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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
publication
Title:
Developmental toxicity study of piperonyl butoxide in CD rats
Author:
Tanaka T, Fujitani T, Takahashi O, Oishi S, Yoneyama M.
Year:
1995
Bibliographic source:
Toxicol Ind Health 11, 175-184

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
treatment only on gestation days 11 and 12
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Reference substance name:
Piperonyl butoxide
IUPAC Name:
Piperonyl butoxide
Test material form:
other: liquid
Details on test material:
Piperonyl butoxide (Lot No DZ01) from Tokyo Kasei Co, Ltd (Tokyo, Japan)
Purity >95%

Test animals

Species:
rat
Strain:
other: Crj:CD
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan inc (Kanagawa, Japan)
- Age at study initiation: 8 weeks
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing:
- Diet : ad libitum (nihon Clea, CE-2)
- Water: ad libitum):
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ± 1 °C
- Humidity (%): 55 ± 5%
- Air changes (per hr): air conditioned
- Photoperiod (hrs dark / hrs light): no data

IN-LIFE DATES: From: To: no data

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on exposure:
not applicable
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
test item was administered directly by gavage
Details on mating procedure:
no data
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1 male/ 2 females
- Length of cohabitation: over night
- Proof of pregnancy: vaginal plug / referred to as day 0 of pregnancy
- Any other deviations from standard protocol: none
Duration of treatment / exposure:
day 11-12 of gestation
Frequency of treatment:
daily
Duration of test:
until caesarian on gestation day 20
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 630, 1065, 1800 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
15 control mated females
10 mated females per treatment group
Control animals:
other: saline by gavage
Details on study design:

preliminary pilot studies to determine dose and timing of treatment

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: no data


DETAILED CLINICAL OBSERVATIONS:o data

BODY WEIGHT: Yes
- Time schedule for examinations: gestation days 11-20

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: no data

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: No data
- Number of implantations: Yes
- Number of resorptions: Yes
-
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: No data
- Skeletal examinations: Yes: all per litter
- Head examinations: No data
Statistics:
Bonferroni's multiple comparison test after ANOVA or Kruskal-Wallis-test
Chi-square test

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
No abnormal behaviour
No mortality
3/15 not pregant in control group
2 litters were totally resorbed at 1800 mg/kg bw/d
reduced bw gain (gestation day 11-20)

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
630 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
630 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
The average fetal body weight of each sex was significantly reduced in the 1065 and 1800 mg/kg bw groups. External limb deformity (oligodactyly, syndactyly, and polydactyly) was significantly increased in the 1065 and 1800 mg/kg bw groups in a dose-related manner.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

 

Dose level (mg/kg bw/day)

 

0

630

1065

1800

No of females examined

15

10

10

10

No of pregnant females

12

10

10

10

No of dams with viable fetuses

12

10

10

8

Maternal body weight gain

109

92.5

83.0

69.0**

Total implantation sites

179

142

142

153

Average implantation sites

14.9

14.2

14.2

15.3

No of resorptions

1

0

3

54

Total resorption rate (%)

0.56

0

2.1

35.3**

Number of viable fetuses

178

142

139

99

Sex ratio(male/female)

1.31

1.06

1.28

1.15

Average litter size

14.8

14.2

13.9

12.4

Fetal body weight male(g)

3.52

3.61

3.35

3.01**

Fetal body weight (female)

3.33

3.40

3.21

2.88**

Proportion of fetuses with limb deformity (%)

0

0

19.4**

44.4**

Applicant's summary and conclusion

Conclusions:
Developmental effects at maternally toxic dose levels. NOAEL for maternal and developmental toxicity was 630 mg/kg bw/day.
Executive summary:

Piperonylbutoxide was administered to pregnant rats by gavage at a level of 0 (control), 630, 1065, and 1800 mg/kg bw on days 11-12 of gestation. The animals were killed on day 20 of gestation. Average maternal body weight gain (gestational days 11-20) was significantly reduced in the 1065 and 1800 mg/kg bw groups. Total resorption rate was significantly increased in the 1800 mg/kg bw group and those effects were significantly dose-related. The average fetal body weight of each sex was significantly reduced in the 1065 and 1800 mg/kg bw groups. External limb deformity (oligodactyly, syndactyly, and polydactyly) was significantly increased in the 1065 and 1800 mg/kg bw groups in a dose-related manner. The dose levels of piperonylbutoxide in the present study produced limb deformities in rats at maternally toxic dose levels only..