Methylcyclopentadiene

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well conducted, GLP compliant study, according to recognised international test methods

Data source

Reference

Reference Type:

other: USEPA High Production Volume Information System (HPVIS)

Title:

Unnamed

Year:

2003

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Methylcyclopentadiene

EC Number:

247-724-5

EC Name:

Methylcyclopentadiene

Cas Number:

26472-00-4

Molecular formula:

not applicable, UVCB substance

IUPAC Name:

3a,4,7,7a-tetrahydro-1H-4,7-methanoindene

Test material form:

liquid

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

At least 28 days

Frequency of treatment:

Daily, 7 days/week

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 20, 100 and 300 mg/kg
Basis:
no data

No. of animals per sex per dose:

12 male / 12 female

Control animals:

yes, concurrent vehicle

Details on study design:

- Rationale for selecting satellite groups: Assessment of reproductiuve toxicity parameters

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION AND COMPOUND INTAKE
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

WATER CONSUMPTION AND COMPOUND INTAKE: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At end of treatmet period
- Anaesthetic used for blood collection: No data
- Animals fasted: No data

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At end of treatment period
- Animals fasted: No data

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Prior to treatmemt and again at end of treatment period
- Dose groups that were examined: All
- Battery of functions tested: sensory activity / grip strength / motor activity

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Statistics:

Group means and standard deviations were calculated for all measured parameters.

Jonckheere-Terpstra trend test - Body weight, weight gain, food consumption and organ weights
One-way analysis of variance followed with Dunnett’s test - Food efficiency and clinical pathology parameters
Cochran-Armitage trend test - Clinical observations and FOB parameters
One-way analysis of variance and Dunnett’s test - Grip strength, foot splay, rearing and body temperature
Repeated measures analysis of variance with linear contrasts or Jonckheere’s trend test - Motor activity

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 consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

effects observed, treatment-related

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Behaviour (functional findings):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Details on results:

CLINICAL SIGNS AND MORTALITY
Increased incidences of salivation, stained fur and/or wet fur were observed in males and females dosed at 100 or 300 mg/kg/day. Lachrymation was observed in females dosed at 300 mg/kg/day. Salivation was observed males and satellite females dosed at 20 mg/kg/day.
No treatment related mortality occurred.

BODY WEIGHT AND WEIGHT GAIN
Treatment related decreases in body weight and/or weight gain were observed in males and females dosed at 300 mg/kg/day. On test day 28 the body weight of males and females dosed at 300 mg/kg/day was 7.5% and 4% lower than control values, respectively.
Body weight gain over the interval of test days 1-28 for males and females dosed at 300 mg/kg/day was 19% and 16% lower than control values, respectively.
Instances of decreased body weight and/or weight gain were observed in males and females dosed at 100 mg/kg/day.

FOOD CONSUMPTION AND FOOD EFFICIENCY
Significant decreases in food consumption and/or food efficiency occurred in females dosed at 300 mg/kg/day. Food consumption was 9% lower than control value over the test days 1-28 interval. Transient changes in food consumption and/or food efficiency were also observed in males and/or
females dosed at 100 or 300 mg/kg/day.


HAEMATOLOGY AND CLINICAL CHEMISTRY
Haematological or clinical chemistry parameters in male or female rats showed no effects of treatment.

NEUROBEHAVIOUR
Significantly decreased motor activity was observed in males dosed at 300 mg/kg/day during the last 20 minutes of the assessment period for the Week 4 evaluation. This was not apparent in females dosed at the same level. No treatment related effects were observed in grip strength, foot splay, rearing, body temperature, or in any of the other FOB parameters.

ORGAN WEIGHTS
Females dosed at 300 mg/kg/day exhibited a slight increase in kidney weight.
Increased liver weight observed in females dosed at 100 and 300 mg/kg/day and in males dosed at 300 mg/kg/day.
Adrenal gland weights in females dosed at 300 mg/kg/day were slightly increased.

HISTOPATHOLOGY: NON-NEOPLASTIC
An increase in hyaline droplets in the kidneys was observed in all treated male rats. Increased
hyaline droplets were not observed in females. The hyaline droplet accumulation in male rats is species and sex specific and is not predictive of an effect on other species.
Hepatocellular hypertrophy was observed in females dosed at 100 and 300 mg/kg/day and in males dosed at 300 mg/kg/day. It was considered that this change may be secondary to enzyme induction as a pharmacological response to treatment with the substance.
Minimal to mild thyroid follicular hypertrophy was observed in males dosed at 300 mg/kg/day which was considered to be substance related.
The change in adrenal gland weights noted in females dosed at 300 mg/kg/day was not associated with morphological changes.

Effect levels

1

Dose descriptor:

NOEL

Effect level:

20 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Systemic toxicity and pahology

2

Dose descriptor:

NOAEL

Effect level:

20 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Systemic toxicity and pathology

Remarks on result:

not determinable

Remarks:

no NOAEL identified

3

Dose descriptor:

LOEL

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Systemic toxicity and pathology

4

Dose descriptor:

LOEL

Effect level:

20 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Systemic toxicity and pathology

5

Dose descriptor:

NOEL

Effect level:

300 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Neurobehaviour parameters

6

Dose descriptor:

NOEL

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Neurobehavioural parameters

7

Dose descriptor:

LOEL

Effect level:

300 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Neurobehavioural parameters

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Repeated administration of the test substance to male and female Sprague Dawley rats at a dose level of 300 mg/kg/day resulted in clinical signs of toxicity, effects on body weight, food consumption, motor activity and histopathological changes. Effects on body weight, clinical signs and food consumption were observed at the lower dose of 100 mg/kg/day. Clinical signs of toxicity were observed in males at 20 mg/kg/day.
Based on these findings the no-observed-adverse-effect level (NOAEL) for systemic toxicity was 20 mg/kg/day in females and was not established in males.

Executive summary:

Repeated administration of the test substance to male and female Sprague Dawley rats at a dose level of 300 mg/kg/day resulted in clinical signs of toxicity, effects on body weight, food consumption, motor activity and histopathological changes. Effects on body weight, clinical signs and food consumption were observed at the lower dose of 100 mg/kg/day. Clinical signs of toxicity were observed in males at 20 mg/kg/day.

Based on these findings the no-observed-adverse-effect level (NOAEL) for systemic toxicity was 20 mg/kg/day in females and was not established in males.