Carbon disulphide

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

July-November 1981

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented study, similar to the guidelines. GLP status unclear.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1984

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Carbon disulphide

EC Number:

200-843-6

EC Name:

Carbon disulphide

Cas Number:

75-15-0

Molecular formula:

CS2

IUPAC Name:

methanedithione

Details on test material:

- Name of test material (as cited in study report): carbon disulfide (purchased by Aldrich Chemical Co. )
- Molecular formula (if other than submission substance): CS2
- Physical state: liquid
- Analytical purity: >99.1 ± 2.1%
- Purity test date: 01/03/1982
- Lot/batch No.: A091280/ 01

Test animals

Species:

rat

Strain:

other: CD

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc. (Kingston, NY)
- Age at study initiation: 8-12 weeks
- Housing: solid bottoom polypropylene or polycarbonate cages with stainless steel wire lids
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 14 days quarantine period

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-20
- Humidity (%): 52-77
- Air changes (per hr): 12-14
- Photoperiod (hrs dark / hrs light): 12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

yes

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: overnight
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

from gestation day 6 to 15

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 100, 200, 400, and 600 mg/kg bw
Basis:
Nominal doses

No. of animals per sex per dose:

22-27 (in total; two replicates)

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: based on a preliminary toxicity study performed. The doses applied were: 0, 10, 50, 100 and 200 mg/kg bw/day

Examinations

Maternal examinations:

CLINICAL OBSERVATIONS: Yes
- Time schedule: before exposure, 0 and 4 h after exposure

BODY WEIGHT: Yes
- Time schedule for examinations: gestation day 0, 6 through 15 (prior to daily dosing) and 20 (immediately after sacrifice)

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organ weights measured: liver, gravide uterine
- Status of uterine implantation sites were examined (i.e. number of implants, resorptions, dead fetuses and live fetuses)

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

The following observations were recorded: live litter size, individual body weight, sex and gross morphological abnormalities
- External examinations: Yes
- Visceral examinations: Yes, all live fetuses
- Skeletal examinations: Yes, all per litter
- Head examinations: Yes, half per litter

Statistics:

Non-parametric statistics, Kruskal-Wallis test, ANOVA, Mann-Whitney U test, Jonckheere's test, one-tailed Fischer's exact test, two-way ANOVA design, William's test, Dunnett's test

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes
Details on maternal toxic effects:
Substance-treated animals exerted clinical signs of toxicity: lehtargy, ataxia, abnormal posture, rigidity and/or paralysis of the hindlimbs, and rough or erect coat. No deaths were observed, except for 1 (1/25, 4%) animal at the 400 mg/kg bw dose level. After sacrifice pregnacy was confirmed in 92%, 82.8%, 81.5%, 92.3, and 100% of females in the control, 100, 200, 400 and 600 mg/kg bw/ day groups, respectively. Maternal body weights were depressed significantly on gestation days 11, 15 and 20 for the groups exposed to the last two doses, when compared to the controls. For the dose groups of 200, 400 and 600 mg/kg bw/day, a significant decrease in absolute body weight gain was observed during treatment. Gravid uterine weights showed a dose-consistent decreasing trend; still, not significant. Larger relative liver weights were measured in the two high dose groups.

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Maternal abnormalities

Abnormalities:

not specified

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes. Remark: fetal toxicity, but no teratogenic effects
Details on embryotoxic / teratogenic effects:
No statistically signifcant changes were observed in: implantation sites/litter, proportion of litters with resorbed, dead, nonlive or affected fettuses, number of live fetuses/live litter, % of males/live litter. Average fetal body weight/litter was decreased significantly in both sexes for the dose groups of 200, 400, and 600 mg/kg bw. The percent of fetuses malformed per litter (but not the proportion of litters with one or more malformed fetuses) and the percent of females malformed per litter was significantly different across the groups. However, a clear dose-related trend was not observed. The percent of of malformed fetuses declined at the high dose group (0.53%) in comparison to the control (~5%) and no individual group showed a significant difference when compared to the control. What follows is stated in the report, with some modifications: Four fetuses exhibited malformations which had not been previously observed in historical control fetuses. These anomalies included (1) branched rib observed in one fetus with multiple skeletal defects, edema and low body weight (2.32 g) in the 100 mg/kg/day CS2 group; (2) micromelia observed in one fetus (200 mg/kg/day CS2 group), with low body weight (2.58 g), edema and bilateral anophthalmia, (3) constricted tail in one fetus (200 mg/kg/day CS group) with low body weight (2.95 g), and (4) displaced ovaries, fused kidneys and missing adrenals in one fetus with low body weight (2.32 g) and multiple skeletal malformations in the 400 mg/kg/day CS2 group.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Basis for effect level:

other: fetotoxicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

yes

Lowest effective dose / conc.:

200 mg/kg bw/day

Treatment related:

yes

Relation to maternal toxicity:

developmental effects as a secondary non-specific consequence of maternal toxicity effects

Dose response relationship:

yes

Relevant for humans:

not specified

Applicant's summary and conclusion

Conclusions:

Carbon disulfide oral gavage treatment produced dose-related maternal and fetal toxicity when administered in CD rats at doses including and above 200 mg/kg bw/daily, but did not increase the incidence of malformed fetuses.

Executive summary:

Carbon disulfide (CS2), was evaluated for teratogenic effects in timed-pregnant CD rats. The following doses were administered: 0, 100, 200, 400 and 600 mg/kg/day in corn oil by gavage, in a volume of 5 ml/kg bw, on gestational days (gd) 6 to 15. All animals were sacrificed on gestation day 20. The gravid uterus for each dam was weighed and the number of implantation sites, and live, dead or resorbed fetuses were recorded. All live fetuses were weighed and examined for external, visceral and skeletal malformations. For the dose groups of 200, 400 and 600 mg/kg bw/day, a significant decrease in absolute maternal body weight gain was observed during treatment. Gravid uterine weights showed a dose-consistent decreasing trend; still, not significant. Larger relative liver weights were measured in the two high dose groups. Fetal body weights were decreased in rats exposed to 200 mg/kg bw/day and above.

There was no compound-related increase in malformations of the offspring.