Sodium O-ethyl dithiocarbonate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

It is concluded that the substance SEX  does not meet the criteria to be classified for human health hazards for Reproductive toxicity.Non-ER binder due to non-cyclic molecular structure. Sodium O-ethyl dithiocarbonate have a molecular weight of less than 500, but  do not possess a cyclic structure is reported to non-binders to the receptor and therefore Sodium O-ethyl dithiocarbonate (SEX) does not cause reproductive toxicity.

Link to relevant study records

Reference

Reference 1

Endpoint:

one-generation reproductive toxicity

Remarks:

based on test type

Type of information:

other: published data

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 is both a reagent in the manufacture, as well as a decomposition product of xanthates. SEX 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 SEX.

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.
Carbon disulphide is both a reagent in the manufacture, as well as a decomposition product of xanthates.SEX 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 SEX.

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).

Reference 2

Endpoint:

fertility, other

Remarks:

based on test type

Type of information:

other: published data

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 is both a reagent in the manufacture, as well as a decomposition product of xanthates. SEX 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 SEX.

Qualifier:

no guideline followed

Principles of method if other than guideline:

The present study was performed to evaluate the endocrinologic and spermatogenic effects of CS2 exposure in the rat. Male rats were exposed to 600 ppm of CS2 for 6 hr/day for 5 days/week for 10 weeks. One week before exposure and at weeks 1,4,7, and 10, males were placed with ovariectomized, hormonally primed females, and copulatory behaviours were scored. Postcopulation, the females were killed and the ejaculate was recovered from the excised uterine tract along with the semen plug. Sperm counts, sperm motility, and morphology were determined.

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Long-Evans

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratory (Wilmington, Mass).
- Age at study initiation: (P) 120 days
- Housing: singly, in stainless stell hanging cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

not specified

Vehicle:

unchanged (no vehicle)

Details on mating procedure:

One week prior to exposure and at weeks 1,4,7, and 10, males were placed with ovariectomized, hormonally primed females, and copulatory behaviors were scored. Fifteen minutes postcopulation, the female was killed and the ejaculate was recovered from the excised uterine tract along with the semen plug. Sperm counts, sperm motility, and morphology were determined.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Monitored by a Baselin gas chromatograph

Duration of treatment / exposure:

6 h/d for 10 w

Frequency of treatment:

daily, 5 d/w

Remarks:

Doses / Concentrations:
0, 1870 mg/m3 (0, 600 ppm)
Basis:
nominal conc.

No. of animals per sex per dose:

24

Control animals:

yes, sham-exposed

Details on study design:

- Dose selection rationale: a dose that does not exert neurotoxic effects was chosen; additionally, according to pilot experiments no effects were seen at 350 ppm, while at 900 ppm reduced body weight gains were recorded.

Positive control:

no

Parental animals: Observations and examinations:

A blood sample was collected for analyses of testosterone, follicle-stimulating (FSH), and luteinizing hormone (LH). At the end of the 10th week, five animals from each group were treated with either human chorionic gonadotropin (HCG, 50 IU/animal, iv) or gonadotropin-releasing hormone (GnRH, 100 ng/animalt iv), and the testosterone or gonadotropin responses were recorded over time.

Oestrous cyclicity (parental animals):

not examined, only males were tested

Sperm parameters (parental animals):

Parameters examined in male parental animals:
Sperm counts, sperm motility, and spem morphology

Litter observations:

not examined

Postmortem examinations (parental animals):

Animals were killed and one epididymis and testis were taken for histologic examination. The other epididymiswas used for determinationof sperm count. In addition to the mated animals, 10 more control and CS2-exposed non-mated animals were maintained. The animals were killed after 10 weeks of exposure and thereafter, reproductive organs were excised and weighed.

Postmortem examinations (offspring):

not examined

Statistics:

A repeated measures analysis of variance with one between factor (dose) and one within factor (weeks) was applied to the analyses of body weight, copuiatory behaviors, and sperm parameters. All significant effects were further tested by the method of Least Squares Difference (Kirk, 1968). Significance levels were set at p < 0.05 for all comparisons.

Offspring viability indices:

not examined

Clinical signs:

no effects observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

no effects observed

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

effects observed, treatment-related

Reproductive performance:

effects observed, treatment-related

A decrease in body weight gain was observed between exposure weeks 4 to 10, that was significant in week 10.

Mount and intromission data exhibited marked variability. In general mount latency gave a decreasing trend, being signifcantly different from controls in week 10. Ejaculation latency was significantly different during weeks 4 to 10.

CS2 exposed rats elicited significant depressions on sperm counts in weeks 7 and 10, compared to controls. Motility decreased in both groups, but no significant effects were observed. 'Analysis of semen plug weights revealed significant effects (p≤ 0.05) resulting from a greater increase in absolute plug weights in the controls over weeks compared to the CS2-exposed group. This difference was not significant when analyzed as "percentage-change from baseline".

Regarding the levels of testosterone, FSH and LSH, there were no CS2-induced changes. A normal increase in FSH and LSH, following injection of GnRH and a normal increase in testosterone levels, following injection of HCG, was detected.

No CS2-exposure related effects were seen in the histopathological examinations of the epididymis and testis, as well as in the sperm counts obtained from the cauda epididymis. Regarding to the organ/body weigh ratios, the only change observed was a decrease in prostate weight.

Dose descriptor:

LOAEC

Effect level:

600 ppm

Based on:

test mat.

Sex:

male

Basis for effect level:

other: effects on the copulatory behaviour of animals; decreased mount and ejaculation latencies; decreased sperm count in the ejaculate

Dose descriptor:

LOAEC

Effect level:

1 870 mg/m³ air

Based on:

test mat.

