Sodium O-isobutyl dithiocarbonate

Toxicity to reproduction

Administrative data

Endpoint:

one-generation reproductive toxicity

Remarks:

based on test type (migrated information)

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:

1992

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Female rats were exposed to CS2 by whole body inhalation for 6 h daily for 14 days prior mating, during mating and until gestation day 19. Potential adverse effects on gonadal function, estrous cycles, conception rates, perturition and lactation of the F0 maternal generation were examined. Viability, growth and development of the F1 litters were also assessed.

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:

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 (received from Akzo Chemicals, Inc., Delaware City)
- Molecular formula (if other than submission substance): CS2
- Physical state: liquid
- Analytical purity: 99.99%
- Stability under test conditions: yes
- Storage condition of test material: temperature room

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River breeding Laboratories, Mischigan
- Age at study initiation: (P) 104 days
- Weight at study initiation: Females: 215-300 g
- Housing: individually, clean stainless stell wire-mesh cages suspended above cage-board till gaestation day 19; after mating the females were put to plastic maternity cages with nesting material, ground corn cob bedding
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-22.8
- Humidity (%): 28-76
- Air changes (per hr): 10
- 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:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
The test atmospheres was generated as vapors by introducing liquid carbon diaulfide into 1/4 J Air Atomizers (nebulizers) fitted with Model 1050 Fluid Caps and Model 84 Air Caps (Spraying Systems, Inc.). The air atomizer assemblies were located in the rear wall of the tangential turret head of each exposure chamber at a 90 degree angle to the direction of mass air flow. Liquid test material feed to the air atomizers was accomplished by use of Harvard Apparatus Co., Inc. Model 975 Compact Infmion Pumps. A positive flow of dried air was introduced to the air atomizers at a rate of approximately 6 liters per minute to aid in the complete vaporization of the test material.

- Temperature, humidity: 22 ± 2, 40-70%,
- Air flow rate: 12-15 changes/hour

Details on mating procedure:

- M/F ratio per cage: 1:1
- Proof of mating was confirmed by the presence of sperm on the vaginal smear or a vaginal copulatory plug, referred to as day 0 of gestation
- After 10 days of unsuccessful pairing replacement of first male by another male with proven fertility took place.
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged as described above

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

6 h

Frequency of treatment:

daily

Details on study schedule:

The parental animals were exposed for at least 14 days and thereafter, they were paired with unexposed males. Exposure continued throughout mating until the 19th day of gestation.
- Age at mating of the mated female animals in the study: 17 weeks

Doses / concentrations

Remarks:

Doses / Concentrations:
389, 777, 1554 mg/m3 (125, 250, 500 ppm)
Basis:
other: target concentrations

No. of animals per sex per dose:

15, 24 in the control group

Control animals:

yes

Examinations

Parental animals: Observations and examinations:

CLINICAL OBSERVATIONS AND MORTALITY
- Time schedule: moratlity and moribundity were observed twice daily; detailed clinical observations were recorded daily during the treatment period (before and after exposure). After treatment period clinical observations were recorded weekly.

BODY WEIGHT: Yes
- Time schedule for examinations: weekly till mating; after mating on gestation days 0, 6, 9, 12, 15, and 20 and on lactation days 0, 3, 6, 9, 15 and 21.

FOOD CONSUMPTION :
- Food consumption for each animal determined: weekly, gestation or lactation body weights

Oestrous cyclicity (parental animals):

Vaginal smears were evaluated 10 days before CS2 administration and throughout the 14 day pre-pairing exposure period. During mating smearing continued until evidence of copulation.

Sperm parameters (parental animals):

not examined

Litter observations:

STANDARDISATION OF LITTERS
- yes, maximum of 10 pups/litter, 5/sex when possible randomly selected; excess pups were killed and discarded on lactation day 4.

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, physical development: pinnal detachment, incisor eruption, palpebral seperation, testicular descent, vaginal patency

GROSS EXAMINATION OF DEAD PUPS: yes

Postmortem examinations (parental animals):

SACRIFICE
- Maternal animals: All Fo female rats with viable pups were killed on lactation day 21. The females that failed to deliver were also sacrificed, on post coital day 25. Females with total litter loss were sacrificed within 24 h.

GROSS NECROPSY
- Complete gross necropsy performed including examinations of the abdominal, thoracic, and pelvic cavities

HISTOPATHOLOGY
Tissues were examined only when deemed necessary after the gross necropsy

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring were sacrificed on lactation day 42.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination)
Pinnal detachment: started on lactation day 4 and continued daily until the pup had both pinnae detached
Incisor eruption: incisors were xhecked on lactation day 9
Palpebral seperation: started on lactation day 13 and continued until both eyelids were seperated
Testicular descent: from lactation day 25, the day were the testis apperared in the scotrum was recorded
Vaginal patency: on day 30 (open vaginal lumen)

GROSS NECROPSY
- Gross necropsy performed

HISTOPATHOLOGY / ORGAN WEIGTHS
Tissues were examined only when deemed necessary after the gross necropsy

Statistics:

Two-tailed tests (significance level of 5%): Chi-square test with Yates' correction factor and one-way ANOVA with Dunett's test

Reproductive indices:

Fertility index (%): No of females paired resulting in pregnancy/total No of females paired with males

Offspring viability indices:

Each litter was examined daily for survival and all deaths were recorded. Livebirth index (%): No of viable pups at birth/No of implantation sites

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, treatment-related

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

not examined

Description (incidence and severity):

female animals

Reproductive performance:

no effects observed

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): all animals survived treatment; treatment related clinical observations at 500 ppm were clear material around the eye, red material around the nose, within 1 h after completion of exposure

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): no significant effects detected on the mean weekly body weight or body weight gain and weekly food consumption (evaluated as g/animal/day and g/kg/day). The same was observed during the lactation period measuremnts. Throughout gestation body weights were significantly reduced at the highest concentration group, while food consumption appeared slightly affected at the same group during days 15-20.

