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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP status unknown, near guideline study, animal experimental study, published in peer reviewed literature. No restrictions, fully adequate for assessment

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1986

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: standard NTP methodology
Principles of method if other than guideline:
Standard NTP methodology for dose selection on the 2 year study
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 4-vinylcyclohexene
- Substance type: a dimer of 1,3-butadiene
- Physical state: colourless liquid
- Lot/batch No.: C592777 (supplied by Chemical Samples Company, Columbus, Ohio, USA) for initial 44 weeks, A061181 (supplied by Aldrich Chemical Company, Milwaukee, WI, USA) for remainder of study.
- Analytical purity: Lot C592777 >99%, Lot A061181 >98%
- Impurities (identity and concentrations): Lot C592777 100 ppm (0.01%) butylated hydroxytoluene (BHT). Lot A061181 50 ppm (0.005%) tert-butylcatechol. (Inhibitors of peroxide formation).
- Stability under test conditions: yes
- Storage condition of test material: room temperature

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: 7 weeks
- Housing: 5/cage in polycarbonate cages
- Diet: NIH 07 Rat and Mouse Ration pellets ad libitum
- Water: acidified water (pH 2.5) ad libitum
- acclimatisation: 17 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22-24°C
- Humidity: 30-70 %
- Air changes: 15 per hr
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: 21 January 1980 To: 22 April 1980

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: 4-vinylcyclohexene and corn oil were mixed to give the desired dosing concentrations.
Dose volume = 3.33 mL/kg.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
GC analysis of the dosing solutions demonstrated that the achieved concentration was 95 - 100% of target.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50, 100, 200, 400 or 800 mg/kg bw/d
Basis:
other: nominal in corn oil
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice per day
BODY WEIGHT: Yes
- Time schedule for examinations: Once per week
FOOD CONSUMPTION: No
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: No
CLINICAL CHEMISTRY: No
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes. Necropsies were performed on all animals (survivors and decedents).
HISTOPATHOLOGY: Yes. Kidneys and stomachs of all males and stomachs of all females. The following tissues from all animals in control and 800 mg/kg/day groups and any animal dying before scheduled termination: gross lesions and masses, adrenal glands, blood smear, brain, colon, oesophagus, eyes, heart, kidneys, liver, lung and mainstem bronchi, mammary gland, mandibular lymph nodes, salivary glands, sternebrae (including marrow), thyroid gland, parathyroids, small intestine, colon, liver, prostate/testes or ovaries/uterus, lungs and mainstem bronchi, skin, heart, oesophagus, stomach, brain, thymus, pancreas, spleen, kidneys, adrenal glands, urinary bladder, pituitary gland, trachea, eyes, mammary gland, blood smear, and spinal cord (if neurologic signs present).
Statistics:
It is not stated if any statistical analysis was applied to the data.

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
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Details on results:
CLINICAL SIGNS AND MORTALITY: There were premature deaths in single animals from the 400 mg/kg bw/d (male) and 800 mg/kg bw/d (female) groups. (No further details.)

BODY WEIGHT AND WEIGHT GAIN: Body weight gain was decreased in the higher dose males, with a less marked effect in females. Final bw by dose level relative to controls: males: 100%, 101%, 96%, 97%, 93%, 87%, females: 100%, 101%, 96%, 97%, 99%, 94%

GROSS PATHOLOGY: No gross macroscopic lesions are described in the report.

HISTOPATHOLOGY: Microscopic examination revealed hyaline droplet degeneration of the proximal convoluted tubule of the kidney in males (not females). Severity was diagnosed as minimal for all groups with the exception of 800 mg/kg males (where it was described to be of a degree that might reduce longevity in a 2 year study). Inflammation of the submucosa of the nonglandular stomach (severity not defined) was present in 1 male and 3 females given 800 mg/kg bw/d. No other treatment-related histological abnormalities present.

Effect levels

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Dose descriptor:
NOAEL
Remarks:
subchronic (13 week)
Effect level:
200 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: single mortality at 400 mg/kg. Inflammation of the stomach and decreased terminal body weight at higher doses
Dose descriptor:
NOAEL
Remarks:
subchronic (13 week)
Effect level:
400 mg/kg bw/day (nominal)
Sex:
female
Basis for effect level:
other: inflammation of the stomach and decreased terminal body weight at higher doses

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The sub-chronic NOAEL for 4-vinylcyclohexene in the rat was 200 mg/kg bw/d in males and 400 mg/kg bw/d in females (based on increased severity of hyaline droplet degeneration of the renal proximal convoluted tubule, inflammation of the stomach and decreased terminal body weight at higher doses in both sexes).
Executive summary:

In a 13 week gavage study, male and female F344 rats were administered 4-VCH in corn oil, 5 days/week for 13 weeks at 0, 50, 100, 200, 400 or 800 mg/kg bw/d. There was a single mortality at 400 mg/kg and decreased body weight gain in males at >400 mg/kg body weight/day and females at 800 mg/kg/day. There was a minimal increased severity of hyaline droplet degeneration of the renal proximal convoluted tubule in males at 800 mg/kg/d and some inflammatory changes in non-glandular stomach of high dose males and females. Overall the findings indicate a sub-chronic oral NOAEL of 200-400 mg/kg body weight/day for male and female rats, respectively.