Sex:

male

Basis for effect level:

other: effects on the copulatory behaviour of animals; decreased mount and ejaculation latencies; decreased sperm count in the ejaculate

Clinical signs:

not examined

Mortality / viability:

not examined

Body weight and weight changes:

not examined

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

not examined

Remarks on result:

not measured/tested

Reproductive effects observed:

not specified

Conclusions:

In the present study, exposure of rats to CS2 via inhalation, exerted effects on the copulatory behaviours of the animals, characterized by decreased mount and ejaculation lattencies, as well as decreases in sprem counts in the ejaculate. Exposed rats had significantly reduced weight gains during the experiment. However, the authors suggest these changes were not due a direct effect of CS2 on the testis of the animals.
Carbon disulphide is both a reagent in the manufacture, as well as a decomposition product of xanthates. SEX 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 f SEX.

Executive summary:

Male Long-Evans rats were exposed to CS2 via inhalation for 6 h/d, 5 d/w for 10 consecutive weeks, in a concentration of 1870 mg/m3 (600 ppm). One week prior to exposure and at weeks 1,4,7, and 10, males were placed with ovariectomized, hormonally primed females, and copulatory behaviors were scored. Postcopulation, the female was killed and the ejaculate was recovered from the excised uterine tract along with the semen plug. Sperm counts, sperm motility, and morphology were determined. A blood sample was obtained for analyses of testosterone, follicle-stimulating (FSH), and luteinizing hormone (LH). At the end of the 10th week, five animals in each group were challenged with either human chorionic gonadotropin (HCG, 50 IU/animal) or gonadotropin-releasing hormone (GnRH, 100 ng/animal), and the testosterone or gonadotropin responses were monitored over time. Animals were killed with one epididymis and testis processed for histology and a sperm count determined from the other epididymis. Animals appeared to be in good health and the only indication of systemic toxicity was a small reduction in body weight gain. Decreased mount and ejaculation lattencies, as well as depression of sperm counts in the ejaculate, indicate effects on the mating behaviour patterns. Nonetheless, the authors suggest that the decreased amounts of ejaculated sperm is due to alteration in the sperm production in the testes or sperm maintenance in the epididymides. This is also supported by the absence of histological lesions in these tissues. The findings imply that at this dose level CS2 does not exert a direct effect on the testis, but it may interfere with processes which regulate the sperm transport and the ejaculate.

Reference 3

Endpoint:

two-generation reproductive toxicity

Remarks:

based on test type

Type of information:

other: published data

Adequacy of study:

weight of evidence

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:

Dithiocarbamates are related compounds to xanthates. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium or potassium hydroxide: They arise from the reaction of the amine with CS2.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

Deviations:

yes

Remarks:

Not all required organ weights were determined. - Sperm parameters were not assessed for all animals.

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage, Michigan, USA
- Age at study initiation: 6 weeks
- Weight at study initiation: ♂: 144-218 g, ♀: 117-174

Route of administration:

oral: feed

Vehicle:

other: diet

Details on mating procedure:

- M/F ratio: 1:1
- Length of cohabitation: Up to 15 days
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of gestation
- After 10 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no
- Any other deviations from standard protocol: Litters were culled to 8 pups/litter on lactation day 4.

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

F0 parents: from study initiation until scheduled sacrifice
F1 parents: from weaning (day 22) until scheduled sacrifice
F2 pups: from weaning (day 22) until scheduled sacrifice
Duration of exposure before mating (F0 / F1 parents): 10 weeks

Frequency of treatment:

Ad libitum

Remarks:

Doses / Concentrations:
0, 72, 210, or 540 ppm, equal to 0, 3, 10, or 25 mg/kg bw per day for males and 0, 5, 13, or 32 mg/kg bw per day for females.
Basis:
nominal in diet

No. of animals per sex per dose:

30

Control animals:

yes, plain diet

Details on study design:

- Actual doses
F0 ♂:
5, 15, 37 mg/kg/day (prior to breeding)
3, 10, 25 mg/kg/day (after breeding)

F0 ♀: 6, 17, 43 mg/kg/day (prior to breeding)
5, 13, 33 mg/kg/day (gestation)
12, 33, 85 mg/kg/day (lactation)
5, 15, 37 mg/kg/day (after weaning)

F1 ♂:
6, 18, 46 mg/kg/day (prior to breeding)
3, 10, 26 mg/kg/day (after breeding)

F1 ♀:
7, 20, 51 mg/kg/day (prior to breeding)
5, 13, 32 mg/kg/day (gestation)
11, 30, 79 mg/kg/day (lactation)
5, 14, 34 mg/kg/day (after weaning)

Positive control:

none

Parental animals: Observations and examinations:

MORTALITY
- Twice daily

CLINICAL SIGNS
- Twice daily

BODY WEIGHT
- Weekly during treatment and prior to terminal sacrifice for males.
- Confirmed mated ♀ were weighed on presumed gestation Days 0, 7, 10, 14, and 20. Nursing dams were weighed on Days 1, 4, 7, 14, and 21 post partum. After weaning (day 22) once weekly until scheduled sacrifice.

FOOD CONSUMPTION
- Daily until pairing for all animals.
- Male food consumption was measured after mating again daily until scheduled sacrifice.
- Female food consumption was measured daily throughout gestation and lactation period.
- No food consumption data was obtained during the mating period.

Oestrous cyclicity (parental animals):

- Daily during mating.

Sperm parameters (parental animals):

- Only performed on males which were paired, but failed to sire a litter.

Litter observations:

- Sex-determination, pup viability, body weight gain, clinical signs, necropsy on dead pups, behavioural testing (F2)

Postmortem examinations (parental animals):

ORGAN WEIGHTS
- Yes
- Organs: testes + epididymides/ovaries, brain, pituitary gland, kidneys, liver

HISTOPATHOLOGY
- All animals from control and high-dose group.
- Tissues: Cervix, coagulating gland, epididymides, kidneys, liver, ovaries, pituitary gland, prostate, seminal vesicles, testes, uterus, vagina, vas deferens, all internal gross lesions

Postmortem examinations (offspring):

- neuropathological examination (F2)

Clinical signs:

no effects observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

no effects observed

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

F0 (♂+♀):
- Mean body weights and body weight gains in the 540 ppm group males were reduced early in the treatment period. In females mean body weights and body weight gains in the 540 ppm group were generally reduced throughout gestation and lactation and after weaning.
- Food consumption in the 540 ppm group was generally reduced in males and prior to breeding, during gestation and lactation and after weaning in females.

