Reaction mass of 4-vinylcyclohexene, cyclohexane and n-hexane

Repeated dose toxicity: oral

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

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

Test material information

Constituent 1

Reference substance name:

4-vinylcyclohexene

EC Number:

202-848-9

EC Name:

4-vinylcyclohexene

Cas Number:

100-40-3

Molecular formula:

C8H12

IUPAC Name:

4-vinylcyclohexene

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 or test system 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

1

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

2

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.