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

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

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

Parental animals: Observations and examinations:

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION: Yes

Litter observations:

- No. of total live pups born
- Sex ratio
- No. of live pups on Day 4
- No. of dead pups born

Postmortem examinations (parental animals):

GROSS PATHOLOGY: Yes
ORGAN WEIGHTS: Yes
HISTOPATHOLOGY: Yes

Reproductive indices:

- Gestation index
- Implantation index
- Delivery index
- Live birth index

Offspring viability indices:

- Viability index on Day 4

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

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). In addition with three females of the same treatment group all pups died during the lactation period. A tendency for decrease in the viability index of the pups at Day 4 after birth was also observed in this group.

Dermal irritation (if dermal study):

not examined

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 examined

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

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

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:

not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Description (incidence and severity):

The compound showed no effects on estrous cycle.

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Description (incidence and severity):

The compound showed no effects on mating and fertility.

Effect levels (P0)

1

Key result

Dose descriptor:

NOEL

Effect level:

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

Based on:

test mat.

Sex:

male

Basis for effect level:

reproductive performance

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:

reproductive performance

Target system / organ toxicity (P0)

Key result

Critical effects observed:

no

Results: F1 generation

General toxicity (F1)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

A tendency for decrease in the viability index of the pups at Day 4 after birth was also observed in the group of females given 150 mg/kg bw.
Viability index on day 4 (%, mean ± SD) for males: from 95.5 ± 15.1 (non parametric analysis) (0 mg/kg) to 71.4 ± 42.9 (150 mg/kg)
Viability index on day 4 (% mean ± SD) for females: from 95.5 ± 15.1 (non parametric analysis) (0 mg/kg) to 69.7 ± 44.0 (150 mg/kg)
In 3 females of the same treatment group all pups died during the lactation period.

Dermal irritation (if dermal study):

not examined

Mortality / viability:

mortality observed, treatment-related

Description (incidence and severity):

A tendency for decrease in the viability index of the pups at Day 4 after birth was also observed in the group of females given 150 mg/kg bw.
Viability index on day 4 (%, mean ± SD) for males: from 95.5 ± 15.1 (non parametric analysis) (0 mg/kg) to 71.4 ± 42.9 (150 mg/kg)
Viability index on day 4 (% mean ± SD) for females: from 95.5 ± 15.1 (non parametric analysis) (0 mg/kg) to 69.7 ± 44.0 (150 mg/kg)
In 3 females of the same treatment group all pups died during the lactation period.

Body weight and weight changes:

not specified

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

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings:

not specified

Other effects:

not examined

Developmental neurotoxicity (F1)

Behaviour (functional findings):

not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:

not examined

Effect levels (F1)

Key result

Dose descriptor:

NOEL

Generation:

F1

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

viability

Target system / organ toxicity (F1)

Key result

Critical effects observed:

no

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

NOELs for reproductive performance of males and for that of females and pup development are considered to be 150 mg/kg/day and 30 mg/kg/day, respectively.

Executive summary:

6-tert-Butyl-2,4-xylenol was studied in an OECD combined repeat dose and reproductive/developmental toxicity screening test (OECD Guideline 422) at doses of 0, 6, 30 and 150 mg/kg/day.The compound showed no effects on mating, fertility and oestrous cycle. In terms of reproductive/developmental toxicity, one female given 150 mg/kg died during the delivery. With three females in the same treatment group all pups died during the lactation period. A tendency to decrease of viability index of pups at Day 4 after birth was observed in 150 mg/kg group. The NOELs for reproductive performance of males and for that of females and pup development are considered to be 150 mg/kg/day and 30 mg/kg/day, respectively.