Dose descriptor:

NOAEL

Effect level:

10 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

other: (post-breeding intake

Remarks on result:

other: Generation: maternal (migrated information)

Dose descriptor:

NOAEL

Effect level:

10 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: (post-breeding intake

Remarks on result:

other: Generation: neonatal (migrated information)

Dose descriptor:

NOAEL

Effect level:

25 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: (post-breeding intake)

Remarks on result:

other: Generation: reproduction (migrated information)

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Sexual maturation:

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings:

no effects observed

F1 (♂+♀):
- Mean pup body weights in the 540 ppm group litters were slightly reduced during lactation. Mean body weights and body weight gains in the 540 ppm group males were reduced throughout the treatment period. In females mean body weights and body weight gains in the 540 ppm group were generally reduced throughout gestation and lactation and after weaning.
- Food consumption in the 540 ppm group was generally reduced in males and prior to breeding, during gestation and lactation and after weaning in females.
F2 (♂+♀):
- Mean pup body weights in the 540 ppm group litters were slightly reduced during lactation and throughout the remainder of the study until the postnatal day 70 neuropathology evaluation.

Basis for effect level:

body weight and weight gain

Remarks on result:

other: no effects observed

Reproductive effects observed:

not specified

Table 7.8.1-A1         Body weight changes in reproductive toxicity study
Parameter	Genera­tion	Controls		60 ppm		180 ppm		540 ppm		Dose-response +/–
		♂	♀	♂	♀	♂	♀	♂	♀	♂	♀
Body weight [g]
average weight on gestation Day 14	F 0 dams	/	348.4	/	338.6	/	356.0	/	343.8	/	−
	F 1 dams	/	357.1	/	339.1	/	344.7	/	316.7*	/	−
average pup weight on lactation Day 21	F 1 pups	44.8	42.8	44.6	41.8	46.3	43.5	40.2*	37.7*	−	−
	F 2 pups	40.7	39.5	41.0	39.3	44.1	41.2	38.5	36.9	−	−
* statistically significant different from control p </= 0.05

 

Conclusions:

NOAEL for maternal toxicity was 210 ppm, equal to 10 mg/kg bw per day, on the basis of reduced food consumption and body-weight gain; that for neonatal toxicity was 210 ppm, equal to 10 mg/kg bw per day, on the basis of reduced body weight; and that for reproductive and developmental neurotoxicity was 540 ppm, equal to 25 mg/kg bw per day.
Dithiocarbamates are related compounds to xanthates. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium or potassium hydroxide: They arise from the reaction of the amine with CS2.

Executive summary:

In a two-generation study of reproductive and developmental neurotoxicity, groups of 30 male and 30 female Crl:CD BR Sprague-Dawley rats were fed ziram at concentrations of 0, 72, 210, or 540 ppm, equal to 0, 3, 10, or 25 mg/kg bw per day for males and 0, 5, 13, or 32 mg/kg bw per day for females. The parental animals received thediets from about six weeks of age for the F₀generation and on day 22 postnatally for the F₁generation, for at least 70 days before matingand throughout all subsequent phases of the study until termination of  the generation. All animals were observed twice daily for appearance and behaviour. Body weights and food consumption were recorded at appropriate intervals. All females were allowed to deliver and rear their pups to weaning on lactation day 21. Offspring from the pairingof the F₀animals (30 pups of each sex per group) were selected to constitute the F₁generation. Thirty F₂pups of each sex per group were selected for testing of developmental landmarks and behaviour, neuropathological examination, and brain weight measurement. Surplus F₁pups were killed and necropsied on postnatal day 28, and surplus   F₂pups were killed and necropsied on postnatal day 22. The F₀and F₁parental animals and selected F₂pups that were not allocated for  measurements underwent detailed gross necropsy; and the weights of  the brain, kidneys, liver, pituitary gland, ovaries, or testes an epididymides (F₀and F₁only) were recorded. Designated tissues from the controls and from F₀and F₁parental animals at 540 ppm and F₂ pups selected for neuropathological evaluation were evaluated for histopathological changes.

 

Reproductive parameters (fertility, mating, and days between pairing and coitus, gestation, and parturition) in the F₀and F₁generations were not adversely affected by concentrations of 72, 210,  or 540 ppm ziram. All F₀and F₁parental animals survived to the scheduled necropsies, and no adverse clinical signs attributable to treatment were observed. The mean body weights and body-weight gains of F₀males at 540 ppm were reduced early in the treatment period, and the mean body weights and body-weight gains of F₁males at 540 ppm were generally reduced. The mean body weights and body-weight gains of F₀and F₁females at 540 ppm were generally reduced before  breeding, during gestation and lactation, and after weaning.

No adverse effects were seen on the body weights or body-weight gains of animals in either generation at 72 or 210 ppm. The food consumption of F₀and  F₁males at 540 ppm was generally reduced throughout each generation. The food consumption of F₀and F₁females at 540 ppm was reduced before breeding, during gestation and lactation, and after weaning of   the F₀and F₂generations. No adverse effects on food consumption   were observed in males or females given ziram at concentrations of 72 and 210 ppm in either generation. No treatment-related, macroscopic internal changes were found in treated F₀or F₁animals, and no adverse effects on organ weights were observed at any dose. No microscopic lesions attributable to treatment were observed intissues from animals at 540 ppm on histopathological examination. Microscopic examination of gross lesions seen at the scheduled necropsies of animals at 540 ppm did not reveal any adverse effects.

