1-chlorobutane

Toxicity to reproduction

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 for cross-reference:

reference to same study

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1993

Reference 2

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

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

GLP compliance:

yes (incl. QA statement)

Remarks:

Nihon Bioreseach Center Inc., Hashima Laboratory, Hashima, Japan

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

1-chlorobutane

EC Number:

203-696-6

EC Name:

1-chlorobutane

Cas Number:

109-69-3

Molecular formula:

C4H9Cl

IUPAC Name:

1-chlorobutane

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 or test system 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 generation)

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)

1

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)

2

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