Registration Dossier

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP compliant dose range finding study, non-guideline, animal experimental study, limitations in design and/or reporting but otherwise adequate for assessment.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993
Report Date:
1993

Materials and methods

Test guideline
Qualifier:
no guideline followed
Deviations:
not applicable
Remarks:
dose range finding study for developmental toxicity
Principles of method if other than guideline:
dose range finding study
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): DCPD
- Source: Aldrich Chemical Company
- Analytical purity: 98%
- Stability: Corn oil solution containing 10 mg/mL dicyclopentadiene was stable when stored for 30 days in sealed glass bottles at room temperature

Test animals

Species:
rat
Strain:
other: Sprague Dawley CD(SD)BR
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Raleigh, NC, USA
- Status: Certified viral antibody-free. Time-mated GD 0
- Age at study initiation: Young adults (approximately 77 days)
- Weight at study initiation: No individual data. GD 5, overall mean weight range 238.2-241.8 g
- Housing: Individual
- Diet: no data
- Water: no data
- Acclimation period: Not applicable; delivered GD 5

ENVIRONMENTAL CONDITIONS
- no data

IN-LIFE DATES:
- no data

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
- The test chemical was formulated in corn oil on a weight to volume basis and administered via gavage at 5 mL/kg bw for all dose levels
- The control group received corn oil
- The dosage volume was adjusted based on bodyweight on gestation days 6, 8, 10, 12, and 14
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Gas chromatography. All concentrations found to be at least 94.8% of nominal.
Details on mating procedure:
- Impregnation procedure: purchased time-mated
- Proof of pregnancy: vaginal plug on gestation day 0 (GD0)
Duration of treatment / exposure:
Days 6-15 of gestation
Frequency of treatment:
Daily
Duration of test:
from gestation day 0-20
No. of animals per sex per dose:
11 female rats/group for dose groups from 50 - 400 mg/kg/day and 10 female rats/group at 500 mg/kg/day
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Based on the reported LD50 for dicyclopentadiene in rats which ranged from 378-820 mg/kg.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily (once post-dosing)

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: On gestational days 5, 6, 8, 10, 12, 14, 16 and 20 (termination)

POST-MORTEM EXAMINATIONS: No data
- Killed on gestation day 20
Ovaries and uterine content:
The ovaries and uterine content examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: No data
- Number of implantations: Yes
- Number of resorptions: Yes
- Number of live/dead foetuses: Yes
- Live litter weight: Yes
Fetal examinations:
- External examinations: No
- Soft tissue examinations: No
- Skeletal examinations: No
- Head examinations: No
Statistics:
Data analyzed using non-parametric statistical methods to identify dose response trends among treatment groups and differences between control and treatment groups. Kruskal-Wallis one-way analysis of variance used for all parameters except gestation day 5-20 body weights, gravid uterus weight and average foetal weights. Mann-Whitney Wilcoxon U test was used when Kruskal-Wallis was significant (p<0.05). Jonckheere’s test for k independent samples was used for dose-response trends for gestation day 5 to day 20 body weight data. If no trend was found, Dunn’s test was used for differences among dose groups; if a trend was present Shirley’s test was applied. Body weight data from non-pregnant rats were not included.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
All animals in the 400 and 500 mg/kg groups were found dead by GD 9. Eight and 3 animals in the 300 and 200 mg/kg groups respectively, were found dead or were killed for humane reasons by GD 9. All animals in the 50 mg/kg/day group survived to scheduled termination. Signs of systemic toxicity were noted in all animals given 200 mg/kg/day group or more, from GD 7. Clinical signs included dried material around nose and mouth, rough hair coat, and lethargy increased in severity with increasing dose. Other signs included convulsions (1 rat given 200 mg/kg/day), hunched posture (6 rats given 300 mg/kg/day) and ataxia (5 rats given 300 mg/kg/day, 11 rats given 400 mg/kg/day and 9 rats given 500 mg/kg/day). Maternal body weights of the treated animals were decreased in a dose-related manner. These differences were statistically different (p<0.05) from the control group during the treatment period in the 50 mg/kg/day group and during the treatment and post-treatment period in the 200 mg/kg/day group.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
< 50 mg/kg bw/day (nominal)
Basis for effect level:
other: maternal toxicity
Remarks on result:
not determinable
Remarks:
no NOAEL identified

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Only the control, 50 and 200 mg/kg/day groups had litters with live foetuses at scheduled necropsy on day 20. Average foetal weight in the 200 mg/kg/day group was significantly decreased (p<0.05) compared to the control group; the mean number of live foetuses was unaffected by treatment.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Summary of reproductive performance

Number of females

Dose Level (mg/kg/day)

0

50

200

300

400

500

Total

11

11

11

11

11

11

Died during study

0

0

3

8

11

11

Not pregnant

2

1

4

2

-

-

Total resorption

0

0

0

1

-

-

Litters with live foetuses

9

10

4

0

0

0

Applicant's summary and conclusion

Conclusions:
A NOAEL for maternal toxicity was not established in this study and is therefore, < 50 mg/kg/day. However, this dose level was a NOAEL for developmental toxicity based on average foetal weight only. No foetal examination was included in this study.
Executive summary:

Dose levels of 200, 300, 400 and 500 mg/kg/day were lethal to pregnant rats when given from day 6 of gestation. Clinical signs included dried material around nose and mouth, rough hair coat, lethargy, hunched posture and ataxia. Maternal body weights were decreased in a dose-related manner. All animals given 50 mg/kg/day survived to termination of the study; all maternal bodyweights were significantly lower than the controls during the treatment period. Only the control, 50 and 200 mg/kg/day groups had litters with live foetuses at necropsy on gestation day 20. Foetal weight in the 200 mg/kg/day group was significantly decreased but there was no similar effect at 50 mg/kg/day. The mean number of live foetuses was unaffected by treatment.