 

 The mean body weights of F₁and F₂pups in the litters of animals at 540 ppm were slightly reduced (usually statistically   significantly) during lactation and throughout the remainder of the  study until postnatal day 70 (selected F₂pups). The F₁and F₂pup   sex ratios, live litter sizes, number of dead pups on lactation day 0,  viability indices, general physical condition, and brain weight (selected F₂pups) were not adversely affected by parental treatment at any concentration. The findings at necropsy of F₁and F₂pups that died or were killed at the scheduled postnatal necropsies did not   suggest any correlation with parental treatment. Various indicators of physical and functional development and behavioural responses in the selected F₂pups were comparable to those in controls. Neuropathological examinations on postnatal days 11 and 70 showed no   gross or microscopic treatment-related lesions in the F₂pups.

The NOAEL for maternal toxicity was 210 ppm, equal to 10 mg/kg bw per day, on the basis of reduced food consumption and body-weight gain; that  for neonatal toxicity was 210 ppm, equal to 10 mg/kg bw per day, on the basis of reduced body weight; and that for reproductive and developmental neurotoxicity was 540 ppm, equal to 25 mg/kg bw per day.

 

Reference 4

Endpoint:

two-generation reproductive toxicity

Remarks:

based on test type

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1985

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:

Ethanol/ Ethyl Alcohol is both reagents used in the manufacture of sodium O-ethyl dithiocarbonate . Therefore, Ethanol/ Ethyl Alcohol need to be considered in the assessment of sodium O-ethyl dithiocarbonate

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

Deviations:

yes

Remarks:

P generation no organ weights, sperm parameters or oestrous cycle included; P animals slightly older than recommended at first exposure; low number of pregnant females

Qualifier:

according to guideline

Guideline:

other: NTP Protocol. Fertility assessment by continuous breeding

GLP compliance:

yes

Limit test:

no

Species:

mouse

Strain:

CD-1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding laboratories
- Age at study initiation: (P) animals 6 weeks at receipt, 11 weeks at first exposure.
- Fasting period before study: no
- Housing: 4-5 per cage by sex. In pairs during breeding and thereafter individually for 21 days.
- Diet (e.g. ad libitum): Pelleted feed (NIH-07 open formula rodent chow) ad libitum
- Water (e.g. ad libitum): deionized/filtered ad libitum
- Acclimation period: 2 weeks prior to preliminary range-finding study


ENVIRONMENTAL CONDITIONS
- Temperature : approx 21 C
- Humidity (%):
- Air changes (per hr): 12-14
- Photoperiod (hrs dark / hrs light): 10/14

Route of administration:

oral: drinking water

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Ethanol administered in deionized, filtered water.

Details on mating procedure:

- M/F ratio per cage: 1:1
- Proof of pregnancy: litters were proof of pregnancy.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Samples of ethanol formulation in drinking water, control drinking water and bulk chemical were sent to Midwest Research Institute (Kansas City, MO), prior to preliminary range finding study, and at weeks 1, 6, 12, and 18 of main study with Parental animals.

Duration of treatment / exposure:

Exposure period: 18 weeks

Premating exposure period (males): Parental 7 days; F1 74 days

Premating exposure period (females): Parental 7 days; F1 74 days

Frequency of treatment:

ad libitum

Details on study schedule:

Number of generation studies: 2

Remarks:

Doses / Concentrations:
5, 10 and 15% v/v in water
Basis:
nominal in water

No. of animals per sex per dose:

20 for P generation, also 20 F1 animals at the high dose mated at 74 days old

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale: 14 day dose range finding study conducted. High dose for the 13 week study chosen such that depression of weight gain <10%

Positive control:

N/A

Parental animals: Observations and examinations:

DETAILED CLINICAL OBSERVATIONS: No. Only twice daily cage side inspections.

BODY WEIGHT: Yes
- Time schedule for examinations: at end of week 1, 2, 5, 9, 13 and 18.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: at end of week 1, 2, 5, 9, 13 and 18.

Oestrous cyclicity (parental animals):

Gestation index, changes in lactation and changes in oestrus cycles were not studied.

Sperm parameters (parental animals):

Epididymal and vas sperm were evaluated for concentration, motility and morphology in F1 males only.

Litter observations:

Litters were not standardized.

Postmortem examinations (parental animals):

Not conducted

Postmortem examinations (offspring):

GROSS NECROPSY
- High dose F1 animals had liver, kidney/adrenal and male sex organs weighed at termination.

Statistics:

Fertility and mating indices: Cochran-Armitage test for dose related trend and Fisher's exact test for comparisons between groups.
Size and number of litters, proportion of live pups and sex ratio, pup body weight, necropsy weight and sperm characteristics: Kruskal-Wallis for overall differences among groups, Jonckheere's test for dose related trends and Wilcoxon's test for pairwise tests.
Litter and dam weight: Williams' test

Reproductive indices:

Fertility indices were 97, 100, 100 and 94% in the controls and 5%, 10%, 15% ethanol groups respectively.
The F1 offspring of the 15% ethanol pairs had fewer live pups per litter. Unadjusted F1 live pup weight was greater for females and combined sexes at 5% but not at the higher concentrations. Body weights were lower than control in the 15% ethanol treated F1 offspring at mating and on day 21. Fertility indices in F1 matings were 85% and 65% in the controls and 15% ethanol groups respectively. Their F2 offspring weighed less as ethanol treated pups than control pups (males, females or both sexes). Other reproductive performance indices e.g. gestation index, changes in lactation and changes in oestrous cycles were not studied.

Offspring viability indices:

Proportion of pups born alive

Clinical signs:

not examined

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:

not examined

Other effects:

not examined

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
Mortality in P animals is reported but not discussed.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Body weights at week 13, 38.4+/-0.6 (5, 10 and 15% ethanol) and 39.6+/-0.6g (control); for females 3.4% lower in at 15% ethanol compared with control at week 13.

