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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Carbon disulphide is both a reagent in the manufacture, as well as a decomposition product of xanthates. Sodium isobutyl xanthate readily decomposes to carbon disulphide, especially in the presence of moisture/water. Therefore, the health effects of carbon disulphide (CS2) need to be considered in the assessment of sodium isobutyl xanthate.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
animals were not exposed to CS2 throught the whole gestation period, but only from gestation day 6 to 18.
GLP compliance:
not specified
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Carbon disulphide
EC Number:
200-843-6
EC Name:
Carbon disulphide
Cas Number:
75-15-0
Molecular formula:
CS2
IUPAC Name:
dithioxomethane
Test material form:
aerosol dispenser: not specified
Remarks:
migrated information: aerosol
Details on test material:
Carbon disulphide is both a reagent in the manufacture, as well as a decomposition product of xanthates. Sodium isobutyl xanthate readily decomposes to carbon disulphide, especially in the presence of moisture/water. Therefore, the health effects of carbon disulphide (CS2) need to be considered in the assessment of sodium isobutyl xanthate.
- Name of test material (as cited in study report): carbon disulfide (obtained by Alkzo Chemicals Inc., Delaware)
- Molecular formula (if other than submission substance): CS2
- Physical state: liquid
- Analytical purity: >99.9%

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hazleton, Research Animals, Denver, Pennsylvania
- Age at study initiation: 5.5 to 7 months
- Weight at study initiation:
- Diet (e.g. ad libitum): on a restricted basis to avoid enteritis (based on the advice of the supplier)
- Water: ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature: 65 ±5 F
- Humidity (%): 55±15
- Photoperiod (hrs dark / hrs light): 12

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
Carbon disulfide atmospheres were generated by nebulization of liquid carbon disulfide into a 1.2 cubic meter stainless steel and glass plenum. The aerosol was allowed to evaporate, and the carbon disulfide vapor was delivered to the exposure chambers. The delivery apparatus for the inhalation chambers was set up to bypass the chambers until the target concentration was reached. The target concentration used to develop subsequent exposure levels was based on the highest exposure level, and subsequent exposure levels were produced by dilution with HEPA filtered air. Chamber concentrations were controlled by adjustment of the ratio of dilution air to carbon disulfide vapor. The target concentration was produced and maintained at a stable level for approximately 15 minutes prior to incorporation into the air flow entering the exposure chambers. Carbon disulfide vapor used to obtain the target concentration bypassed the exposure chambers until the appropriate concentration was reached at which time the air flow containing the carbon disulfide vapor was routed into one of the five exposure chambers. The 0 ppm control chamber received HEPA filtered air only.
The exhaust from the exposure chambers was delivered to an activated charcoal collection system, which removed carbon disulfide vapor from the exhaust chamber air prior to venting the air to the outside.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Monitored by infrared spectrophotometry. The mean chamber concentration for each exposure level was within the required 10% relative standard deviation for both the pre-exposure and exposure periods.
Details on mating procedure:
- Impregnation procedure: natural insemination (gestation day 0) at the vendor's facility
Duration of treatment / exposure:
6 h/day for 12 days (gestation days 6-18)
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 60, 100, 300, 600, 1200 ppm (0, 190, 316, 948, 1896, 3792 mg/m3)
Basis:
nominal conc.
No. of animals per sex per dose:
24
Control animals:
yes
Details on study design:
- Dose selection rationale: based on dose range finding study were 100, 300, 1000 or 3000 ppm were tested. Exposure to 3000 ppm was lethal to rabbits. Surviving animals in the remaining exposure levels were euthanitized on gestation day 29, cesarean sections were performed, and uterine contents were evaluated. Exposure to 1000 ppm of carbon disulfide did not produce overt maternal toxicity, and only a transient exposure-related anoxia was suggested. However, it produced significant embryo and fetal toxicity. From these data, concentrations of carbon disulfide were selected for the main study.

Examinations

Maternal examinations:
CLINICAL OBSERVATIONS: Yes
- Time schedule: at least twice a day; prior to, during and following exposure period to gestation day 29

BODY WEIGHT: Yes
- Time schedule for examinations: on gestation day 0, 5, 6, 9, 12, 15, 18, 19 and 29

HEMATOLOGY: 10 animals per group; blood was collected on gestation days 6, 8, 11 and 19; the following parameters were examined: reciculocyte count, total hematology count, white blood cell differential, methemoglobin, hematocrit, and packed cell volume (PCV).

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29; cesarian sections were performed
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: yes
- Number of late resorptions: yes
Fetal examinations:
All fetuses were examined for gross visceral , skeletal and cephalic malformations. Enhanced fetal evaluations included a double stain to evaluate skeletal and cartilaginous malformations. In addition, cephalic evaluations were conducted on all viable fetuses based on results from the dosage range-finding study.
Statistics:
ANOVA, Dunett's test, Fischer's exact test, Chi-Square test, Kruskal- Wallis test

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
see below in section 'any other information on results incl. tables'

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEC
Effect level:
300 ppm
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEC
Effect level:
600 ppm
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEC
Effect level:
948 mg/m³ air
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEC
Effect level:
1 896 mg/m³ air
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Mean corpora lutea, mean crown-rump measurements, and mean number of implantations were not statistically different from the controls. Preimplantation losses were statistically different when compared to the 0 ppm control exposure level for the 100 ppm and 1200 ppm exposure groups. Because the animals were not exposed during the preimplantation period (Gestation Days 0-5), these data were not considered biologically significant. The fetal sex ratio was comparable among all treatment groups.

