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Toxicity to reproduction: other studies

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Administrative data

Endpoint:
toxicity to reproduction: other studies
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well conducted study, carried out by Nihon Bioresearch Inc..

Data source

Reference
Title:
No information
Author:
MHLW, Japan (2001) Ministry of Health, Labor and Welfare,|Toxicity Testing Reports of Environmental Chemicals 8 (2),|1101-1112

Materials and methods

Principles of method if other than guideline:
Type: other: One generation study
Method: other: OECD TG 421
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
TS-Freetext:
Source; Wako Pure Chemical Ind., Ltd., Lot No. PAK5633,
Purity; 98.2%( m-58.5366%, p-39.7107%)

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Duration of treatment / exposure:
Males: 50-52; Females: from 14 days before mating to day 3 of lactation
Frequency of treatment:
once daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0(vehicle), 6, 30, 150, 750 mg/kg/day
Basis:

Control animals:
yes, concurrent vehicle

Results and discussion

Any other information on results incl. tables

RS-Freetext:
NOAEL: Parental; 750 mg/kg for male and female
       Offspring; 750 mg/kg for male and female

1) Effects on reproduction and development of parent animals
(1) Number of estruses, copulation index and fertility index
The number of estruses during the administration period (14
days) before mating showed no significant difference in any
treatment group compared with the control group.
The number of days required for copulation showed no
significant difference between any treatment group and the
control group.
The pair showing no copulation was observed in one pair each
in the 6 and 30 mg/kg groups.  However, there was no
significant difference in the copulation index between any
treatment group and the control group.
There were two females showing no conception in the 6mg/kg
group. However, there was no significant difference in the
fertility index between any treatment group and the control
group.

(2) Pregnancy period, parturition, number of corpora lutea,
implantation index and delivery index
The pregnancy period showed no significant difference in any
treatment group compared with the control group.  In the
control group and the 30, 150 and 750mg/kg groups, there was
no abnormality in the parturition in any dam. In one animal
in the 6 mg/kg group, since the born offspring died (one
stillbirth was confirmed), no neonate could be obtained.
In any treatment group, there were no significant
differences in the number of corpora lutea, the number of
implantations and the implantation index compared with the
control group.
In the control group and the 30, 150 and 750 mg/kg groups,
the delivery index was 100%. In the 6mg/kg group, since 1
dam could obtain no neonate, the delivery index was 88.9%,
but there was no significant difference from the control
group. In the control group and any treatment group, there
was no abnormality in the lactation.

RS-Freetext:
2) Effects on offspring
(1) Parturition index and live birth index
In any treatment group, there were no significant
differences in the total number of delivered offspring, the
number of stillbirth, the number of neonates on Day 0 of
lactation, the sex ratio, the parturition index, the
delivery index of offspring and the live birth index
compared with the control group.

(2) Clinical signs and viability index of offspring
In any treatment group, there were no significant
differences in the number of offspring surviving on Day 4 of
lactation and the viability index of neonates on Day 4
compared with the control group.  In the external
observation of neonates, there was no abnormality in any
group.  In the clinical signs of offspring, there was no
abnormality in any group.

(3) Change in body weight of offspring
In any treatment group, there were no significant
differences in the body weights on Days 0 and 4 of lactation
for males and females compared with the control group.

(4) Autopsy of offspring
In any group, no abnormality was observed.

Applicant's summary and conclusion

Conclusions:
CL-Freetext:
The reproductive and developmental toxicological NOAEL is
considered to be 750 mg/kg/day since there was no effect on
male and female parent animals and offspring after
administration at a dose of 750 mg/kg.