Registration Dossier

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

Endpoint:
repeated dose toxicity: oral
Remarks:
combined repeated dose and carcinogenicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP status not known, near guideline study, published in peer reviewed literature, limitations in design and/or reporting but otherwise adequate for assessment.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1986

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: EU Method B.32 (Carcinogenicity Test)
Principles of method if other than guideline:
Mixed xylene was administered by oral gavage to groups of 50 male and 50 female F344/N rats at doses of 0, 250 or 500 mg/kg bw/day for 103 weeks. Animals were observed for survival, clinical signs and body weight gain and subject to a full necropsy with tissue histopathology at termination. However, only two dose levels were tested and ophthalmoscopy, food consumption, haematology, blood clinical chemistry and urinalysis were not assessed.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
composition: 60.2% m-xylene, 13.6% p-xylene, 9.1% o-xylene, and 17% ethylbenzene
source: Shell Oil Company (Houston, Texas) in a single lot #.F-3091

Test animals

Species:
rat
Strain:
other: F344/N
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
Oral (gavage): 0, 250 or 500 mg/kg xylenes (mixed) in corn oil; 4 mL/kg

Preparation: Weighed portions of xylenes (mixed) were placed in a graduated cylinder and mixed with corn oil to achieve the proper volume. The mixtures were shaken vigorously for 10 seconds.

Maximum Storage Time: 2 wks

Storage Conditions: Approximately 24ºC, 46% humidity under fluorescent light.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentrations of xylenes in corn oil was analysed by gas chromatography with flame ionization detection following extraction with methanol.
During the 2-year studies, the dose preparations were analyzed once every 2 months, with concentrations varying from 94.6% to 106.9% (within 10% target concentrations).
Duration of treatment / exposure:
5 days per week for 103 weeks.
Frequency of treatment:
Once daily (5 days / week).
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 250 or 500 mg/kg
Basis:
other: nominal concentration
No. of animals per sex per dose:
50 male / 50 female per group
Control animals:
yes, concurrent vehicle
Details on study design:
Dose selection rationale: Based on weight gain depression at 1,000 mg/kg in both sexes in the 14-day studies and in males in the 13-week studies and on the clinical signs in the 14-day studies, doses selected for rats for the 2-year studies were 0, 250, and 500 mg/kg xylenes (mixed) in corn oil by gavage, administered 5 days per week.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- All animals were observed twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Clinical signs were recorded once per day for 16 months and then once per month.

BODY WEIGHT: Yes
- Body weights were recorded weekly for 12 weeks and monthly thereafter

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: No data

CLINICAL CHEMISTRY: No data

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

Data were recorded in the NTP Carcinogenesis Bioassay Data System. The data elements included descriptive information on the chemicals, animals, experimental design, survival, body weight, and individual pathologic results.
Sacrifice and pathology:
Necropsy and histopathological examination performed on all animals, where possible. During necropsy, all organs and tissues were examined for grossly visible lesions. Tissues were preserved in 10% neutral buffered formalin, embedded in paraffin, sectioned, and stained with haematoxylin and eosin. The following tissues were examined: gross lesions and tissue masses, mandibular lymph nodes, salivary gland, femur, including marrow, thyroid gland, parathyroids, small intestine, colon, liver, prostate / testis or ovaries / uterus, heart, oesophagus, stomach, brain, thymus, trachea, pancreas, spleen, skin, lungs and mainstem bronchi, kidneys, adrenal glands, urinary bladder, pituitary gland, eyes (if grossly abnormal), and mammary gland.
Statistics:
Survival Analyses: Kaplan and Meier (1958); Cox (1972) and Tarone (1975). All reported P values for the survival analysis are two-sided. Calculation of Incidence for neoplastic and non-neoplastic lesions. Analysis of Tumour Incidence: Mantel and Haenszel (1959). Continuity-corrected tests were used in the analysis of tumour incidence, and reported P values are one-sided. Life Table Analyses-- Mantel-Haenszel (1959) method used to obtain an overall P value. Life table method of Cox (1972) and of Tarone (1975). The underlying variable considered by this analysis is time to death due to tumour. Incidental Tumour Analyses-- (Haseman, 1984) Unadjusted Analyses--Primarily, survival-adjusted methods are used to evaluate tumour incidence. The Fisher exact test for pairwise comparisons and the Cochran-Armitage linear trend test (Armitage, 1971; Gart et al., 1979).

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
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
Mortality - Although the mortality was dose related in male rats (final survival: vehicle control 36/50, low dose 26/50, high dose 20/50), many of the early deaths in the dosed males were gavage related. Survival of the high dose males was significantly lower than that of the vehicle control after week 103.

Bodyweight - Bodyweights of high dose male rats were 5%-8% lower than those of the vehicle controls after week 59.

Tumour findings - There were no significant changes in the incidences of neoplastic or non-neoplastic lesions which were considered to be related to the administration of xylenes (mixed).

Testis findings - Although the overall incidences of interstitial cell tumours were comparable in male rat groups (vehicle control, 43/50; low dose,38/50; high dose, 41/49), survival-adjusted analyses indicated an increased incidence in the high dose group relative to vehicle controls. This apparent effect was due primarily to animals dying between weeks 62 and 92, for which the incidence of interstitial cell tumours was 13/13 for the high dose group compared with 4/9 for vehicle controls. Tumour incidences were comparable during the other time intervals. It is doubtful that this marginal effect is compound related.

Haematopoietic System and Pituitary Gland - Dose-related decreases in the incidences of mononuclear cell leukaemia (vehicle control,22/50; low dose, 18/50; high dose, 11/50) and pituitary gland adenoma or carcinoma (combined) (vehicle control, 24/49; low dose, 22/50; high dose, 12/45) were observed in male rats. However, these differences were due primarily to decreased survival of the high dose group relative to that of the vehicle controls.

Effect levels

Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: decreased body weights in males from week 59 at 500 mg/kg bw/day and no evidence of systemic toxicity of xylenes (mixed) for male or female F344/N rats given 250 or 500 mg/kg

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
There was no evidence of treatment-related systemic toxicity or carcinogenicity following gavage administration of mixed xylenes to male and female F344/N rats at doses of 0, 250 or 500 mg/kg body weight/day for up to 103 weeks.
Executive summary:

The toxicity of mixed xylene was investigated in male and female F344/N rats following oral (gavage) administration at doses of 0, 250 or 500 mg/kg bw/day for 103 weeks. Animals were observed for survival, clinical signs and body weight gain and subject to a full necropsy with tissue histopathology at sacrifice. There was no evidence of treatment-related systemic toxicity in either sex under these conditions.