6-tert-butyl-m-cresol

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well conducted study, carried out by Research Institute for Animal Science in Biochemistry and Toxicology (Japan)

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1999

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)

Principles of method if other than guideline:

TC-Freetext:
*Age at study initiation: 8 week old for both sexes
*Mean weight at study initiation Dose levels(mg/kg) 0 2.5 12.5 60 Body weight (g±SD) Male 291.5±9.0 291.6±9.0 291.7±8.7 291.8±8.1 Female 220.1±7.0 220.1±7.5 219.9±6.7 220.2±7.2 No. of animals per sex per dose: 13 per sex per dose group
*Study Design
-Terminal killing: Males; day 43, Females; day 4 of lactation
-Clinical observations performed and frequency: General condition was observed once a day. Body weight and food consumption were determined once a week. Food consumption in mating period was not. Hematological and serum biochemical examinations, and urinary test were performed for all males.
-Organs examined at necropsy: Organ weight: brain, heart, liver, kidneys, spleen, thymus, adrenal glands, testes, epididymides Microscopic: control & all treated groups/ liver, spleen(female only),adrenal glands(female only), control & 60 mg/kg groups/brain, heart, kidneys,spleen, thymus, adrenal glands, testes, epididymides.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Automatically generated during migration to IUCLID 6, no data available

IUPAC Name:

Automatically generated during migration to IUCLID 6, no data available

Details on test material:

Produced by Sumitomo Chemical, Lot No.1271012. Purity 99.23%

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:

male: 42 days,
female: from 14 days before mating to day 3 of lactation

Frequency of treatment:

7 days/week

Doses / concentrations

Remarks:

Doses / Concentrations:
2.5, 12.5, 60 mg/kg/day (in corn oil)
Basis:

No. of animals per sex per dose:

13 per sex per dose group

Control animals:

yes, concurrent vehicle

Details on study design:

Post-exposure period: no

Positive control:

no data

Examinations

Observations and examinations performed and frequency:

-Clinical observations performed and frequency: General condition was observed once a day. Body weight and food consumption were determined once a week. Food consumption in mating period was not. Hematological and serum biochemical examinations, and urinary test were performed for all males.

Sacrifice and pathology:

-Terminal killing: Males; day 43, Females; day 4 of lactation
-Organs examined at necropsy: Organ weight: brain, heart, liver, kidneys, spleen, thymus, adrenal glands, testes, epididymides Microscopic: control & all treated groups/ liver, spleen(female only), adrenal glands(female only), control & 60 mg/kg groups/brain, heart, kidneys,spleen, thymus, adrenal glands, testes, epididymides.

Other examinations:

reproductive and developmental toxicity parameters were also examined, for detail see 7.8 (toxicity to reproduction)

Statistics:

no data

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

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not specified

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

effects observed, treatment-related

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

effects observed, treatment-related

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

12.5 mg/kg bw/day (nominal)

Sex:

male/female

2

Dose descriptor:

LOAEL

Effect level:

60 mg/kg bw/day (nominal)

Sex:

male/female

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

RS-Freetext:
*LOAEL= 60 mg/kg/day, NOEL = 12.5 mg/kg/day
males : histopathological changes in liver
females: suppression of body weight gain and histopathological changes in  liver
* Body weight: Suppression of body weight gain was observed at day 14 of  pregnancy and day 4 of lactation in the 60 mg/kg female.
Body weight in female

Dose level(mg/kg/day) 0 2.5 12.5 60
Body weight (g, mean±SD)
day 14 of pregnancy 338.7±15.1 343.8±13.5 335.7±26.7 310.1±24.9**
Day 4 of lactation 327.4±20.9 336.5±19.9 311.8±23.9 280.1±29.8**
(**P< 0.01)
*Food consumption: Decrease in food consumption was observed lactation  period in the female group at 60 mg/kg.(Statistical significant was P<  0.01 on the day 4 of
lactat ion)
*Clinical signs (description, severity, time of onset and duration): No  significant effect was observed.
in the female group at 60 mg/kg.(Statistical significant was P< 0.01 on  the day 4 of lactation)
*Clinical signs (description, severity, time of onset and duration): No  significant effect was observed.
*Mortality and time to death: The death was not observed in any group.
*Hematology and biochemical findings: No significant effect was observed.
*Gross pathology incidence and severity: No significant effect was  observed.
*Organ weight changes :
Male: Increase in absolute kidneys weight was observed in the 60 mg/kg  group (P<0.05).
Female: Decrease in absolute heart and spleen weights , and increase in  relative brain,liver and kidneys weights were observed in the 60 mg/kg  group (P< 0.01).
*Histopathology (incidence and severity)
Male & female: Hypertrophy of centrilobular hepatocytes with eosinophilic  was observed at 60 mg/kg group. Histopathological change considered to be  significant
biologically was not observed in other organs.

Histopathological changes in the liver

Sex     Male        Female

Dose level( mg/kg/day)
0 2.5 12.5 60 0 2.5 12.5 60 Hypertrophy,eosinophilic
Hepatocyte,centrilobular
0/13 0/13 0/13 5/13* 0/13 0/13 0/13 10/13** Necrosis
2/13 1/13 1/13 1/13 4/13 2/13 1/13 6/13 Fibrosis,focal
1/13 0/13 1/13 0/13 0/13 0/13 1/13 1/13 Fatty hange,periportal
13/13 13/13 13/13 13/13 3/13 1/13 2/13 7/13
( * P< 0.05 , ** P< 0.01)
Necrosis, Fibrosis and fatty change in peripotal region are thought to be  spontaneous lesion on the liver of male and female rats. Historical  control incidence of fifteen Combined Repeated Dose and  Reproductive/Developmental
Toxicity Studies performed at the same laboratory was checked out. The  range of Necrosis, Fibrosis and Fatty change in periportal region were  0-31%, 0-23% and 0-
100%, respectively. Especially, the historical incidence of Fatty change,  periportal was 100% in all of 15 studies investigated in male rats in the  laboratory. In the
study of 6-tert-butyl-m-cresol, the incidence of Necrosis, focal (15% in  male, 23% in female), Fibrosis, focal (8% in male, 0% in female), Fatty  change, periportal (100% in male, 23% in female) in control animals falls  within historical control range. Therefore, these lesions in the male and  female liver of 6-tert-butyl-mcresol study were considered to be  spontaneous and animals used in the study were normal.

Applicant's summary and conclusion

Conclusions:

Toxic effects in this study are suppression of body weight gain and increase of relative liver weight in the 60 mg/kg female, and histopathologica changes of the liver in the 60 mg/kg male and female. The NOEL is considered to be 12.5 mg/kg/day for both sexes.

Executive summary:

method: combined repeat dose reproductive/developmental toxicity screening study according OECD TG 422

result: NOEL = 12.5 mg/kg/day (rat, male + female), LOAEL = 60 mg/kg/day (rat, male + female); Toxic effects in this study are suppression of body weight gain and increase of relative liver weight in the 60 mg/kg female, and histopathologica changes of the liver in the 60 mg/kg male and female.

reference: MHW, Japan (1999)