study report
Title:
Unnamed
Year:
1993
Report Date:
1993

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): dicyclopentadiene
- Analytical purity: 94.65%
- Physical state: colourless liquid with a camphor-like odour
- Lot/batch No.: D93028
- Stability under test conditions: confirmed to be stable by the manufacturer for the study period
- Storage condition of test material: room temperature

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan, Inc.
- Age at study initiation: 8 weeks
- Weight at study initiation: males 304-339 g, females 186-227 g
- Housing: individually, except during mating, in polycarbonate cages
- Diet: CRF-1 (Oriental Yeast Co) assumed ad libitum
- Water: ultraviolet irradiated water (assumed ad libitum)
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature: 20-25°C
- Humidity: 40-70%
- Air changes: approximately 12 per hr
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: Not reported

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
olive oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Test substance mixed with olive oil, dose rate 10mL/kg bodyweight
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: up to 7 days
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Stability and achieved concentration of dosing preparations was confirmed prior to dosing

Duration of treatment / exposure:
Males 44 days; Females from 14 days before mating through gestation and parturition until day 3 of lactation
Frequency of treatment:
Once daily
Details on study schedule:
- Dose selection rationale: Based on the results obtained in a 10 day oral dosing preliminary study where doses of 0, 30, 100 and 300 mg/kg were administered.

- The test substance was administered to male and female rats daily by oral gavage from 2 weeks prior to mating and during mating (approx. 2 weeks).
- Male rats continue to be dosed until sacrifice of females after day 3 of lactation. Females continue to be dosed through gestation to day 3 of lactation.
- Females were sacrificed on day 4 of lactation and males on day 45 of the study.
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 4, 20 or 100 mg/kg/day
Basis:
nominal conc.
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on the results obtained in a 10 day oral dosing preliminary study where doses of 0, 30, 100 and 300 mg/kg were administered.

Examinations

Parental animals: Observations and examinations:
CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: Yes

FOOD EFFICIENCY: No

WATER CONSUMPTION: No

HAEMATOLOGY: Yes (males only)
- Time schedule for collection of blood: termination
- Anaesthetic used for blood collection: Yes (sodium thiopental)
- Animals fasted: Yes (assumed)
- How many animals: 10/group
- Parameters examined: red blood cell, white blood cell, platelets, haemoglobin, haematocrit, differential white cell count, reticulocyte, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration

CLINICAL CHEMISTRY: Yes (males only)
- Time schedule for collection of blood: termination
- Anaesthetic used for blood collection: Yes (sodium thiopental)
- Animals fasted: Yes (assumed)
- How many animals: 10/group
- Parameters examined: GOT, GPT, ALP, γ-GTP, urea nitrogen, glucose, total cholesterol, triglycerides, creatinine, total bilirubin, total protein, albumin, A/G ratio, calcium, inorganic phosphorus, sodium, potassium, chloride


PREGNANCY DATA: number of pairs with successful mating, mating index (%), number of pregnant females, fertility index (%), pairing days until mating, number of females with live pups, gestation index (%), gestation length, number of corpora lutea, number of implantation sites, implantation index (%), delivery index (%),
Oestrous cyclicity (parental animals):
yes
Sperm parameters (parental animals):
No
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in offspring: number and sex of pups, stillbirths, live pups on day 0, live birth index (%), number of live pups on day 4, viability index on day 4 (%), bodyweight of pups on days0 and 4, bodyweight gain days0-4

GROSS EXAMINATION OF PUPS: Yes (on day 4)
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals on day 45
- Maternal animals: Day 4 of lactation

GROSS PATHOLOGY: Yes

ORGAN WEIGHTS: Yes
- organs weighed: thymus, liver, kidneys, adrenals, testes, epididymes

HISTOPATHOLOGY: Yes (liver, kidney and adrenals all groups, other tissues controls and 100 mg/kg groups only)
- tissues examined: thymus, liver, kidneys, adrenals, testes, epididymes, brain, heart, spleen, ovaries,
Postmortem examinations (offspring):
Gross examination on day 4
Statistics:
Bartlett's test if uniformly distributed analysis of variance, Kruskal-Wallis if non-uniform for quantitative data. When significant differences found between groups, Dunnett-type test or Scheff test. Significance level of 5% or less.
Reproductive indices:
mating index, fertility index, gestation index, implantation index
Offspring viability indices:
delivery index, live birth index, viability index (day 4)

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

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
- Two females in the high dose (100 mg/kg) group died.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Males and surviving females showed slight suppression of body wt gain and decreased food consumption.

ORGAN WEIGHTS (PARENTAL ANIMALS)
- There were increased liver and kidney weights in male rats given 100 mg/kg.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
- Two females in the 100 mg/kg group lost 100% of their litters during lactation (days 1-4). [HPV Reviewer’s note: It is likely that these are the females that died, but not specified in summary].

HISTOPATHOLOGY (PARENTAL ANIMALS)
- In male rats given 100 mg/kg, single cell necrosis in liver, and hyaline droplets and basophilic changes in tubular epithelium of kidneys was seen. Increase in fatty droplets in fascicular zone of adrenals was observed in both males and females in the 100 mg/kg group. Similar histopathological changes were seen in kidneys of 4, 20 mg/kg group male rats and in adrenals of 20 mg/kg group male rats.

OTHER FINDINGS (PARENTAL ANIMALS)
- Blood chemistry of high dose males showed increase in GOT and GPT; no test material related changes occurred in haematology parameters for any treatment group.

Results: F1 generation

General toxicity (F1)

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

Details on results (F1)

A low viability index and tendency to lower birth wt and body wt gain was observed in neonates in the highest dose group (100 mg/kg). No significant differences in number of offspring, live offspring at birth, sex ratio or live birth index were found. No abnormal findings were observed in external features, clinical signs in offspring, or at necropsy of offspring.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
20 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: for systemic and reproductive toxicity

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Dicyclopentadiene induced systemic toxicity in male and female rats at the 100 mg/kg/day dose level. No compound-related effects were seen on reproduction. Effects on neonates included low viability index, lower birth wt and body wt gain in the 100 mg/kg group but not at lower dose levels.