2-(2-butoxyethoxy)ethyl 6-propylpiperonyl ether

Developmental toxicity / teratogenicity

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

Test material information

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)

1

Dose descriptor:

NOAEL

Effect level:

630 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

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..