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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)
Rationale for reliability incl. deficiencies:
other: GLP-guideline study
Cross-reference
Reason / purpose:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1993
Reference Type:
secondary source
Title:
1-chlorobutane, CAS No. 109-69-3
Author:
OECD SIDS
Year:
1997
Bibliographic source:
SIDS Initial Assessment Report for SIAM 6

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD Guideline For Testing Of Chemicals, Preliminary Reproduction Toxicity Screening Test
Deviations:
no
GLP compliance:
yes
Remarks:
Nihon Bioreseach Center Inc., Hashima Laboratory, Hashima, Japan
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 1-Chlorobutane

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Japan
- Age at study initiation: 8 weeks
- Weight at study initiation: females: ~230 g; males: ~340 g
- Housing: stainless steel and plastic cages
- Diet (ad libitum): solid pellets (CRF-1, Oriental Yeast Co. Ltd.)
- Water (ad libitum): tap water
- Acclimation period: 11 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 40-70
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
VEHICLE
- Concentration in vehicle: 0, 0.048, 0.24, 1.2, 6%
- Amount of vehicle (if gavage): max. 5 mL/kg/bw
- Lot/batch no.: 5233 and 8250
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Stability of test solutions were confirmed 1 and 3 hours after preparation of doses.
Details on mating procedure:
Mating was performed in hanging stainless steel cages.
Duration of treatment / exposure:
males: 49 days
females: 41-46 days
Frequency of treatment:
once daily
Duration of test:
males: 49 days
females: 41-46 days (from 14 days before mating to day 3 of lactation)
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 2.4, 12, 60, 300 mg/kg bw/d
Basis:
nominal conc.
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Preliminary study with male rats was conducted. Dose levels: 0, 10, 30, 100, 300, 1000 mg/kg bw/d
Within 5 days all animals of the top dose died. Salivation was observed 3 days after treatment in group 300 mg/kg, 7 days after treatment in group 100 mg/kg bw/d. Actual concentrations were selected on the basis of these results.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations: general conditions and mortality

BODY WEIGHT: Yes
- Time schedule for examinations: twice a week

FOOD CONSUMPTION: Yes
twice a week (converted to a daily dose measured over two consecutive days)

POST-MORTEM EXAMINATIONS: Yes
- Organs examined: testes, epididymes, ovaries, stomach, small intestine


OTHER:
reproductive indices
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: Yes
- Number of implantations: Yes
- Number of early resorptions: No data
- Number of late resorptions: No data
Fetal examinations:
- External examinations: Yes: number of dead pups at day 0 and 4, body weight at day 0 and 4, necropsy findings on day 4
Statistics:
Bartlett-test, Dunnet-test, Scheffe-test, χ2-test
Indices:
gestation index, delivery index, birth index, viability index

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Details on maternal toxic effects:
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
males:
- salivation in all dose groups

females:
- salivation: before and during mating in animals receiving 60 and 300 mg/kg bw/d, during pregnancy in animals receiving 12 mg/kg bw/d - 300 mg/kg bw/d and during lactation in highest dose females (300 mg/kg bw/d)
- One dam died on day 22 of pregnancy and one dam died on day 4 of lactation in the 300 mg/kg bw/d group.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
- statistically significant suppressed body weight gain in males and females of the 300 mg/kg bw/d dose group
- reduced food consumption in males and females receiving 300 mg/kg bw/d

GROSS PATHOLOGY (PARENTAL ANIMALS)
- surviving females on day 4 of lactation: 12/12 controls, 12/12 animals of 2.4 mg/kg bw/day, 11/11 animals of 12 mg/kg bw/day, 10/10 animals of 60 mg/kg bw/day and 5/9 animals of 300 mg/kg bw/day did not show necropsy findings. At a dose of 300 mg/kg bw/day the following effects were observed: in two of 9 animals white glandular mucosa of the stomach, in 1 of 9 animals each dark red spots, black spots and edema in the glandular mucosa of the stomach, in 1 of 9 animals black discoloration of the small intestine
- males: no necropsy findings

HISTOPATHOLOGY (PARENTAL ANIMALS)
females: histopathological examinations of the ovary in the other dose groups of n-butyl chloride except 300 mg/kg bw/day group were not carried out. No remarkable changes were recognized in the ovary.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOEL
Effect level:
2.4 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
60 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
2.4 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
MORTALITY (OFFSPRING):
- Control: 2 pups from 2 dams until day 4 of lactation
- 2.4 mg/kg bw/d: 3 pups from 2 dams until day 4 of lactation; the survival rate of pups was the same as control.
- 12 mg/kg bw/d: 1 pup from a dam, all pups on day 2 of lactation from a dam (No. 251) which didn’t take care of pups (maternal toxicity); The survival rate of pups tended to be decreased slightly.
- 60 mg/kg bw/d: 5 pups from 4 dams, all pups on day 2 of lactation from a dam (No. 356) which didn’t take care of pups (maternal toxicity); The survival rate of pups tended to be decreased slightly.
- 300 mg/kg bw/d: 3 pups from 2 dams, 8 pups from a dam (No. 456) which died on day 4 of lactation, 15 pups from a dam (No. 459) which showed decrease of food consumption and didn’t take care of pups and lost weight significantly on day 4 of lactation (maternal toxicity); The survival rate of pups was decreased but not statistically significant.

BODY WEIGHT (OFFSPRING):
depression of body weight gain in the highest dose group on day 4 of lactation (males: control 10.19 +/- 1.45 g, 300 mg/kg bw/d 8.19 +/- 2.18 g; females: control 9.47 +/- 1.47 g, 300 mg/kg bw/d 7.77 +/- 1.85 g); no changes in body weight in all dose groups compared to the control group on day 0 of lactation.

GROSS PATHOLOGY (OFFSPRING):
no remarkable changes in necropsy in pups on day 4 of lactation

The decreased survival rate of pups in the 12, 60 and 300 mg/kg bw/d dose group was clearly due to maternal toxicity resulting in lack of pup care behaviour and subsequently in mortality of pups. No remarkable changes at gross necropsy were observed in pups even in the highest dose group confirming, that maternal toxicity is the cause for the reduced viability index on day 4 of lactation.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
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

Observation of pups (F1)

Group [mg/kg bw/d]

Control

n-butyl chloride

0

2.4

12

60

300

Number of dams

12

12

12

11

11

Number of implantation scars total

190

200

214

189

197 (12)

Number of implantation scars per dam

15.8 +/- 3.6

16.7 +/- 2.1

17.8 +/- 1.3

17.2 +/- 2.0

16.4 +/- 2.1 (12)

Gestation index (%)

100

100

100

100

91.7 (12)

Numer of live pups born total

172

180

198

169

164

Numer of live pups born per dam

14.3 +/- 3.7

15.0 +/-2.0

16.5 +/- 1.6

15.4 +/-3.6

14.9 +/- 2.0

Number of dead pups on day 0 total

7

4

1

4

1

Number of dead pups on day 0 per dam

0.6 +/- 0.9

0.3 +/- 0 0.5

0.1 +/- 0.3

0.4 +/- 0.5

0.1 +/- 0.3

Birth index (%)

90.8 +/- 11.0

90.2 +/- 7.5

92.4 +/- 5.5

88.5 +/- 15.7

92.4 +/- 6.0

Number of dead pups on day 4 total

170

177

181

146

138

Viability index (%)

99.0 +/- 2.3

98.3 +/- 4.0

91.2 +/- 28.8

88.2 +/- 29.5

85.7 +/- 28.6

Number of external abnormalities

0

0

0

0

0

Applicant's summary and conclusion