No food consumption determined only water consumption: Daily water consumption at week 13, 7.0+/-0.1 g per mouse for controls, 7.1+/-0.2g for 5% group, 6.4+/-0.2g for 10% and 5.3+/-0.2g for 15%.

Dose descriptor:

NOAEL

Effect level:

15 other: % in drinking water

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects observed in parameters studied at all doses. 15% (equivalent to 20.7 g/kg/day)

Dose descriptor:

NOAEL

Effect level:

20 700 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects observed in parameters studied at all doses. 15% (equivalent to 20.7 g/kg/day)

Clinical signs:

not examined

Mortality / viability:

not specified

Body weight and weight changes:

effects observed, treatment-related

Sexual maturation:

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

not examined

Histopathological findings:

not examined

VIABILITY (OFFSPRING)
- Not reported. Litters born to P at 15% ethanol had reduced number of live pups per litter.

BODY WEIGHT (OFFSPRING)
- Litter size and weights were not given. Pups born in final F1 generation of animals exposed to 15% ethanol pre- and post-natally weighed less than controls at birth and days 21 and 74.

SEXUAL MATURATION (OFFSPRING)
- Sex ratios: Not influenced by treatment

ORGAN WEIGHTS (OFFSPRING)
F1 males from the 15% group at adulthood had decreased bodyweight and and decreased weight of testis and epididymides and seminal vesicles. In F2 females, relative liver and kidney/adrenal weights were increased.
- Vaginal opening or preputial separation: Not studied.
- Anogenital distance: Not measured.

GROSS PATHOLOGY (OFFSPRING)
- Not examined.

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

10 other: % in drinking water

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: At the highest dose fewer pups per litter were observed and significant changes to sperm motility. 10% (equivalent to 13.8 g/kg/day)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

13 800 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: At the highest dose fewer pups per litter were observed and significant changes to sperm motility 10% (equivalent to 13.8 g/kg/day)

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

< 15 other: % in drinking water

Sex:

male/female

Basis for effect level:

other: Lower live pup weight observed at the 15% dose studied

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Reproductive effects observed:

not specified

Result: No observed effect on fertility. Parental/F1 data: Ethanol treatment had no effect on bodyweights and on the proportion of breeding pairs producing at least 1 litter during the continuous breeding phase or the number of litters per pair. Effects on sperm and male reproductive organs: In the F1, 15% ethanol group there was a significantly decreased % motile sperm but no changes in sperm concentration, % abnormal sperm or % tailless sperm. There was a significant decrease in testis, epididymis and seminal vesicle weight but not when adjusted for body weight. Post natal survival until weaning: Not reported. Estimated daily intakes were 0, 6.9, 13.8 and 20.7g/kg ethanol.

Conclusions:

Overall, ethanol in drinking water at concentrations up to 15% (equivalent to 20.7 g/kg/day) had no demonstrable effect on fertility in this two-generation study.
Ethanol/ Ethyl Alcohol is both reagents used in the manufacture of sodium O-ethyl dithiocarbonate . Therefore, Ethanol/ Ethyl Alcohol need to be considered in the assessment of sodium O-ethyl dithiocarbonate

Executive summary:

A two-generation study investigated the effects of 5%, 10% and 15% ethanol in drinking water in reproduction and fertility. Male and female CD-1 mice were continuously treated for 1 week prior to mating and for a 14 week breeding period followed by a 21 day holding period when they were separated and housed individually. The F1 offspring of the 15% ethanol pairs had fewer live pups per litter but ethanol treatment had no effect on the proportion of breeding pairs producing at least 1 litter during the continuous breeding phase or the number of litters per pair. The F1 offspring from the 15% group had decreased bodyweight at weaning and mating, and a decreased weight of testis, epididymides and seminal vesicles which was no longer evident when these were adjusted for body weight. There was also a significantly decreased percentage motile sperm but no changes in sperm concentration, and percentage of abnormal sperm or tailless sperm. When reproductive performance of F1 control and 15% ethanol-treated breeding pairs was assessed at 74 days of age, there was no significant difference in mating and fertility between the groups. However, adjusted live pup weight for the ethanol group was significantly reduced compared to controls which was likely due to generalized maternal toxicity.

Reference 5

Endpoint:

one-generation reproductive toxicity

Remarks:

based on test type

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1995

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:

Ethanol/ Ethyl Alcohol is both reagents used in the manufacture of sodium O-ethyl dithiocarbonate . Therefore, Ethanol/ Ethyl Alcohol need to be considered in the assessment of sodium O-ethyl dithiocarbonate

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]

Deviations:

yes

Remarks:

Females were untreated, number of pregnant females low, no histopathology conducted

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, Portage, MI but test animals bred in laboratory.
- Age at study initiation: 70 days
- Diet: Laboratory feed ad libitum
- Water: ad libitum
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 1 degree C
- Humidity: 45 ± 5%
- Photoperiod: 12 hr light/12 hrdark cycle.

Route of administration:

oral: gavage

Vehicle:

water

Details on mating procedure:

Males were bred in once after 3 weeks exposure and twice after 9 weeks of exposure to 75-90 day old females for 2 weeks or until sperm plugs were observed. Males were intubated throughout the mating period. Females with plugs were separated and housed individually. At 20-days gestation, females from the 3-week exposure breeding and one from the 9 week exposure breeding were killed and their foetuses counted, sexed and weighed. The second female from the 9 week breeding was allowed to deliver its litter, which was similarly assessed.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Premating exposure period (males): 3 and 9 weeks

Premating exposure period (females): not treated

Frequency of treatment:

daily

Details on study schedule:

Number of generation studies: 1

Remarks:

Doses / Concentrations:
2.5 and 5.0g/kg
Basis:
actual ingested

No. of animals per sex per dose:

18-26 per dose group.

Control animals:

yes, concurrent vehicle

Details on study design:

- Controls: Vehicle (distilled water without ethanol) and non-intubated controls to evaluate the effects of intubation stress. Animals in the low and control treated groups were pair-fed to the high dose group animals.

