35XY60

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

experimental study

Adequacy of study:

key study

Study period:

26 July 2004 - 17 Sept 2004

Reliability:

1 (reliable without restriction)

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2005

Report date:

2005

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Xylenols isomer mixture

IUPAC Name:

Xylenols isomer mixture

Details on test material:

- Name of test material (as cited in study report): 2,5-xylenol (CAS 95-87-4), 3,4-xylenol (CAS 95-65-8), 2,4-xylenol (CAS 105-67-9), 3,5-xylenol (CAS 108-68-9), 2,3-xylenol (CAS 526-75-0), 2,6-xylenol (CAS 576-26-1). Test substancec was a mixture of xylenol isomers.
- Analytical purity: 99.74%
- Isomers composition: 2,5-xylenol (CAS 95-87-4): 16.4 mole %, 3,4-xylenol (CAS 95-65-8): 16.9 mole %, 2,4-xylenol (CAS 105-67-9): 22.7 mole %, 3,5-xylenol (CAS 108-68-9): 11.1 mole %, 2,3-xylenol (CAS 526-75-0): 18.2 mole %, 2,6-xylenol (CAS 576-26-1): 14.7 mole %.
- Lot/batch No.: 20NOV2003

Test animals

Species:

rat

Strain:

other: Crl:CD (SD)IGS BR VAF/Plus

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

The test substance was prepared as a solution in the vehicle and administered orally by gavage.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

GC/FID analysis of dosing preparation concentration, stability and homogeneity.

Duration of treatment / exposure:

28 days for males and 54 days for females.

Frequency of treatment:

Daily administration beginning 14 days prior to cohabitation and continuing until the day before sacrifice.

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 30, 100 and 245 mg/kg/day
Basis:
actual ingested

No. of animals per sex per dose:

10 rats per sex per group

Control animals:

yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least 2/day

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: 2/day

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

Observations were performed for viability, clinical signs of toxicity, food consumption, body weight gain, functional observational battery and motor activity, hematology, clinical chemistry, developmental toxicity and reproductive performance, gross and microscopic post-mortem examination.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Statistics:

Body weight, weight gains and reproductive end points analysed by ANOVA and Dunnett's. Reproductive data analysed by Fisher's exact test.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

Relative weights of kidney, liver and ovaries were increased in the high dose group.

Effect levels

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: Due to clinical observations (urine-stained fur, increased kidney, liver and ovarian relative weight).

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

All rats survived the treatment. In males, urine stained fur was observed at the 245 mg/kg/day level. Body weight gain and food consumption were unaffected by treatment. Mating frequency was reduced at the 245 mg/kg/day level. Neurotoxicity was not observed during the study and there were no treatment related effects observed at gross necropsy or histopathologically. Urine staining of the fur was observed in females at the 245 mg/kg/day level. F1 animals showed no treatment related clinical or necropsy signs. Haematology and clinical pathology parameters were unaffected.

Reproductive indices are discussed under section 7.8.1.

Applicant's summary and conclusion

Conclusions:

The test substance mixed xylenol isomers was administered to rats by oral gavage at 0, 30, 100 and 245 mg/kg/day. The general toxicological No Observable Adverse Effect Level was shown to be 100 mg/kg/day.

The reproductive NOAEL is discussed under section 7.8.1.