Reaction mass of 4-tert-butyl-2,5-xylenol and 6-tert-butyl-2,4-xylenol

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Remarks:

Meets the requirements of GLP. There are no deviations from the recommended guideline.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1994

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:

6-tert-butyl-2,4-xylenol

EC Number:

217-533-1

EC Name:

6-tert-butyl-2,4-xylenol

Cas Number:

1879-09-0

Molecular formula:

C12H18O

IUPAC Name:

2-tert-butyl-4,6-dimethylphenol

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Duration of treatment / exposure:

Males: 45 days including 14 days before mating
Females: from 14 days before mating to day 3 of lactation

Frequency of treatment:

Daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (actual dose received)

Remarks:

(vehicle)

Doses / concentrations 2

Dose / conc.:

6 mg/kg bw/day (actual dose received)

Doses / concentrations 3

Dose / conc.:

30 mg/kg bw/day (actual dose received)

Doses / concentrations 4

Dose / conc.:

150 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

Males,12; females, 12/group

Control animals:

yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION: Yes

HAEMATOLOGY: Yes

CLINICAL CHEMISTRY: Yes

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
ORGAN WEIGHTS: Yes
HISTOPATHOLOGY: Yes

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

There were no clinical abnormal signs attributable to the administration of the test substance. However, two female animals given 150 mg/kg died at the end of gestation period (one of them during the delivery).

Mortality:

mortality observed, treatment-related

Description (incidence):

Two female animals given 150 mg/kg died at the end of gestation period (one of them during the delivery).

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

The body weight gain of females given 150 mg/kg was lower than that of the controls during the gestation period. However, body weights of males did not demonstrate any effects attributable to the administration of test substance.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Food consumption of both males and females did not demonstrate any effects attributable to the administration of test substance.

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

Hematological examination revealed decreases in hematocrit, hemoglobin and red blood cells, increases in reticulocytes and a slight tendency for anemia in males given 150 mg/kg. Blood clinical examination revealed decreases in GOT and increases in gamma-GTP in the 30 and 150 mg/kg males.

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Liver and kidney weights showed increases or a tendency for increase in males given 30 mg/kg or more and females given 150 mg/kg. At necropsy enlargement of the liver in males given 30 and 150 mg/kg, and of the liver and kidneys in females given 150 mg/kg was noted.

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Histopathological examination revealed swelling of centrilobular hepatocytes in males given 150 mg/kg and swelling and necrosis of centrilobular hepatocytes, and single cell necrosis in females given 150 mg/kg. The dead females and females with pups which all died showed increased incidences of parakeratosis of the tongue, esophageal swelling and necrosis of centrilobular hepatocytes, as well as a variety of degenerative charges, single cell necrosis and mitosis in the liver. Degeneration and protein cast in the proximal tubules and PAS positive granules deposited in the renal papilla, were observed in the kidneys of females given 150 mg/kg.

Histopathological findings: neoplastic:

not specified

Other effects:

no effects observed

Effect levels

1

Key result

Dose descriptor:

NOEL

Effect level:

6 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Changes in clinical chemistry, liver and kidney weights, histopathological examination.

2

Key result

Dose descriptor:

NOEL

Effect level:

30 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Changes in liver and kidney weights and histopathological examination.

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

NOELs for repeat dose toxicity are considered to be 6 mg/kg/day in males and 30 mg/kg/day in females.

Executive summary:

The substance 6-tert-Butyl-2,4-xylenol was studied in an OECD combined repeat dose and reproductive/developmental toxicity screening test at doses of 0, 6, 30 and 150 mg/kg/day. With regard to repeat dose toxicity, two female rats given 150 mg/kg died at the end of the gestation period (one of them during delivery). Body weight gain of females given 150 mg/kg was lower than that of the control during the gestation period. Hematological examination showed decreases of hematocrit, hemoglobin and red blood cells, and increases of reticulocytes and a slight tendency for anemia in male rats given 150 mg/kg. Blood chemical examination revealed decreases in levels of GOT and increases in γ-GTP in males given 30 and 150 mg/kg. Liver and kidney weights showed increases or a tendency for increase in the male rats given 30 mg/kg or more and in the females given 150 mg/kg. As gross findings, enlargement of the liver was observed in males given 30 and 150 mg/kg, and enlargement of the liver and kidneys was observed in females given 150 mg/kg. Histopathological examination revealed swelling of liver cells in the centrilobular zone in males and females of the 150 mg/kg group, and degeneration of liver cells, necrosis of centrilobular hepatocytes and single cell necrosis in the females of the same group. NOELs for repeat dose toxicity are considered to be 6 mg/kg/day in males and 30 mg/kg/day in females of the group.