Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: OECD guideline used
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1999

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD TG421
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Mitsuboshi Chemical Co., Ltd.: purity >99%

Test animals

Species:
rat
Strain:
Crj: CD(SD)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: Sesame oil
Details on exposure:
VEHICLE
- Amount of vehicle (if gavage): 5 ml/kg bw
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
According to the random sampling, actual dose received was between -
12.5 to -0.4 % of each dose level
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
Duration of treatment / exposure:
male: 48 days, female: 41-48 days
Frequency of treatment:
once a day by oral gavage
Duration of test:
male: 48 days, female: 41-48 days
No. of animals per sex per dose:
12 per sex per dose
Control animals:
yes, concurrent vehicle
Details on study design:
ADMINISTRATION
- male: before mating 14 days, during mating 14 days, after mating 20 days; total 48 days
- pregnant female: before mating 14 days, during mating (max.) 14 days, during gestation (about 21 days), after pregnant 3 days; total 41-46 days; not pregnant female: till 25 days after gestation; total 41-43 days; not copulated female: till 20 days after mating period; total 48 days
- According to the random sampling, actual dose received was between 12.5 to -0.4 % of each dose level.

Examinations

Maternal examinations:
CLINICAL OBSERVATION AND FREQUENCY
- clinical signs and mortality: daily
- male body weight: once a week, total 8 times in the 49 days
- female body weight: 1st, 8th, l5th day before mating; 0th, 7th, 14th, 21st day after copulated; 0th, 4th day after pregnance
- food consumption: in conformity with those body weight, except during mating for female
- water consumption: not checked
Fetal examinations:
- Pups number, sex, weight by sex in each litter, appearance were observed on 0th and 4th day. Dead pups were checked separately.

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

STATISTICAL RESULTS

There were no significant differences in number of offspring or live offspring, sex ratio, the live birth index, the viability index and the body weight. No abnormal findings related to the test substance were noted for external features, clinical signs, or on necropsy finding for the offspring. No pups with malformation were found in any group. No change in clinical signs and necropsy finding were observed in offspring.

FINDINGS OF DELIVERY IN DAMS AND OBSERVATIONS ON THEIR PUPS (F1)

Dose (mg/kg)

0

100

300

1000

No.of dams observed

11

10

12

12

No. of dams delivered live pups

11

10

12

12

Duration of gestation (mean±sd)

22.7±0.6

22.4±0.5

22.3±0.5

22.8±0.4

No. of total corpora lutea

216

170

218

222

Mean ± sd

19.6±4.5

17.0±2.1

18.2±3.7

18.5±3.2

No. of total implants

188

161

186

175

Mean ± sd

17.1±1.6

16.1±2.0

15.5±3.0

14.6±3.0

No. of total pups born

172

150

178

160

Mean±sd(=litter size)

15.6±1.6

15.0±1.8

14.8±2.6

13.3±3.3

Live Male

81

69

91

79

Mean±sd

7.4±1.9

6.9±2.3

7.6±2.4

6.6±1.8

Live Female

87

81

87

81

mean±sd

7.9±1.9

8.1±1.7

7.3±1.9

6.8±2.7

Sex ratio (male/female, mean±sd)

1.00±0.41

0.93±0.51

1.13±0.43

1.21±0.81

No. of total live pups an day 4; Male

66

66

85

78

Mean ± sd

6.0±3.2

6.6±2.2

7.1±2.5

6.5±1.7

Female

66

77

80

79

Mean ± sd

6.0±3.3

7.7±1.4

6.7±1.6

6.6±2.6

No. of total dead pups born

4*

0

0

0

Mean±sd

0.4±1.2

0.0±0.0

0.0±0.0

0.0±0.0

Gestation index(%)

100.0

100.0

100.0

100.0

Implanation index (%, mean ± sd)

89.5±12.3

94.7±2.0

86.6±15.8

80.2±18.2

Delivery index (%, mean ± sd)

91.6±5.6

93.5±7.7

96.2±4.8

90.9±8.6

Livebirth index (%, mean ± sd)

97.4±8.6

100.0±0

100.0±0

100.0±0

Viability index on day 4(%, mean ± sd); Male

77.8±39.1

96.0±8.4

93.1±9.7

99.1±3.2

Female

77.0±39.1

95.7±5.6

94.4±15.8

98.0±4.8

Gestation index = (No. of females with live pups/No. of pregnant females) x 100

Implanation index = (No. of implant/ No. of corpora Iutea) x 100

Delivery index = (No. of pups born/No. of implants) x 100

Livebirth index = (No. of live pups born/No. of pups born) x 100

Viability index an day 4 = (No. of live pups an day 4 after birth/No. of live pups born) x 100

*The reason of 4 dead pups born at 0 mg/kg bw was cannibalism.

Applicant's summary and conclusion

Conclusions:
NOAEL for Developmental Toxicity and Teratogenicity is considered to be 1000 mg/kg/day.
Of low toxicity to offspring
Executive summary:

There were no significant differences in number of offspring or live offspring, sex ratio, the live birth index, the viability index and the body weight. No abnormal findings related to the test substance were noted for external features, clinical signs, or on necropsy finding for the offspring. No pups with malformation were found in any group. No change in clinical signs and necropsy finding were observed in offspring.