4-methylstyrene

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From January 1981 to April 1981

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1990

Report date:

1990

Materials and methods

Principles of method if other than guideline:

Design similar to OECD 413, but did not include clinical pathology investigations.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Vinyltoluene

EC Number:

246-562-2

EC Name:

Vinyltoluene

Cas Number:

25013-15-4

Molecular formula:

C9H10

IUPAC Name:

Ethenylmethylbenzene

Test material form:

liquid

Details on test material:

- Mix of isomers: 65-71% s-isomer, 32-35% p-isomer

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

Rats were obtained from Charles River Breeding Laboratories (Kingston, NY) and acclimatised in the facility for 20 days prior to the start of the study, approximately 7-8 weeks old at first exposure. Housed singly. Tap water (glass bottles) and diet (NIH-07 Rat and Mouse Ration, Zeigler Bros, PA) available ad libitum, except during exposure period.
Chamber environment: Temperature was maintained between 69-810 °F and relative humidity 30 to 51 %. Fluorescent lighting was on a 12 hours/day cycle and room air changes were 10-18 hour.

Administration / exposure

Route of administration:

inhalation: gas

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

The test substance was metered from a reservoir via a precision pump into a J-tube containing 1/4 inch glass beads. Compressed air, heated to 60 °C-70 °C, was passed through the system. The test substance vapor then entered the airstream at the top of the chamber (Hazleton 2000@, Lab Products, Inc.) and was mixed in the chamber plenum before entering the exposure area of the chamber and delivered at 30 – 50 litres/minute.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

6 hours

Frequency of treatment:

daily, 5 days/week for 13 weeks (64 days)

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

25 ppm

Remarks:

nominal

Doses / concentrations 2

Dose / conc.:

60 ppm

Remarks:

nominal

Doses / concentrations 3

Dose / conc.:

160 ppm

Remarks:

nominal

Doses / concentrations 4

Dose / conc.:

400 ppm

Remarks:

nominal

Doses / concentrations 5

Dose / conc.:

1 000 ppm

Remarks:

nominal

No. of animals per sex per dose:

10 males and 10 females

Control animals:

yes, sham-exposed

Examinations

Observations and examinations performed and frequency:

Clinical observations: daily
Bodyweight: weekly

Sacrifice and pathology:

Necropsy performed on all animals.
Histopathology: all control and high dose animals. Tissues examined include: adrenal glands, bone, brain, cecum, colon, duodenum, epididymid seminal vesicle, prostate/testes or oviduct /ovaries/uterus, esophagus heart, ileum, jejunum, kidneys, larynx, liver, lungs, mammary gland, mandibular and mesenteric lymph nodes, mesentery, nasal passage, pancreas, parathyroid glands, pituitary gland, preputial or clitoral gland, rectum, salivary glands, skin, spinal cord, spleen, stomach, thymus, thyroid gland, trachea, and urinary bladder.

Statistics:

Lesion incidence was assessed using the Fisher exact test. Normally distributed data (organ and body weights) were analysed using Dunnett and Williams test.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Excessive lacrimation, palpebral closure, and rough hair coats were seen in rats exposed to 1000 ppm.

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

The final mean body weights of rats exposed to 160, 400, or 1000 ppm were 6%, 8%, or 19% lower than that of controls for males and 5%, 6%, or 12% lower for females.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Relative liver weights, but not absolute weights, for rats exposed to 1000 ppm were significantly greater than those for controls.

Gross pathological findings:

no effects observed

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

A mild nephropathy characterized by increased tubular casts was found in male rats exposed to 160,400, or 1000 ppm. No compound-related lesions were observed in female rats.

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Effect levels

Key result

Dose descriptor:

NOAEC

Effect level:

60 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Reduced bodyweight gain at 160 ppm

Remarks on result:

other: (equivalent to 290.04 mg/m3 based on a molecular weight of 118.19)

Target system / organ toxicity

Key result

Critical effects observed:

no

Any other information on results incl. tables

Mean bodyweight (BWT) and liver weight (mg/g):

	Untreated	test substance ppm
		25	60	160	400	1000
MALES
Survival	10/10	10/10	10/10	10/10	10/10	10/10
Week 13 BWT (% of controls)	NA	100	99	94	92	81
Liver wt /body wt (mg/g)+SD	39.5+1.66	43.6+1.37	43.0+1.29	43.8+1.27	43.9+1.51	52.9+0.1.55**
FEMALES
Survival	10/10	10/10	10/10	10/10	10/10	10/10
Week 13 BWT (% of controls)	NA	99	98	95	94	88
Liver wt /body wt (mg/g)+SD	38.0+2.41	38.8+1.55	41.0+1.30	40.4+1.54	41.7+2.37	48.3+1.51**

*  Significantly different (p <0.05) from the control, Dunnett’s test

** Significantly different (p <0.01) from the control, Dunnett’s test

 

Applicant's summary and conclusion

Conclusions:

Under the study conditions, clinical signs of excessive lacrimation, palpebral closure, and rough coats were observed at 1000 ppm only. Bodyweight gain was reduced at 160 ppm and greater. Liver weight was increased at 1000 ppm only, but not associated with any histopathological changes. Histology was restricted to male animals where a mild nephropathy characterized by increased tubular casts was found in male rats exposed to 160 ppm or greater. The study report did not cite a NOAEC but this can be considered to be 60 ppm, equivalent to 290.04 mg/m3 based on a molecular weight of 118.19 .

Executive summary:

A study was conducted to determine the repeated dose toxicity of the test substance by inhalation in F344 rats. Groups of 10 male and 10 female rats were exposed to the substance at concentrations of 0, 25, 60, 160, 400 and 1000 ppm, daily for 6 h, 5 d a week for 13 weeks (total of 64 exposures). Clinical observations were recorded daily and body weight was monitored weekly. At the end of the study, all animals were subject to necropsy.  Histopathology was conducted on the control group and all rats in high dose group. Clinical signs of excessive lacrimation, palpebral closure, and rough coats were observed at 1000 ppm only. Bodyweight gain was reduced at 160 ppm and greater. Liver weight was increased at 1000 ppm only, but not associated with any histopathological changes. Histology was restricted to male animals where a mild nephropathy characterized by increased tubular casts was found in male rats exposed to 160 ppm or greater. The study report did not cite a NOAEC but this can be considered to be 60 ppm, equivalent to 290.04 mg/m3 based on a molecular weight of 118.19 (NTP, 1990).