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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 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:
publication
Title:
Oral toxicology studies with xylene isomers and mixed xylenes
Author:
Condie LW, Hill JR and Borzelleca JF
Year:
1988
Bibliographic source:
Drug and Chemical Toxicology, Vol. 11 (4), pp. 329-354

Materials and methods

Test guidelineopen allclose all
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Qualifier:
equivalent or similar to
Guideline:
EPA OPP 82-1 (90-Day Oral Toxicity)
Principles of method if other than guideline:
Observations included assessment of clinical chemistry, haematology, organ weights and microscopic examination of liver and kidney.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
Technical grade mixed xylenes (17.6% o-xylene, 62.2% m-xylene and p-xylene (co-eluted), 20.0% ethyl benzene.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories (Wilmington, MA) or Simonsen Laboratories (Gilroy, CA, USA)
- Age at study initiation: 6-8 weeks
- Diet: Commercial rodent diet (Ralston Purina Company, St. Louis, MO, USA) ad libitum
- Water: ad libitum
- Housing: 5 per cage
- Acclimation period: quarantined for 1 week

ENVIRONMENTAL CONDITIONS
- Temperature: 21-24°C
- Humidity: 30-70%
- Photoperiod: 12hrs dark / 12hrs light

IN-LIFE DATES: Not reported

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: Prepared freshly each day in corn oil and dosed at a constant volume of 5 mL/kg bw
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
90 days
Frequency of treatment:
Daily: once/day
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 150, 750 or 1500 mg/kg/day
Basis:

No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes (normal behavioural response and mortality)
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE: No

WATER CONSUMPTION AND COMPOUND INTAKE : No
- Time schedule for examinations:
OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: day of sacrifice
- Method of blood collection: cardiac puncture
- Animals fasted: No data
- How many animals: 10/sex/group
- Parameters examined: RBC, WBC, Hgb, Hct, MCV, MCH, MCHC, platelets, differential count of PMN, Lymph, mono, eosino

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: day of sacrifice
- Animals fasted: No data
- How many animals: 10/sex/group
- Parameters examined: BUN, creatinine, AST, ALT, ALP (females only), LDH, Calcium, Total protein, Albumin, Sodium, Potassium

URINALYSIS: Yes
- Time schedule for collection of urine: once during final week
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No data
- Parameters examined: pH, protein, glucose, bilirubin, urobilinogen, occult blood

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:
GROSS PATHOLOGY: Yes (major organs preserved for future possible examination)

ORGAN WEIGHTS: brain, liver, spleen, lungs, thymus, kidneys, heart and gonads of all animals

HISTOPATHOLOGY: Yes (liver and kidney)
Statistics:
For each treatment group, the mean weekly body weights, clinical chemistry, haematology and organ weights were compared by analysis of variance. Comparisons of each treatment group with their respective vehicle control groups were made by Student's t-test. Results of the urinalysis and gross necropsy findings were not statistically analyzed.

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY: No mortalities. Only clinical sign was increase in aggressiveness during handling at 1500 mg/kg, especially males.

BODY WEIGHT AND WEIGHT GAIN: Reduced body weight gain at 1500 mg/kg in males. Overall weight gain was 104, 100 and 86% of control for 150, 750 and 1500 mg/kg respectively.

HAEMATOLOGY: No toxicologically significant effects. Statistically significant changes were present which indicated the presence of mild polycythaemia and leukocytosis in some of the dose groups. These changes were considered not to be toxicologically significant since the clinical health of the rats did not appear to be affected.

CLINICAL CHEMISTRY: Several instances of statistically significant variations were detected between control and treated groups but none are considered to be toxicologically significant. The modest increases in AST values in the 1500 mg/kg females and in ALT values in 1500 mg/kg males and 750 and 1500 mg/kg females, were not of sufficient magnitude to indicate liver damage but are consistent with hepatomegally.

ORGAN WEIGHTS:  Relative liver weights were statistically significantly increased in males (5.7, 17.1 and 37.1 % difference from controls for 150, 750 and 1500 mg/kg/day respectively) and females (13.9 and 27.8% difference from controls for 750 and 1500 mg/kg/day respectively). Relative kidney weights were statistically significantly increased in males (17.5 and 27.0% difference from controls for 750 and 1500 mg/kg/day respectively) and in females (16.4% difference from controls for 1500 mg/kg/day). Relative spleen and heart weights increased slightly in females at 1500 mg/kg (12.2 and 11.5% difference from controls respectively).

HISTOPATHOLOGY: NON-NEOPLASTIC: In male kidneys - dose-related increase (all dose levels 0/9, 3/9, 5/10, 8/10, in 0, 150, 750 and 1500 mg/kg bw/day groups respectively) in the incidence of slight to mild hyaline droplet formation in tubules which the authors concluded to be related to male rat-specific alpha-2u-globulin accumulation and not to be relevant to humans. In females - minimal nephropathy (incidence 1/10, 3/10, 6/10, 7/10 in 0, 150, 750 and 1500 mg/kg bw/day groups respectively). This was described as scattered tubular dilation and atrophy, with occasional tubular regeneration. These kidney changes in female rats are typical of chronic progressive nephropathy in ageing rats. There were no treatment-related liver changes.

Effect levels

open allclose all
Dose descriptor:
LOAEL
Effect level:
150 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: increased relative liver weight, no adverse liver histopathology, no alteration in clinical chemistry or haematological parameters. 750 mg/kg bw/day is a no effect level for decreases in body weight gain.
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day (nominal)
Sex:
female
Basis for effect level:
other: increased liver weights and increased incidence of minimal kidney nephropathy at 750 and 1500 mg/kg bw/day

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Treatment-related alterations following subchronic oral treatment with mixed xylenes were mild and limited to decreased body weight gain and increased relative organ weights (affecting primarily the liver and kidney; no histopathological involvement).
Executive summary:

The repeated dose toxicity of technical grade mixed xylenes was investigated in male and female Sprague-Dawley rats following oral gavage administration for 90 days at 0, 150, 750 or 1500 mg/kg/day. Treatment-related alterations were mild and limited primarily to increased relative liver weight (LOAEL 150 mg/kg bw/d for males; NOAEL 150 mg/kg bw/d for females; no histopathological alterations), relative kidney weight (higher LOAELs and NOAELs) and a reduction in body weight gain (males, NOAEL 750 mg/kg/d).