3,4-dichlorobut-1-ene

Toxicity to reproduction

Administrative data

Endpoint:

one-generation reproductive toxicity

Remarks:

based on generations indicated in Effect levels (migrated information)

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP-Guideline study. Adopted according to OECD SIDS (public available peer reviewed source). The original source is available and has been reviewed.

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Toxicity testing|reports of environmental chemicals

Author:

Ministry of Health & Welfare (Japan): Toxicity testing|reports of environmental chemicals, Vol. 4, chapter: 3,4-|Dichloro-1-butene, pp. 529-533, ISSN 1340-3842 (1996)

Year:

1996

Bibliographic source:

Vol. 4, chapter: 3,4-Dichloro-1-butene, pp. 529-533

Reference 2

Reference Type:

secondary source

Title:

SIDS Initial Assessment Report for 11th SIAM

Author:

OECD SIDS

Year:

2003

Bibliographic source:

UNEP Publications

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Combined Repeated Dose and Reproductive / Developmental Toxicity Screening Test (Precursor Protocol of GL 422)

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

3,4-dichlorobut-1-ene

EC Number:

212-079-0

EC Name:

3,4-dichlorobut-1-ene

Cas Number:

760-23-6

Molecular formula:

C4H6Cl2

IUPAC Name:

3,4-dichlorobut-1-ene

Details on test material:

- Name of test material (as cited in study report): 3,4-Dichlorobut-1-ene
- Analytical purity: 99.7 %
- Lot No.: FHD01
- Storage condition of test material: Kept at 4 °C until use

Test animals

Species:

rat

Strain:

other: Crj:CD (SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 9 weeks old for males, 8 weeks old for females
- Weight at study initiation: 343-384 g for males, 192-222 g for females

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: Sesam oil

Details on exposure:

No further data

Details on mating procedure:

- M/F ratio per cage: 1:1
- Length of cohabitation: at the most 5 days, until proof of pregnancy
- Proof of pregnancy: vaginal plug or sperm in vaginal smear.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Exposure period: males: 44 days; females: from 14 days before mating to day 3 of lactation .
Premating exposure period (females): 14 days Duration of test: males: 45 days; females: until day 4 of lactation

Frequency of treatment:

Once daily

Details on study schedule:

No further data

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 0.4, 2, 10 or 50 mg/kg bw
Basis:
actual ingested

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

no data

Positive control:

no data

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
Once a day
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: general conditions were observed once a day

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

FOOD/ WATER CONSUMPTION: once a week

OTHER: Hematology, biochemistry and urinalysis for males only at time of necropsy after 44 days of chemical exposure

Oestrous cyclicity (parental animals):

Not performed.

Sperm parameters (parental animals):

Not perfomed.

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, body weights of live pups (on day 0 and 4), physical abnormalities

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: The animals were sacrificed on day 45 after exposure.
- Maternal animals: The animals were sacrificed on the day 4 of lactation for females. Females with no delivery were killed 4 days after the delivery expected date.

GROSS NECROPSY
- Gross necropsy consisted of brain, heart, liver, kidney, spleen, adrenal, thymus, testes, epididymis.

HISTOPATHOLOGY / ORGAN WEIGHTS
Microscopical analysis was performed in all animals (in control, 50 mg/kg group and unfertilised animals in other groups): brain, pituitary gland, eyeball, thyroid gland, parathyroid gland, thymus, heart, lung, liver, kidney, adrenal, spleen, stomach, small intestine, large intestine, pancreas, urinary bladder, bone marrow, ovary, uterus, vagina, mammary gland.

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring were sacrificed at 4 days of age.
- These animals were subjected to postmortem examinations (macroscopic and microscopic examination) as follows:

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including viscera.

HISTOPATHOLOGY / ORGAN WEIGTHS
Full microscopic examinations were perfomed on all pups.

Statistics:

Dunnett’s or Scheffe’s test for continuous data and Chi square test for quantal data.

Reproductive indices:

Copulation index (%), Fertility index (%), Gestation index (%), Implantation index (%), Delivery Index (%)

Offspring viability indices:

Live birth index (%); Viability index (%), Sex ratio

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

1 female was dying 2 days after parturition

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Significant differences from controls were not observed

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Significant differences from controls were not observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

male and female showed hepatocellular hypertrophy at 50 mg/kg

Other effects:

not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): One female was sacrificed in a moribund condition on day 2 of lactation.
Males: Ephemeral decreased locomotor activity (all rats, the first day of the study in the 50 mg/kg bw/day group, 1/10, day 5-12) and ephemeral slaver (50 mg/kg: 10/10, the first day of the study).
Females: Death(50 mg/kg: 1/10), ephemeral decreased locomotor activity (50 mg/kg: 10/10), and ephemeral slaver (50 mg/kg: 5/10, the first day of the study)

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): Low body weight gain during the pregnancy period in females at 50 mg/kg.

FOOD/WATER CONSUMPTION: In both sexes, food consumption was decreased on day 1, but were not significant difference from controls after day2.
REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS): There were no statistically significant differences from controls.

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS): There were no statistically significant differences from controls.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): There were no statistically significant differences from controls.

ORGAN WEIGHTS (PARENTAL ANIMALS): In males, absolute kidney weights were slightly increased with 10 mg/kg/day dose. Absolute and relative weights of the liver and kidneys were increased with 50 mg/kg/day dose. Blood chemical examination revealed an increase in total protein.

GROSS PATHOLOGY (PARENTAL ANIMALS): There were no statistically significant differences from controls.

HISTOPATHOLOGY (PARENTAL ANIMALS): The histopathological examination revealed increased hyaline droplets in the renal tubular epithelium with doses of 10 and 50 mg/kg/day and hepatocellular hypertrophy with dose of 50 mg/kg/day. However, no histopathological changes considered to be related to the change of the kidney weight were detected. Hepatocellular hypertrophy was observed at the dose of 50 mg/kg/day.
NOAELs for repeated dose toxicity in this repeat dose study are 2 mg/kg/day for males and 10 mg/kg/day for females, but the renal toxicity in males is considered to be male rat specific, probably due to alpha2U-globulin involvement. Therefore, the NOAEL for repeated dose toxicity is considered to be 10 mg/kg/day.

Effect levels (P0)

1

Dose descriptor:

NOAEL

Remarks:

General Toxicology

Effect level:

10 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

2

Dose descriptor:

LOAEL

Remarks:

General Toxicology

Effect level:

50 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Based on ephameral decreased locomotor activity, liver swelling, kidney swelling, liver weight, in male and female animals

3

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Based on no effect on the reproductive performances.

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not examined

Description (incidence and severity):

the pups were killed at 4 days post partum

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings:

no effects observed

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

50 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Based on no effect on offspring development.

Overall reproductive toxicity

Reproductive effects observed:

not specified