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Diss Factsheets

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Link to relevant study records

Referenceopen allclose all

Endpoint:
extended one-generation reproductive toxicity - with developmental neurotoxicity (Cohorts 1A, 1B without extension, 2A and 2B)
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Remarks:
Carbon disulphide has been demonstrated to form during hydrolysis in gastric fluid. Any oral toxicity on the xanthate needs to consider oral effects of carbon disulphide and the corresponding alcohol
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Carbon disulphide has been demonstrated to form during hydrolysis in gastric fluid.
Any oral toxicity on the xanthate needs to consider oral effects of carbon disulphide and the corresponding alcohol
Data access has been requested, but this summary is extracted from disseminated information published by ECHA
Further animal testing on the xanthate cannot be justified
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
exposure-related information
Remarks:
Due to rapid hydrolysis in gastric fluid, oral ingestion of xanthates will result in formation of carbon disulphide
Qualifier:
according to guideline
Guideline:
OECD Guideline 443 (Extended One-Generation Reproductive Toxicity Study)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Once daily 7 days a week.
Details on mating procedure:
Cohabitation 1:1
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentrations of 91%, 95% and 89% were determined
Results are therefore expressed as nominal
Duration of treatment / exposure:
F0-males minimum of 11 weeks, including 10 weeks prior to mating and during the mating period,
F0-females minimum of 16 weeks, including 10 weeks prior to mating, and at least 21 days after delivery, Females were not dosed during littering.

During lactation (up to PND 21), pups were not treated directly
From weaning onwards (PND 21), F1-animals of Cohorts 1A, 1B, 1C and 2A dosed
Frequency of treatment:
Daily
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
1.2 mg/kg bw/day (nominal)
Dose / conc.:
12 mg/kg bw/day (nominal)
Dose / conc.:
120 mg/kg bw/day (nominal)
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle
Parental animals: Observations and examinations:
At least daily observations
Weekly weight assessment
Food consumption assessed for each group
Blood chemistry assessed in parental animals
Oestrous cyclicity (parental animals):
Yes
Sperm parameters (parental animals):
Checked on necropsy as part of post-mortum examinations
Litter observations:
Number and vigour
Postmortem examinations (parental animals):
Full necropsy and gross examination of organs at scheduled termination
Postmortem examinations (offspring):
Pups found dead and at scheduled termination
Statistics:
Statistical analysis was applied as needed
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Slight salivation in response to treatment, predominantly at highest dose.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
120 mg/kg/day, body weights / body weight gain of males and females were slightly decreased
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Minor changes in white blood cell count and reticulocyte count (males) but not considered significant
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Minor but statistically significant effects seen in the top dose.
The changes were not considered to be of toxicological significance.
Endocrine findings:
not examined
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Effects seen at top dose, confirming maximum tolerated dose was used
Minor changes in spleen, thymus and eyes, with the effect on eyes considered adverse
Histopathological findings: neoplastic:
no effects observed
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
effects observed, non-treatment-related
Description (incidence and severity):
A small number of pairs in all treatment and control groups failed to reproduce.
This was in line with background observations and not treatment related
Dose descriptor:
NOAEL
Effect level:
ca. 12 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
ophthalmological examination
Dose descriptor:
LOAEL
Effect level:
ca. 120 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
ophthalmological examination
Critical effects observed:
yes
Lowest effective dose / conc.:
120 mg/kg bw/day (nominal)
System:
eye
Organ:
retina
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified
Clinical signs:
no effects observed
Mortality / viability:
mortality observed, non-treatment-related
Description (incidence and severity):
Mortality across groups not considered to be significantly different to historical levels
No treatment related effects
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Statistically significantly decreased in males at 120 mg/kg/day from Day 8
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Sexual maturation:
no effects observed
Anogenital distance (AGD):
effects observed, non-treatment-related
Description (incidence and severity):
Minimal changes, perhaps based on actual size of pups in highest dose group
Nipple retention in male pups:
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Decrease in brain weight and spleen, male and female at higher dose level
Gross pathological findings:
no effects observed
Histopathological findings:
effects observed, treatment-related
Description (incidence and severity):
Effects seen in top dose group, including significant effect on eyes
Other findings not considered adverse
Behaviour (functional findings):
no effects observed
Effects on F1 similar to those seen in parental animals
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
ca. 12 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
organ weights and organ / body weight ratios
Dose descriptor:
LOAEL
Generation:
F1
Effect level:
ca. 120 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
organ weights and organ / body weight ratios
Critical effects observed:
yes
System:
central nervous system
Organ:
brain
Reproductive effects observed:
no
Conclusions:
Animals were treated at up to the maximum tolerated dose with some parental toxicity observed.
No reproductive or developmental effects were seen, other than a slight reduction in size of the young in the highest treatment group.
Endpoint:
one-generation reproductive toxicity
Remarks:
based on test type
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Well documented GLP study, that provides important information on reproductive and developmental toxic effects of the substance. However, only female animals of F0 (not male) were exposed to CS2 and examined for reproductive effects. Developmental effects were examined in F1.
Justification for type of information:
Read-across from key metabolite, carbon disulphide
Carbon disulphide has been demonstrated to form during hydrolysis in gastric fluid.
Any inhalation toxicity on the xanthate needs to consider inhalation effects of carbon disulphide and the corresponding alcohol
Further animal testing on the xanthate cannot be justified
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across: supporting information
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:
yes
Limit test:
no
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
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
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
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
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: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
not examined
Description (incidence and severity):
female animals
Reproductive performance:
no effects observed
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
Dose descriptor:
NOAEC
Effect level:
250 ppm
Based on:
test mat.
Sex:
female
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEC
Effect level:
500 ppm
Based on:
test mat.
Sex:
female
Basis for effect level:
other: reproductive function and performance
Dose descriptor:
NOAEC
Effect level:
777 mg/m³ air
Based on:
test mat.
Sex:
female
Basis for effect level:
other: maternal toxicity
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
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
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.
Dose descriptor:
NOAEC
Generation:
F1
Effect level:
250 ppm
Based on:
test mat.
Sex:
female
Basis for effect level:
other: overall effects
Reproductive effects observed:
not specified
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.
Read-across from key metabolite, carbon disulphide
Carbon disulphide has been demonstrated to form during hydrolysis in gastric fluid.
Any inhalation toxicity on the xanthate needs to consider inhalation effects of carbon disulphide and the corresponding alcohol
Further animal testing on the xanthate cannot be justified