Postimplantation losses (resorptions and dead fetuses) in the 600 and 1200 ppm exposure groups were statistically different from the 0 ppm control exposure group. Postimplantation losses in the 600 ppm exposure group of 0.64 ± 1.00 were significantly higher when compared to the control 0 ppm exposure group. Accordingly, the number of live fetuses observed in this exposure group was statistically reduced when compared to the control group. Postimplantation loss in the 1200 ppm exposure group was 7.00 ± 3.94 as compared to the 0 ppm group loss of 0.30 ± 0.63.

Dead fetuses were observed in the 0, 100, and 600 ppm exposure groups; yet this was not considered a treatment-related finding because dead fetuses were observed in the control group, and none was observed in the 60, 300, or 1200 ppm exposure groups.

Mean fetal body weights were statistically lower in groups of 600 and 1200 ppm. Two litters of 22 in the 600 ppm group and 14 litters of 21 in the 1200 ppm group consisted of implantation sites with no live fetuses, i.e., the litters consisted exclusively of resorptions. Therefore, only 20 litters from the 600 ppm group and 7 litters from the 1200 ppm group had viable fetuses examined for visceral, skeletal, and cephalic malformations.
Visceral, skeletal and external examinations are summarized in Tables 7, 9 and 11, respectively. The total incidence of visceral and skeletal malformations was statistically higher in the 1200 ppm group (hydrocephaly, right-sided esophagus, absent right subclavian artery, swollen sublingual salivary glands, malformed stomach, small thyroid and parathyroid, abnormal caudal vertebrae, fused sternebrae, and split sternebrae). However, the incidence of any specific skeletal or visceral malformation was not significant.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Maternal toxicity

CLINICAL OBSERVATIONS: Ataxia, labored respiration, wheezing, and tremors were observed in the 1200 ppm exposure level, as well as scant feces and low food consumption, that were clearly associated with CS2 treatment. Three animal deaths at 1200 ppm were considered treatment related.

BODY WEIGHT (Fig.1, attachment): the group mean body weight for animals at 1200 ppm was statistically lower when compared to the control. Two statistically significant reductions in cumulative weight gain for the 100 and 600 ppm exposure groups on gestation day 29, were not considered to be dose-related.

HEMATOLOGY: statistically significant changes in groups exposed to 600 & 1200 ppm, on gestation day 19, in hemoglobin and hematocrit levels. Mean corpuscular volume (on gest.day 29), mean corpuscular hemoglobin concentration (on gest. day 8), segmented neutrophils (on gest. day 19), lymphocytes (on gesta. day 29) were significantly altered in the 1200 ppm exposure level, when compared to the control. Although there some evidence of toxicity on the 600 ppm level it does not seem to be treatment related.

Applicant's summary and conclusion

Conclusions:
In the study of PAI (Pathology Associates, Inc.). 1991, carbon disulfide was embryotoxic, developmentally toxic at exposure levels of 300 ppm (948 mg/m3) and above, while overt maternal toxicity was observed only at the 1200 ppm exposure level.
Carbon disulphide is both a reagent in the manufacture, as well as a decomposition product of xanthates. Sodium isobutyl xanthate readily decomposes to carbon disulphide, especially in the presence of moisture/water. Therefore, the health effects of carbon disulphide (CS2) need to be considered in the assessment of sodium isobutyl xanthate.
Executive summary:

In this developmental toxicity study, pregnant rabbits in groups of 24 were exposed to 0, 60, 100, 300, 600, 1200 ppm carbon disulfide 6 hours per day on days 6-18 of gestation. In dams exposed to 1200 ppm, statistically significant decreases in maternal weight gain and clinical signs of toxicity including ataxia, low food consumption, labored respiration, wheezing, tremors, and abortion with bloody excretion involving the death of two animals, were observed. No exposure-related signs of maternal toxicity were observed in the other dose groups. Post implantation loss had a significantly higher incidence in exposure groups of 600 or 1200 ppm. Total resorption was observed in 2/22 and 14/21 litters of the 600 ppm and 1200 ppm exposure groups, respectively. Mean fetal body weight was significantly reduced in the 600 and 1200 ppm exposure groups. In the 1200 ppm group, the total incidence of skeletal and visceral malformations was significantly increased; however, no single malformation accounted for this increase. In the lower dose groups, significant increases in skeletal malformations were observed in the incidences of rudimentary 13th ribs, extra ribs, extrathoracic vertebrae, or hypoplastic pubis. The malformations in the lower dose groups did not appear to be dose-related by the authors.