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS): variations occured in all study groups; the regularity and duration of estrous were not affected by CS2 exposure

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): not affected by CS2 exposure. Female mating indices were 100% for the control group and the concentrations of 125 and 25 ppm, and 93.3% for the 500 ppm, while fertility indices were 87.5 %, 93.3%, 80% and 80%, respectively. The 80% was very common among the historical control data of the laboratory.

GESTATION: apparent signs of dystocia were observed in two females at the highest concentration group

GROSS PATHOLOGY (PARENTAL ANIMALS)
Females which failed to deliver: 3, 1, 3 and 2 animals in the control, 125, 250 and 500 ppm groups, respectively, were sacrificed on post-mating day 25 and one female of the last group on day 15. The animals were nongravid and internally normal.
Females with total litter loss: three females in the 500 ppm group, on lactation day 3. Two of them were internally normal, while one had pale eyes, kidneys and liver, as well as irregularly shaped white areas on all lobes of the liver.

Females that deliverd and killed on lactation day 21: no treatment-related findings

Effect levels (P0)

1

Dose descriptor:

NOAEC

Effect level:

250 ppm

Based on:

test mat.

Sex:

female

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEC

Effect level:

500 ppm

Based on:

test mat.

Sex:

female

Basis for effect level:

other: reproductive function and performance

3

Dose descriptor:

NOAEC

Effect level:

777 mg/m³ air

Based on:

test mat.

Sex:

female

Basis for effect level:

other: maternal toxicity

4

Dose descriptor:

NOAEC

Effect level:

1 554 mg/m³ air

Based on:

test mat.

Sex:

female

Basis for effect level:

other: reproductive function and performance

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Mortality / viability:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Sexual maturation:

no effects observed

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, treatment-related

Histopathological findings:

not examined

Details on results (F1)

VIABILITY INDICES(OFFSPRING): statistically significant increases in mortality on lactation day 0, was observed in the 500 ppm group. The mean stillbirth litter size was increased at this exposure level. Similarly pup survival was lower at this group on days 1 and 4, before selection. During lactation the numbers of pups found dead for the control, 125, 250 and 500 ppm groups were 7, 5, 6, and 38, respectively. Livebirth and gestation survival indices were comparable to the controls.

CLINICAL SIGNS (OFFSPRING): the general physical conditions in all F1 pups was similar to the controls.

BODY WEIGHT (OFFSPRING): a non statistically significant difference in mean size of live litters; still biologically significant according to the authors. No significant differences detected on mean body weights of the pups through lactation day 42.

PHYSICAL DEVELOPMENT: pinnal detachment, incisor eruption, palpebral seperation, testicular descent and vaginal patency were not affected in any of the pups, due to maternal exposure to CS2.

SEX RATIOS (OFFSPRING): not affected

GROSS PATHOLOGY (OFFSPRING): port mortem examinations of pups found dead were (in 2 pups of the 500 ppm group) dark red lungs, red foamy contents in the trachea, red fluid contents in the esophagus and red contents in the stomach.Dark red lungs and a reddened cortico-medullary junction in each kidney were noted for one pup each in the 250 and 500 pprn groups. One control pup died as a result of a water system malfunction; this pup was internally normal. With the exception of the presence or absence of milk in the stomach, all other remarkable post mortem findings involved malformations and variations. The abnormalities observed did not indicate any specific pattern of maldevelopment. Regarding the pups that were sacrificed on lactation day 42, no treatment related findings were observed.

Effect levels (F1)

Dose descriptor:

NOAEC

Generation:

F1

Effect level:

250 ppm

Based on:

test mat.

Sex:

female

Basis for effect level:

other: overall effects

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

No effects were observed on the reproductive function and reproductive performance of the animals at all concentration levels. Signs of maternal (body weight loss, dystocia) and neonatal (mortality of the pups, decreased viability, decreased litter size) toxicity were exerted by exposure to CS2 in a concentration of 500 ppm.
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 the present study carbon disulfide vapours were administered to 15 Sprague-Dawley female rats/dose via whole body inhalation at dose levels of 125, 250 and 500 ppm (389, 777, 1554 mg/m3) for 14 days before mating, 6 h/day. Twenty- four animals were used as controls and were exposed to clean filtered air. Thereafter, they were paired with unexposed males and exposure to CS2 continued throughout mating and until the 19th day of gestation. The animals were allowed to deliver normally and they were sacrificed on lactation day 21. The pups were sacrificed on lactation day 42. Inhalation of CS2 by Fo maternal animals at a level of 500 ppm elicited maternal toxicity (clinical signs, gestational body weight and food consumption decreases and indications of dystocia) as well as neonatal toxicity (increased pup mortality, decreased pup viability and decreased live litter size). No adverse effects were noted in Fo maternal animals or F1 pups at the 125 and 250 ppm levels. No effects were observed on the reproductive function and performance of the animals at all concentration levels. Based on these results, the NOAEC for maternal toxicity and neonatal toxicity was considered to be 250 ppm (777 mg/m3), while the NOAEC for reproduction toxicity was 500 ppm (1554 mg/m3).