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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
three-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Published peer reviewed study

Data source

Reference
Reference Type:
publication
Title:
Reproductive and neurobehavioural effects in three-generation toxicity study of piperonyl butoxide administered to mice.
Author:
Tanaka T, Takahashi O, Oishi S.
Year:
1992
Bibliographic source:
Food Chem Toxicol 30,l 1015-1019

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
GLP compliance:
not specified
Limit test:
no

Test material

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

Test animals

Species:
mouse
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Chalres River japan
- Age at study initiation: (P) 4 wks;
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: indivividually

- Diet ad libitum
- Water ad libitum
- Acclimation period: no data

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

IN-LIFE DATES: no data

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: with feed
Details on exposure:
no data
Details on mating procedure:
At 9 weeks of age each female was paired with one male of the same treatment group for 5 days after which they were separated and females were allowed to produce and rear their pups.
Analytical verification of doses or concentrations:
not specified
Details on study schedule:
- F1 parental animals not mated until 9 weeks after selected from the F1 litters.
- Selection of parents from F1 generation when pups were 28 days of age.
- Age at mating of the mated animals in the study:9 weeks
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 1000, 2000, 4000, or 8000 ppm
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
0, 90, 180, 360, 720 mg /kg bw/day
Basis:
other: calculated
No. of animals per sex per dose:
10
Control animals:
yes, plain diet
Positive control:
no

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: No data


DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations:

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data
preconception ( 5wks ofage to mating), matin (5 days), gestation (14 days) lactation (from birth to weaning)
Oestrous cyclicity (parental animals):
No data
Sperm parameters (parental animals):
No data
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in [F1 / F2 / F3] offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, other: neurobehavioural tests FOB, whole litter: surface righting, negative geotaxix, cliff avoidance, swimming behaviour, olfactory orientation
Postmortem examinations (offspring):
no data
Statistics:
Scheffe's multiple comparison test
Chi-square test
Mann-Whitney test

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
reduced feed intake at 0.8% dose level
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
reduced feed intake at 0.8% dose level
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Test substance intake: reduced intake at 0.8% dose level

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
reduced survival at day 21 post partum for 0.8% dose
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
mean litter weight decreased at 0.8%
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Details on results (F1)

F1 generation:
Reduced survival (21 days) at 0.8%
Pup weights decreased at all dose levels but dose-related response only at 0.4 and 0.8%
Neurobehavioural effects were not dose related.

F2 Generation
Reduced litter size reduced at 0.4 and 0.8%
Mean litter weights reduced at all dose levels
Reduced survival (21 days) at 0.8%
Pup weights decreased at all dose levels
Neurobehavioural effects were not dose related.

Effect levels (F1)

Dose descriptor:
LOAEL
Generation:
F1
Effect level:
1 000 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on the recorded effect on pup weights at all dose levels a NOAEL could not be set for this study.

Results: F2 generation

Effect levels (F2)

Dose descriptor:
LOAEL
Generation:
F2
Effect level:
1 000 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on the recorded effect on pup weights at all dose levels a NOAEL could not be set for this study.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Pupweight in lactation period in F1 generation mice

 

Dose level (%)

 

PND

0

0.1

0.2

0.4

0.8

Male

0

1,64

1,50**

1,60

1,57

1,42**

 

7

4,59

3,93**

4,23

3,74**

3,17**

 

21

12,21

9,68**

10,80

9,10**

5,85**

Survival index at PND 21

90,6

96,1

96,1

94,4

63,0

 

Female

0

1,58

1,51

1,52

1,53

1,33**

 

7

4,39

3,87

4,01

3,66**

3,20**

 

21

11,91

9,41**

10,06**

8,82**

6,60**

Survival index at PND 21

88,7

87,7

100

93,3

78,9

 

Applicant's summary and conclusion

Conclusions:
Based on the recorded effect on pup weights at all dose levels a NOAEL could not be set for this study.
LOAEL was 0.1% PBO in feed
Executive summary:

Piperonylbutoxide (PB) was administered continuously to mice from 5 weeks of age in the F0 generation to weaning of the F2 generation. PB was administered in the diet at levels of 0 (control), 0.1, 0.2, 0.4 and 0.8%. Selected reproductive, developmental and behavioural parameters were measured. Litter size and litter weight were reduced in higher-dosed groups, and the body weight of the pups in the lactation period was reduced in dosed pups in each generation. The survival index at postnatal day 21 of the group receiving 0.8% PB was reduced in each generation. The developmental and behavioural parameters in the lactation period were little different from those of the controls, apart from olfactory orientation in the F1 generation. However, in the F2 generation mice, surface righting, cliff avoidance and olfactory orientation were adversely affected in treatment groups. The results suggest that PB had adverse effects on reproductive, developmental and behavioural parameters of mice, with increasing effects in subsequent generations of offspring.

Based on the recorded effect on pup weights at all dose levels a NOAEL could not be set for this study.