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Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
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GLP study, guideline study, available as unpublished report and summary information sheet (provided by Japan Chemical Industry Ecology-Toxicology and Information Center (JETOC)), minor restrictions in design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.
Cross-reference
Reason / purpose:
reference to same study

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
Limit test:
no

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:
other: Sprague Dawley Crj:CD(SD)
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 oral exposure:
PREPARATION OF DOSING SOLUTIONS: Test substance mixed with olive oil, dose rate 10mL/kg bodyweight
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
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 4, 20 or 100 mg/kg/day
Basis:
other: nominal in olive oil
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

Observations and examinations performed and frequency:
CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: Yes

FOOD EFFICIENCY: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: 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

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
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,
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.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food efficiency:
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not specified
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Details on results:
CLINICAL SIGNS AND MORTALITY
- Two females in the high dose (100 mg/kg) group died. Transient salivation after dosing at 100 mg/kg for the initial 8 days of dosing was present in approximately half of the males and females. Also occasionally present in males at the two lower doses.

BODY WEIGHT AND WEIGHT GAIN
- Males and surviving females showed slight suppression of body wt gain.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
- Males and surviving females showed slightly decreased food consumption.

HAEMATOLOGY
- No treatment-related effects

CLINICAL CHEMISTRY
- Blood chemistry of 100 mg/kg males showed increase in GOT and GPT

ORGAN WEIGHTS
- Increased weight of liver and kidneys of male rats given 100 mg/kg (neither achieved statistical significance) and statistically significantly increased actual and relative liver weight in males at 20 mg/kg/day.

HISTOPATHOLOGY: NON-NEOPLASTIC
- In male rats given 100 mg/kg, single cell necrosis in liver, and hyaline droplets and basophilic changes in tubular epithelium of kidneys under microscopic examination were observed. 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 four 20 mg/kg group male rats and in adrenals of 20 mg/kg group male rats.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
4 mg/kg bw/day (actual dose received)
Sex:
male
Basis for effect level:
other: histological changes in kidneys and adrenals at 20 mg/kg/day
Dose descriptor:
NOAEL
Effect level:
20 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: 2/10 deaths, lower body weight and food consumption and histological changes in liver and kidney at 100 mg/kg/day

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Dicyclopentadiene induced systemic toxicity in male and female rats including death of two females at the 100 mg/kg/day dose level.
Executive summary:

In a combined repeat dose toxicity study with reproduction/developmental toxicity screening, groups of 10 males and 10 females were dosed by oral gavage with solutions of 0, 4, 20 or 100 mg/kg DCPD in olive oil. Animals were dosed for 2 weeks prior to mating and during mating (approximately 2 weeks). Males and females were then dosed through gestation until day 3 of lactation. Females were killed on day 4 of lactation and males were killed on day 45 of the study. Two females at 100 mg/kg/day died during the study and surviving males and females showed decreased food consumption and bodyweight gain at this dose level. Pathological changes in the liver and kidney were seen in males dosed at 100 mg/kg/day (single cell necrosis in the liver, hyaline droplet formation and basophilic changes in the tubular epithelium of the kidney) and an increase in fatty droplets in the adrenals was observed in both males and females in the 100 mg/kg group. Similar changes were seen in the kidney and adrenals of some male rats dosed at 20 mg/kg group male rats. The no effect level for systemic toxicity was therefore considered to be 20 mg/kg/day for females and 4 mg/kg/day for male rats.