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).

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
120 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
777 mg/m³
Study duration:
subchronic
Experimental exposure time per week (hours/week):
42
Species:
rat
Effect on fertility: via dermal route
Endpoint conclusion:
no adverse effect observed

Effects on developmental toxicity

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Remarks:
Read-across from key metabolite, carbon disulphide
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Carbon disulphide has been demonstrated to form during hydrolysis in gastric fluid.
Any oral toxicity on the xanthate needs to consider oral effects of carbon disulphide and the corresponding alcohol
Data access has been requested, but this summary is extracted from disseminated information published by ECHA
Further animal testing on the xanthate cannot be justified
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
exposure-related information
Remarks:
Due to rapid hydrolysis in gastric fluid, oral ingestion of xanthates will result in formation of carbon disulphide
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
not specified
Remarks:
Pre-dates widespread introduction of GLP Data set considered valid
Limit test:
no
Species:
rat
Strain:
other: CD
Details on test animals or test system and environmental conditions:
Age 8 - 12 weeks at start of study
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
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:
Gestation day 6 to 15
Frequency of treatment:
Daily
Duration of test:
From gestation day 6 to 15
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
200 mg/kg bw/day (nominal)
Dose / conc.:
400 mg/kg bw/day (nominal)
Dose / conc.:
600 mg/kg bw/day (nominal)
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
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
Blood sampling:
Not specified
Fetal examinations:
Yes; external, visceral, skeletal and head

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
Historical control data:
Not specified
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Lethargy, ataxia, abnormal posture and rough coat
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One female, mid dose
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Decrease in body weight for highest doses
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Endocrine findings:
not examined
Urinalysis findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Increased liver weights in higher dose groups
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not examined
Other effects:
no effects observed
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.
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
organ weights and organ / body weight ratios
Remarks on result:
other: Toxicological significance of maternal effects not specified
Abnormalities:
not specified
Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Weight decrease in highest dose groups
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
effects observed, treatment-related
Description (incidence and severity):
Reduced weights of litters at higher doses, mirroring maternal effect
Changes in postnatal survival:
no effects observed
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Across various dose levels and within historical control
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Across various dose levels and within historical control
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Across various dose levels and within historical control
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.
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes
Abnormalities:
effects observed, non-treatment-related
Localisation:
other: Various changes - no obvious significance
Description (incidence and severity):
Various effects observed but within historical levels.
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
Conclusions:
Oral treatment produced dose-related maternal and foetal toxicity at 200 mg/kg bw/day or higher.
There was no increase in the incidence of malformed foetuses.
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.

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Remarks:
Read-across from key metabolite, carbon disulphide
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
Carbon disulphide has been demonstrated to form during hydrolysis in gastric fluid.
Any oral toxicity on the xanthate needs to consider oral effects of carbon disulphide and the corresponding alcohol
Data access has been requested, but this summary is extracted from disseminated information published by ECHA
Further animal testing on the xanthate cannot be justified
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across: supporting information
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
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
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
Dose / conc.:
100 ppm
Dose / conc.:
300 ppm
Dose / conc.:
1 000 ppm
Dose / conc.:
3 000 ppm
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.
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
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'
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
Abnormalities:
not specified
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.
Dose descriptor:
NOAEC
Effect level:
300 ppm
Based on:
test mat.
Sex:
male/female
Remarks on result:
other: carbon disulfide was embryotoxic, developmentally toxic at exposure levels of 300 ppm (948 mg/m3) and above,
Abnormalities:
not specified
Developmental effects observed:
not specified

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.

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 Isopropyl Xanthate (SIPX) 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 Isopropyl Xanthate (SIPX)
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.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
948 mg/m³
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

Additional information