Registration Dossier
Registration Dossier
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EC number: 200-076-7 | CAS number: 51-03-6
Toxicity to reproduction
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:
- 1 992
- 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
- Reference substance name:
- Piperonyl butoxide
- IUPAC Name:
- Piperonyl butoxide
- Details on test material:
- Supplier Tokyo Kasei Ltd (Tokyo, Japan)
Lot No DZ01
Purity >95%
Constituent 1
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)
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.
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