[No public or meaningful name is available]

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

Combined Repeated Dose Toxicity Study and Reproductive/Developmental Toxicity Screening Test in Rats

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP compliant, guideline study, available as unpublished report, no restrictions, fully adequate for assessment.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2004

Report date:

2004

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: OPPTS 870.3650 Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

CAS 6847-10-4

IUPAC Name:

CAS 6847-10-4

Constituent 2

Reference substance name:

Dicyclopentadiene/Codimer concentrate

IUPAC Name:

Dicyclopentadiene/Codimer concentrate

Constituent 3

Reference substance name:

DCPD/Codimer concentrate

IUPAC Name:

DCPD/Codimer concentrate

Details on test material:

- Name of test material (as cited in study report): Dicyclopentadiene/ Codimer concentrate- Supplier: ExxonMobil
- Substance type: Low DCPD Resin Oil is a C8 to C10 distillate obtained from a pyrolysis gasoline stream produced by an ethylene production process (steam cracking process).
- Physical state: colourless liquid
- Composition of test material, percentage of components: 29.175 wt % endo- and exo-DCPD, 18.726 wt % C4-MCPD and C5-MCPD codimers, 13.210 wt % MCPD dimer, 12.903 wt % CPD-MCPD codimer, 8.129 wt % C8 aliphatic and aromatic hydrocarbons, 7.144 wt % C4-CPD and C5-CPD codimers, 3.625 wt % MCPD-C7 dimer, 2.771 wt % Tetrahydroindene, 1.917 wt % Trimers, 0.927 wt % C7 cyclic hydrocarbon, 0.697 wt % C5 acyclic hydrocarbon dimer, 0.634 wt % MCPD monomer, 0.078 wt % CPD monomer, 0.063 wt % C6 acyclic hydrocarbons: The test substance appeared to be stable under the conditions of the study.
- Storage condition of test material: stored at or below 70º F, and protected from light and air.

Test animals

Species:

rat

Strain:

other: Crl:CD (Sprague-Dawley) IGS BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS- Source: Charles River Laboratories, Inc. (Raleigh, North Carolina, USA)
- Age at study initiation: Approximately 8-10 weeks- Weight at study initiation: 172.0-286.4l
- Housing: Rats were housed singly in stainless steel, wire-mesh cages, suspended above cage boards, except during cohabitation when one male was added to each cage. Females in the satellite group were housed in polycarbonate pans with bedding (Bed-o-Cobs®) from gestation day 19 or the end of the cohabitation period (if evidence of copulation was not detected) until sacrifice.
- Diet: PMI® Nutrition International, LLC Certified Rodent LabDiet® 5002 (chunk chow) ad libitum
- Water: tap water ad libitum- Acclimation period: At least 6 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22° ± 4°C
- Humidity: 40%-60%
- Air changes (per hr): Not reported
- Photoperiod: approximate 12-hour light/dark cycle

IN-LIFE DATES: Not reported

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Dosing formulations of the test substance were prepared daily by adding the corn oil to the measured amount of test substance and stirring to establish uniformity.

DOSE VOLUME: 2 mL/kg bw

Details on mating procedure:

- M/F ratio per cage: 1:1
- Length of cohabitation: 2 weeks
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged in polycarbonate pans with bedding (Bed-o-Cobs®) from gestation day 19 until sacrifice.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Near the beginning of the study, 4 samples (approximately 3 mL per sample) were collected from each formulation, and were analyzed for homogeneity/concentration verification, and 5-hour stability at room temperature. Near the middle and end of the dosing period, duplicate samples were taken from all formulations and analyzed for concentration verification. Analysis was by gas chromatography. The test substance was mixed homogeneously, was at the targeted levels, and was stable under the conditions of study.

Duration of treatment / exposure:

Groups of 12 young, nulliparous, female rats were administered an oral, daily dose of the test substance during a premating period of approximately 2 weeks, a cohabitation period of approximately 2 weeks, a gestation period of approximately 3 weeks, and a lactation period of approximately 3 days. The males were exposed for 30 days.

Frequency of treatment:

7 days/week

Details on study schedule:

Groups of 12 young, nulliparous, female rats were administered an oral, daily dose of 0, 5, 25, or 100 mg/kg/day during a premating period of approximately 2 weeks, a cohabitation period of approximately 2 weeks, a gestation period of approximately 3 weeks, and a lactation period of approximately 3 days. Following the 2-week premating period, each satellite female was paired with a male of the same respective dosage group during a 2 week cohabitation period.

