Distillates (petroleum), steam-cracked, C8-12 fraction

Toxicity to reproduction

Administrative data

Endpoint:

toxicity to reproduction

Remarks:

other: 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other: GLP compliant, guideline study, available as unpublished report, no restrictions, fully adequate for assessment.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 68477-54-3

IUPAC Name:

CAS 68477-54-3

Constituent 2

Reference substance name:

Low Dicyclopentadiene Resin Oil

IUPAC Name:

Low Dicyclopentadiene Resin Oil

Constituent 3

Reference substance name:

Low DCPD Resin Oil

IUPAC Name:

Low DCPD Resin Oil

Constituent 4

Reference substance name:

CAS 68516-20-1

IUPAC Name:

CAS 68516-20-1

Details on test material:

- Name of test material (as cited in study report): Low Dicyclopentadiene Resin Oil / Low DCPD Resin Oil
- Supplier: Equistar Chemicals, LP
- 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 / light yellow liquid
- Composition of test material, percentage of components: up to 100% aromatics, including substituted mono and diaromatics (<0.01% benzene).
- Stability under test conditions: 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: 114.8-165.3 on day after arrival
- 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±3°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:

Satellite 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 4 days. The males were exposed for 30 days.

Frequency of treatment:

7 days/week

Details on study schedule:

Satellite groups of 12 young, nulliparous, female rats were administered an oral, daily dose of 0, 35, 125, or 375 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 4 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, 35, 125, 375 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:

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:

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)

CLINICAL SIGNS AND MORTALITY: Test substance-related increases in the incidence of stained fur, and/or wet fur were observed in males, and females following administration of 375 mg/kg/day Low DCPD Resin Oil. Stained and/or wet fur were also occasionally observed in males and females administered 125 mg/kg/day.

BODY WEIGHT AND WEIGHT GAIN: Test substance-related increases in the incidence of stained fur, and/or wet fur was observed in males, and females following administration of 375 mg/kg/day Low DCPD Resin Oil. Stained and/or wet fur were also occasionally observed in males and females administered 125 mg/kg/day.

BODY WEIGHT AND WEIGHT GAIN: Decreases in body weight and/or weight gain were observed in males and females as 375 mg/kg/day and 125 mg/kg/day. During the premating period, gestation and lactation, body weight and weight gain of 375 mg/kg/day females was lower than the control. During lactation, body weights of 125 mg/kg/day females were statistically significantly lower than the control values.

FOOD CONSUMPTION AND FOOD EFFICIENCY: Decreased food consumption and food efficiency occurred in 125 mg/kg/day and above males

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)

1

Dose descriptor:

NOAEL

Remarks:

Reproductive toxicity

Effect level:

375 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

2

Dose descriptor:

NOAEL

Remarks:

systemic toxicity

Effect level:

35 mg/kg bw/day (nominal)

Sex:

male

Basis for effect level:

other: lower body weight and food consumption at 125 mg/kg/day

3

Dose descriptor:

NOAEL

Remarks:

systemic toxicity

Effect level:

125 mg/kg bw/day (nominal)

Sex:

female

Basis for effect level:

other: lower body weight at 373 mg/kg/day

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

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: Decreased mean pup weight (15% lower than the control value on lactation day 4) was observed in offspring from the 375 mg/kg/day group. No effects were observed at any dosage for the number of pups born, number of pups born alive, sex ratio, gestation index, external abnormalities, or litter survival for postnatal days 0-4 in the offspring from any dosage group.

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Repeated oral administration of Low Dicyclopentadiene Resin Oil to male and female rats at 0, 35, 125, or 375 mg/kg/day produced no evidence of adverse effects on any measures of reproductive function. Pups from the 375 mg/kg/day group had decreased body weight. The NOAEL for reproductive toxicity was 375 mg/kg/day and the NOAEL for systemic toxicity was 35 mg/kg/day in males and 125 mg/kg in females.

Executive summary:

Low Dicyclopentadiene Resin Oil (Low DCPD Resin Oil; CAS 68477-54-3) 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. At 375 mg/kg/day clinical signs of toxicity, lower body weight and food consumption and histopathological changes were observed in adults. In addition, effects on body weight, clinical signs and food consumption were observed in males at 125 mg/kg/day. Pups from the 375 mg/kg/day group had decreased body weight on day 4.  

The NOAEL for reproductive toxicity was 375 mg/kg/day (the highest dose tested) and the NOAEL for systemic toxicity was 35 mg/kg/day in males and 125 mg/kg in females.