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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
weight of evidence
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:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes (incl. certificate)
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
Sex:
male/female
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
Details on mating procedure:
Mating was performed in hanging stainless steel cages
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.
Duration of treatment / exposure:
males: 49 days
females: 41-46 days (from 14 days before mating to day 3 of lactation)
Frequency of treatment:
once daily
Details on study schedule:
- No mating of F1 generation (study design according to OECD Guideline 421, no mating of F1 generation foreseen)

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 bw/d, 7 days after treatment in group 100 mg/kg bw/d. Actual concentrations were selected on the basis of these results.

Examinations

Parental animals: Observations and 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
Oestrous cyclicity (parental animals):
numbers of times in estrus before and during administration, number of corpora lutea
Sperm parameters (parental animals):
Parameters examined in P male parental generations:
testis weight, epididymis weight
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals on day 50
- Maternal animals: All surviving animals

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGHTS
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring was sacrificed at 4 days of age.

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

Statistics:
Bartlett-test, Dunnet-test, Scheffe-test, χ2-test
Reproductive indices:
copulation index, fertility index, gestation index, delivery index
Offspring viability indices:
birth index, viability index

Results and discussion

Results: P0 (first parental animals)

Details on results (P0)

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

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
- no effect on estrous cycle

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
- All 12 pairs of each dose group copulated successfully (copulation index 100%).
- All females except one female in the 60 mg/kg bw/d dose group became pregnant (fertility index: 0, 2.4, 12, 300 mg/kg bw/d 100%; 60 mg/kg bw/d 91.7%).
-The gestation index was 100% for animals receiving 0 - 60 mg/kg bw/d and for the 300 mg/kg bw/d group 91.7% because of the death of one dam on day 22 of pregnancy.

ORGAN WEIGHTS (PARENTAL ANIMALS)
- There are statistically significant higher relative testis and statistically not significant higher relative epididymis weights (300 mg/kg bw/d). These increases may be due to the reduced body weights because the absolute testis and epididymides weights were not affected.

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)
males testis:
- moderate degeneration of seminiferous tubules with giant cells (1/12 animals at 300 mg/kg bw/d)
males epididymis:
- arteritis in capsule (1/12 animals in the control group)
- slight interstitial cell infiltration (1/12 animals at 300 mg/kg bw/d)
- mild hypospermia in epididymis (1/12 animals at 300 mg/kg bw/d)
The effects observed in histopathology in male reproductive organs occured spontaneous and were not considered compound-related.

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 (P0)

open allclose all
Dose descriptor:
NOAEL
Effect level:
60 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: systemic effects (reduced body weights, food consumption at the LOAEL of 300 mg/kg bw/day)
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects on fertility in highest dose tested

Results: F1 generation

Details on results (F1)

screening study: no data for toxicity on reproduction/fertility of F1 offspring provided
for details on developmental toxicity of F1 offspring see 7.8.2 MHW_Japan_1993

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Number of times in estrus of female rats (P)

Group [mg/kg bw/d]

Control

n-butyl chloride

0

2.4

12

60

300

Number of females

12

12

12

12

12

Number of times in estrus before a administration (7 days)

1.8 +/- 0.5

1.7 +/- 0.5

1.8 +/- 0.4

1.7 +/- 0.5

1.7 +/- 0.5

Number of times in estrus during administration (14 days)

3.2 +/- 0.4

3.3 +/- 0.5

3.3 +/- 0.5

3.3 +/- 0.5

3.3 +/- 0.5

 

 

Organ weight of male rats (P) after mating period

Group [mg/kg bw/d]

Control

n-butyl chloride

0

2.4

12

60

300

Number of animals

12

12

12

12

12

Absolute body weight [g]

483.2 +/- 35.6

496.2 +/- 24.6

481.6 +/- 26.7

475.7 +/- 25.6

432.4 +/- 21.5**

Absolute testes weight [g]

3.265 +/- 0.196

3.272 +/- 0.212

3.356 +/- 0.316

3.369 +/- 0.293

3.243 +/- 0.265

Relative testes weight [g]

0.677 +/- 0.058

0.663 +/- 0.05

0.697 +/- 0.067

0.711 +/- 0.083

0.752 +/- 0.074*

Absolute epididymides weight [g]

1.263 +/- 0.128

1.225 +/- 0.091

1.274 +/- 0.077

1.215 +/- 0.097

1.175 +/- 0.095

Relative epididymides weight [g]

0.264 +/- 0.032

0.248 +/- 0.027

0.264 +/- 0.020

0.257 +/- 0.025

0.272 +/- 0.025

*: P < 0.05

**: P < 0.01

Applicant's summary and conclusion