Statistics:

Chi-square, ANOVA and Duncan Multiple Range Tests were used.

Clinical signs:

effects observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

not examined

Histopathological findings: non-neoplastic:

not examined

Other effects:

not examined

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

effects observed, treatment-related

Dose descriptor:

NOAEL

Effect level:

> 5 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: fertility

Dose descriptor:

NOAEL

Effect level:

2 500 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: fecundity, but only when data from both breeding periods combined.

Clinical signs:

not examined

Mortality / viability:

not examined

Body weight and weight changes:

not examined

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

Dose descriptor:

NOEL

Generation:

F1

Effect level:

> 2 500 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Increase in fetal weight observed at both 2.5g/kg and 5g/kg

Reproductive effects observed:

not specified

There did not appear to by any treatment related effects on resorptions and litter size. The mean BAC’s for the two ethanol dose groups was 248 ± 14 mg% (5g/kg) and 155 ± 9 mg% (2.5g/kg). There was a treatment related increase in the number of male foetuses in the 3 week breeding at 5g/kg, but the effect was not repeated at the 9 week breedings. At the 3 and 9 week breedings there was a significant dose related increase in fetal weights. There was also a significant increase in placental weights, but only at the 9 week breedings. Significantly more males were sired by 5g/kg ethanol treated males than controls in the first breeding.

There were no treatment related effects on newborns sired by alcohol treated males. Male fertility and litter size was not affected by treatment. Fecundity was not reduced in individual breedings but was significantly reduced at the 5 g/kg dose level if the breeding periods were combined. There were no differences between the two control groups. At all breedings the concurrent pair-fed control males weighed significantly less than ad lib controls

Conclusions:

There was no significant effect on male fertility. Female fecundity was reduced at the high dose level when all breedings were combined but litter size was not decreased nor were resorptions significantly increased. The main finding and only finding consistent and repeated across both breedings was an increase in fetal weights of offspring sired by alcohol treated males. It is not clear if this is an adverse toxicological finding.

Executive summary:

Male rats were administered 2.5 or 5g/kg ethanol daily by gavage for 3 weeks or 9 weeks. Animals in the 2.5 g/kg and control groups were pair fed to those in the 5 g/kg group. Males were bred once after 3 weeks of treatment and twice after 9 weeks of treatment. Females in the first two breedings were sacrificed on day 20 of gestation and their offspring examined. Females in the third breeding were allowed to deliver their litters. There were no apparent treatment effects on resorptions or litter size. Fecundity was reduced in females bred to the high dose ethanol-treated males when all breedings were pooled. The number of male fetuses was increased in the high dose ethanol treated group. There was a significant dose related increase in fetal weights at the week 3 and 9 breedings and a significant increase in placental weights at the 9 week breedings. However, there were no treatment related effects on newborns sired by ethanol treated males. The main finding and only finding consistent and repeated across both breedings was an increase in fetal weights of offspring sired by alcohol treated males. It is not clear if this is an adverse toxicological finding.

Reference 6

Endpoint:

one-generation reproductive toxicity

Remarks:

based on test type

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1985

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:

Ethanol/ Ethyl Alcohol is both reagents used in the manufacture of sodium O-ethyl dithiocarbonate . Therefore, Ethanol/ Ethyl Alcohol need to be considered in the assessment of sodium O-ethyl dithiocarbonate

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]

Deviations:

yes

Remarks:

short paternal exposure period; no pathology conducted; number of pregnant females low; male treated rats mated to untreated females.

GLP compliance:

not specified

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 400-500g males; 200-300g females
- Housing: Females housed individually.

ENVIRONMENTAL CONDITIONS
- Temperature: 73 +/- 3F.
- Humidity: 40-50%.
- Light/dark cycle (hrs): 12/12

Route of administration:

inhalation

Type of inhalation exposure (if applicable):

whole body

Vehicle:

other: air in chamber

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Exposure was conducted in 0.5m3 chambers with dynamic air flow
- Air change rate: (one air change per minute.)

Details on mating procedure:

After 2 day non-exposure period males were mated individually with untreated virgin females. Mating period 5 days. Mating confirmed by presence of sperm plugs under cages or vaginal smears.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Exposure period: 7 hours
/day
Premating exposure period (males): 6 weeks

Premating exposure period (females): none

Postmating exposure period (females): Days 1-20 gestation
Duration of test: see method details

Frequency of treatment:

daily

Details on study schedule:

Number of generation studies: 1

Remarks:

Doses / Concentrations:
0, 10000, 16000ppm
Basis:
nominal conc.

No. of animals per sex per dose:

18/group male
15/group female (pregnant)

Control animals:

yes

Details on study design:

Analytical monitoring: Yes (IR analyser) - exposure found to be within 11% of nominal). Independently cross-checked with charcoal adsorption tubes.

Parental animals: Observations and examinations:

BODY WEIGHT: Yes
- Time schedule for examinations: Daily

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food intake were measured.

WATER CONSUMPTION AND COMPOUND INTAKE: Yes

Litter observations:

Pups were individually weighed weekly for five weeks.

Clinical signs:

not examined

Body weight and weight changes:

not examined

Food consumption and compound intake (if feeding study):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Histopathological findings: non-neoplastic:

not examined

Other effects:

not examined

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

not examined

Dose descriptor:

NOAEL

Effect level:

> 16 000 ppm

Based on:

test mat.

Sex:

male

Basis for effect level:

other: No effects on fertility at highest dose studied

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

not examined

Histopathological findings:

no effects observed

Result: negative
No effect on weight gain, feed or water intake. No effect on fertility or litter sizes. Offspring numbers averaged 14/litter. Previous studies quoted as showing exposures to 10000 and 16000 ppm ethanol typically give rise to blood ethanol concentrations of 30 and 500 mg/l ethanol. Authors calculate that for rats exposures in excess of 11000 ppm are required to begin accumulating ethanol in the blood and that ethanol is no more toxic by the inhalation route than by other routes.
No data on offspring body weight gain provided but it is presumed that there was no change from controls.

