Registration Dossier

Administrative data

Endpoint:
toxicity to reproduction: other studies
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 Hatano Research Institute, Food and Drug Safety Center (JAPAN)

Data source

Reference
Reference Type:
publication
Title:
Toxicity Testing Report of Environmental Chemicals 7, 179-181
Author:
MHW (Ministry of Health and Welfare), Japan .
Year:
1999
Bibliographic source:
cited: OECD SIDS Initial Assessment Report, Boston 20-25th Oct. 2002

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD TG 422
Principles of method if other than guideline:
Type: Toxicity to Reproduction
Method : OECD Preliminary Reproduction Toxicity Screening Test (TG 422)
GLP compliance:
yes
Type of method:
in vivo

Test material

Reference
Name:
Unnamed
Type:
Constituent
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
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Male: for 42 days;
Female: for 40-48 days from 14 days prior to mating to the 3 day of lactation
Frequency of treatment:
Daily
Duration of test:
Terminal killing: Male; day 43 Female; day 4 of lactation
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 2.5, 12.5, 60 mg/kg/day (in corn oil)
Basis:
nominal conc.
No. of animals per sex per dose:
No. of animals per sex per dose: 13 per sex per dose group
Control animals:
yes, concurrent vehicle
Details on study design:
[Study Design]
The animals were sacrificed on the day 4 of lactation for females. Females with no delivery were killed on the day 25 of pregnancy. *Satellite groups and reason they were added: none *Mating procedure: Male / female per cage; 1/1, length of cohabitation; at most 14 days, until proof of copulation (formation of vaginal plug or sperm detection in vagina)
Statistics:
Statistical methods: Dunnett's or Scheffe's test for continuous data and Chisquare test for quantal data

Results and discussion

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
12.5 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: for maternal toxicity
Dose descriptor:
NOAEL
Effect level:
12.5 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: for pups toxicity

Observed effects

*Mortality and day of death: the death was not observed in any group
*Body weight: suppression of body weight gain was observed on the day14 of pregnancy and the day 4 of lactation in the 60 mg/kg group.
*Food consumption: Decrease in food consumption was observed during lactation period in 60 mg/kg group.
*Pups data: Grossly visible abnormalities : no significant effect was observed.

Any other information on results incl. tables

NOAEL;
12.5 mg/kg/day for maternal toxicity
12.5 mg/kg/day for pups toxicity.

*Maternal data with dose level (with NOAEL value):
Decrease tendencies, not significant, in number of corpora lutea and number of implantation sites were observed in the 60 mg/kg group.
*Pups data with dose level (with NOAEL value): Decrease in number of live pups at the day 0 and 4 of lactation were observed at 60 mg/kg group. Decrease in body weights of both sexes on the day 0 and 4 of lactation were noted in the 60 mg/kg group.

Dose level (mg/kg/day) 0 2.5 12.5 60
No. of pairs mated 13 13 13 13
No. of pregnant females12 13 13 12
Corpora lutea 16.4±1.8 17.0±0.7 16.5±4.6 14.0±2.4
Implantation scars 14.8±3.2 16.2±1.5 15.0±4.6 12.8±3.2
Pups born 13.8±3.0 15.5±1.6 13.8±4.3 10.5±3.1
Delivery index(% ) 93.5±6.2 95.2±4.2 92.4±7.4 83.3±17.9
Live pups born 13.8±3.0 15.3±1.6 13.5±4.4 10.3±2.9*
Live birth index (% ) 100±0.0 99.0±3.5 91.0±27.898.1±3.5
Live pups on day 4 of lactation
13.5±2.8 14.1±4.5 14.4±1.7 8.8±3.7*

Body weight of live pups (g)
on day 0
Males 7.0±0.7 6.6±0.4 6.8±0.8 5.8±1.2**
Females 6.7±0.6 6.8±1.4 6.3±0.7 5.6±1.3**
on day 4
Males 11.3±1.5 10.9±1.0 10.2±1.5 9.6±2.5*
Females 11.0±1.6 10.4±1.0 9.5±1.2 8.8±2.9**
(*P<0.05, **P<0.01)

Applicant's summary and conclusion

Executive summary:
method: 2 -tert-buty-5 -methylphenol was administered to SD(Crj:CD) rats by gavage at doses of 0 (vehicle ; corn oil) 2.5, 12.5 and 60 mg/kg from 14 days before mating to 14 days after mating in males and from 14 days before mating to day 3 of lactation in females. result: Maternal body weight gain and food consumption were suppressed in the 60 mg/kg group. No adverse effects were observed on copulation, fertility, delivery and lactation in any group. Slight effects to the maternal reproductive index, such as a slight decrease in the number of corpora lutea, implants, number of live neonates at birth and a slight low value of delivery index were observed at 60 mg/kg. In this dose group, the body weight gain of pups was suppressed. Evidence of malformations was not observed grossly at any dose group. based on the above results, the NOAEL for reproductive toxicity is considered to be 12.5 mg/kg for both female parents and pups reference: MHW, Japan (1999)