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 5, 25, 100 mg/kg/day
Basis:
other: nominal in corn oil

No. of animals per sex per dose:

12

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Dose levels for the main study were selected based on the results of a range-finding study conducted in time-mated pregnant female rats.

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule: Days 1, 8 and 15 pre-mating, weekly during mating, daily during gestation and days 0 and 4 lactation.

FOOD CONSUMPTION: - Time schedule: Days 1, 8 and 15 pre-mating, days 0, 7, 14 and 21 of gestation and days 0 and 4 of lactation.

WATER CONSUMPTION: No

Oestrous cyclicity (parental animals):

Not assessed

Sperm parameters (parental animals):

Not assessed

Litter observations:

Offspring were weighed and evaluated for external abnormalities at birth and on lactation days 1 and 4, and were sacrificed on postnatal day 4.

Postmortem examinations (parental animals):

After postpartum day 4, lactating females, and nonpregnant females were sacrificed, selected organs were weighed, and selected tissues were evaluated microscopically. The males were exposed for a total of 30 days, and were then necropsied. Male reproductive organ weights and gross/histopathology of the reproductive tract were assessed.

Postmortem examinations (offspring):

Offspring were evaluated for external abnormalities, and sacrificed on postnatal day 4

Statistics:

Group means and standard deviations were calculated for all measured parameters. Body weight, weight gain, food consumption, and organ weights were analyzed by Jonckheere-Terpstra trend test. Food efficiency was analyzed by one-way analysis of variance followed with Dunnett’s test. Clinical observations, mating index, fertility index, and gestation index were analyzed by Cochran-Armitage trend test. Gestation length, implantation site numbers, implantation efficiency, mean number of pups per litter, percent of pups born alive, day 0-4 viability of pups, viability index, number of corpora lutea, sex ratio, pre-implantation loss, and post-implantation loss were analyzed by Jonckheere-Terpstra trend test. Mean pup weights were analyzed by linear contrast of the least square means.

Reproductive indices:

Mating index, fertility index, gestation length, number of implantation sites, implantation efficiency, pre-implantation loss, post-implantation loss, number of corpora lutea

Offspring viability indices:

Gestation index.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Description (incidence and severity):

There were no statistically significant differences in the incidences of clinical observations. Salivation was observed in 1 female in the 100 mg/kg/day group during the predosing observation period for gestation. In addition, salivation was observed following the daily dose administration in one 100 mg/kg/day rat during gestation days 5-8. Since salivation was observed at higher dosages in the range-finding study, it was considered to be test substance-related. However, since this was a transient observation in 1 animal, it was not considered to be adverse.

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

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)

REPRODUCTIVE INDICES: No test substance-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.

REPRODUCTIVE PATHOLOGY: There were no test substance-related effects on morphology of the reproductive tract in either males or females.

Effect levels (P0)

Key result

Dose descriptor:

NOAEL

Remarks:

Reproductive toxicity

Effect level:

100 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: no effects on any reproductive parameter at the highest dose level tested

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

Details on results (F1)

OFFSPRING PARAMETERS: There were no test substance-related effects on mean pup weight, number of pups born, number of pups born alive, sex ratio, gestation index, clinical observations, or litter survival for postnatal days 0-4 in the offspring from any dosage group.

Effect levels (F1)

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

100 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: Reproductive Toxicity

Target system / organ toxicity (F1)

Key result

Critical effects observed:

no

Overall reproductive toxicity

Key result

Reproductive effects observed:

no

Applicant's summary and conclusion

Conclusions:

Repeated oral administration of Dicyclopentadiene/Codimer Concentrate to male and female rats at 0, 5, 25, or 100 mg/Kg/day produced no evidence of adverse effects on any measures of reproductive function and there were no adverse effects of pup bodyweight or survival.. The NOAEL for reproductive toxicity was 100 mg/Kg/day.

Executive summary:

Dicyclopentadiene/Codimer Concentrate (CAS 68478 -10 -4) was evaluated for potential toxicity using a combined repeated dose toxicity/reproduction/developmental toxicity study. To assess reproductive/developmental effects Low DCPD Resin Oil was administered during premating (approximately 2 weeks), gestation (approximately 3 weeks), and lactation through day 4. Gonadal function, mating behaviour, fertility, implantation, development of the conceptus, parturition, gross pathology, and histopathology were evaluated.

There was no evidence of adverse effects on any measures of reproductive function and there were no test substance-related effects on mean pup weight, number of pups born, number of pups born alive, sex ratio, gestation index, clinical observations, or litter survival for postnatal days 0-4 in the offspring from any dosage group.  

The NOAEL for reproductive toxicity was 100 mg/Kg/day (the highest dose tested).