Remarks on result:

other: Result: negative No effect on weight gain, feed or water intake. No effect on fertility or litter sizes.

Reproductive effects observed:

not specified

Conclusions:

Ethanol treatment did not affect the fertility of male rats determined by number of litters and litter size

Executive summary:

Male rats were exposed to ethanol in an inhalation chamber at concentrations of 11,000ppm or 16,000ppm for six weeks. After a two day non-exposure period they were mated to untreated females for 5 days. The pregnant females received the same experimental exposure from day 1 -20 of gestation and were then allowed to deliver their litters. Ethanol treatment did not affect fertility or litter sizes.

Reference 7

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

other: QSAR model (MC4PC version 2.4.1.5)

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

QSAR prediction:MCASE/MC4PC is a knowledge-based system designed by MultiCASE, Inc. and further developed with the Informatics and Computational Safety Analysis Staff (ICSAS) of the US FDA to reveal the relationship between the structure of a chemical and its activity in a specific biological assay. This method is relevant for reproductive toxicity endpoints in rodentss.

Qualifier:

according to guideline

Guideline:

other: MULTICASE AN1-AN9 FDA Reproductive toxicity in females set

Principles of method if other than guideline:

Multicase
MCASE/MC4PC is a knowledge-based system designed by MultiCASE, Inc. and further developed with the Informatics and Computational Safety Analysis Staff (ICSAS) of the US FDA to reveal the relationship between the structure of a chemical and its activity in a specific biological assay (Klopman et al., 2005). MC4PC, and the predecessor software CASE (Computer Automated Structure Evaluation), were designed to find structural fragments that discriminate between active and inactive molecules, and the backbone of the software is based on the hypothesis that a relationship does exist between chemical structure and activity. Together with the ICSAS, human expert rules were developed to enhance the performance of the MC4PC quantitative structure activity relationship (SAR) software program, which reduces chemicals to 2 - 10 atom fragments and sorts the fragments in relation to biological activity or toxicity (structural alerts), lists the structural alerts linked to a query compound, and lists the structures, names, and activity of compounds in the database that are related to the query substance. The program automatically identifies molecular substructures that have a high probability of being relevant or responsible for an observed toxicological effect from a learning set containing both active and inactive molecules of diverse structure. The program selects its own descriptors from a number of possible sub-structural units and creates a dictionary of molecular descriptors. The selected descriptors are characterized either as activating (biophore) or inactivating (biophobe).

GLP compliance:

no

Remarks:

not applicable. QSAR model

Limit test:

no

Species:

other: rodent, rat and mouse

Strain:

other: QSAR model

Sex:

female

Route of administration:

other: QSAR model

Vehicle:

other: QSAR model

Analytical verification of doses or concentrations:

not specified

Remarks:

Doses / Concentrations:

Basis:
other: QSAR model

Control animals:

not specified

Clinical signs:

no effects observed

Description (incidence and severity):

QSAR model

Body weight and weight changes:

no effects observed

Description (incidence and severity):

QSAR model

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

QSAR model

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

QSAR model

Other effects:

no effects observed

Description (incidence and severity):

Test substance intake: QSAR model

Reproductive function: oestrous cycle:

no effects observed

Description (incidence and severity):

QSAR model

Reproductive function: sperm measures:

no effects observed

Description (incidence and severity):

QSAR model

Reproductive performance:

no effects observed

Description (incidence and severity):

QSAR model

The tested molecule does not contain any confirmed alerts and is assumed to be inactive.
The Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation and therefore Sodium O-ethyl dithiocarbonate does not cause reproductive toxicity.The probability that the prediction is accurate is 80%.

Dose descriptor:

other: RP_AN1,RP_AN5,RP_AN9

Effect level:

80 other: % The probability that the prediction is accurate is 80%.

Based on:

other: RP_AN1Fertility in females, rodent,RP_AN5 Fertility in females, rat, RP_AN9 Fertility in females, mouse

Sex:

not specified

Basis for effect level:

other: see 'Remark'

Remarks on result:

other: Generation: QSAR model (migrated information)

Clinical signs:

no effects observed

Description (incidence and severity):

QSAR model

Mortality / viability:

no mortality observed

Description (incidence and severity):

QSAR model

Body weight and weight changes:

no effects observed

Description (incidence and severity):

QSAR model

Sexual maturation:

no effects observed

Description (incidence and severity):

QSAR model

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

QSAR model

Gross pathological findings:

no effects observed

Description (incidence and severity):

QSAR model

Histopathological findings:

no effects observed

Description (incidence and severity):

QSAR model

The tested molecule does not contain any confirmed alerts and is assumed to be inactive.
The Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation and therefore Sodium O-ethyl dithiocarbonatedoes not cause reproductive toxicity.The probability that the prediction is accurate is 80%.

Remarks on result:

other: The tested molecule does not contain any confirmed alerts and is assumed to be inactive.

Reproductive effects observed:

not specified

Table 7. Reproductive toxicity in female adult rodents

Compound	AN1	AN2	AN3	AN4	RCA Method Expert Call (Overall)	Review expert
O-ethyl dithiocarbonic acid	-	-	-	-	-*	-

 

Table 8. Reproductive toxicity in female adult rats

Compound	AN5	AN6	AN7	AN8	RCA Method Expert Call (Overall)	Review expert
O-ethyldithiocarbonic acid	-	-	-	-	-*	-

 

Table 9. Reproductive toxicity in female adult mice

Compound	AN9	RCA Method Expert Call (Overall)	Review expert
O-ethyldithiocarbonic acid	-	-*	-

The probability that the prediction is accurate is 80%.

Conclusions:

The tested molecule does not contain any confirmed alerts and is assumed to be inactive.
The Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation and therefore Sodium O-ethyl dithiocarbonatedoes not cause reproductive toxicity.The probability that the prediction is accurate is 80%.

Reference 8

Endpoint:

fertility, other

Remarks:

based on test type

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

QSAR prediction:MCASE/MC4PC is a knowledge-based system designed by MultiCASE, Inc. and further developed with the Informatics and Computational Safety Analysis Staff (ICSAS) of the US FDA to reveal the relationship between the structure of a chemical and its activity in a specific biological assay. This method is relevant for reproductive toxicity endpoints in rodentss.

Qualifier:

according to guideline

Guideline:

other: MULTICASE AP1-AP7 Sperm toxicity,mammal,rat,mouse

Principles of method if other than guideline:

Multicase
MCASE/MC4PC is a knowledge-based system designed by MultiCASE, Inc. and further developed with the Informatics and Computational Safety Analysis Staff (ICSAS) of the US FDA to reveal the relationship between the structure of a chemical and its activity in a specific biological assay (Klopman et al., 2005). MC4PC, and the predecessor software CASE (Computer Automated Structure Evaluation), were designed to find structural fragments that discriminate between active and inactive molecules, and the backbone of the software is based on the hypothesis that a relationship does exist between chemical structure and activity. Together with the ICSAS, human expert rules were developed to enhance the performance of the MC4PC quantitative structure activity relationship (SAR) software program, which reduces chemicals to 2 - 10 atom fragments and sorts the fragments in relation to biological activity or toxicity (structural alerts), lists the structural alerts linked to a query compound, and lists the structures, names, and activity of compounds in the database that are related to the query substance. The program automatically identifies molecular substructures that have a high probability of being relevant or responsible for an observed toxicological effect from a learning set containing both active and inactive molecules of diverse structure. The program selects its own descriptors from a number of possible sub-structural units and creates a dictionary of molecular descriptors. The selected descriptors are characterized either as activating (biophore) or inactivating (biophobe).

GLP compliance:

no

Remarks:

not applicable. QSAR model

Limit test:

no

Species:

other: rodent, rat and mouse

Strain:

other: QSAR model

Sex:

male

Route of administration:

other: QSAR model

Vehicle:

other: QSAR model

Analytical verification of doses or concentrations:

not specified

Remarks:

Doses / Concentrations:

Basis:
other: QSAR model

Control animals:

not specified

Clinical signs:

no effects observed

Description (incidence and severity):

QSAR model

Body weight and weight changes:

no effects observed

Description (incidence and severity):

QSAR model

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

QSAR model

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

QSAR model

Other effects:

no effects observed

Description (incidence and severity):

Test substance intake: QSAR model

Reproductive function: oestrous cycle:

no effects observed

Description (incidence and severity):

QSAR model

Reproductive function: sperm measures:

no effects observed

Description (incidence and severity):

QSAR model

Reproductive performance:

no effects observed

Description (incidence and severity):

QSAR model

The tested molecule does not contain any confirmed alerts and is assumed to be inactive.
The Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation and therefore Sodium O-ethyl dithiocarbonate does not cause reproductive toxicity.The probability that the prediction is accurate is 80%.

Dose descriptor:

other: RP_AP1,RP_AP4,RP_AP7

Effect level:

80 other: % The probability that the prediction is accurate is 80%.

Based on:

other: RP_AP1Sperm toxicity, mammal,RP_AP4 Sperm toxicity, rat,RP_AP7 Sperm toxicity, mouse

Sex:

not specified

Basis for effect level:

other: see 'Remark'

Remarks on result:

other: Generation: QSAR model (migrated information)

Clinical signs:

no effects observed

Description (incidence and severity):

QSAR model

Mortality / viability:

no mortality observed

Description (incidence and severity):

QSAR model

Body weight and weight changes:

no effects observed

Description (incidence and severity):

QSAR model

Sexual maturation:

no effects observed

Description (incidence and severity):

QSAR model

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

QSAR model

Gross pathological findings:

no effects observed

Description (incidence and severity):

QSAR model

Histopathological findings:

no effects observed

Description (incidence and severity):

QSAR model

The tested molecule does not contain any confirmed alerts and is assumed to be inactive.
The Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation and therefore Sodium o-isobutyl dithiocarbonate does not cause reproductive toxicity.The probability that the prediction is accurate is 80%.

Remarks on result:

other: The tested molecule does not contain any confirmed alerts and is assumed to be inactive.

Reproductive effects observed:

not specified

Table 4. Sperm toxicity in male adult rodents

Compound	AP1	AP2	AP3	RCA Method Expert Call (Overall)	Review expert
O-ethyl dithiocarbonic acid	-	-	-	-*	-

 

Table 5. Sperm toxicity in male adult rats

Compound	AP4	AP5	AP6	RCA Method Expert Call (Overall)	Review expert
O-ethyldithiocarbonic acid	-	-	-	-*	-

 

Table 6. Sperm toxicity in male adult mice

Compound	AP7	RCA Method Expert Call (Overall)	Review expert
O-ethyldithiocarbonic acid	-	-*	-

The probability that the prediction is accurate is 80%.

Conclusions:

The tested molecule does not contain any confirmed alerts and is assumed to be inactive.
The Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation and therefore Sodium O-ethyl dithiocarbonate does not cause reproductive toxicity.The probability that the prediction is accurate is 80%.

Reference 9

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

QSAR prediction: MCASE/MC4PC is a knowledge-based system designed by MultiCASE, Inc. and further developed with the Informatics and Computational Safety Analysis Staff (ICSAS) of the US FDA to reveal the relationship between the structure of a chemical and its activity in a specific biological assay. This method is relevant for reproductive toxicity endpoints in rodentss.

Qualifier:

according to guideline

Guideline:

other: MULTICASE AQ1-AQ9 Newborn behavioral toxicity, rodent,rat,mouse

Principles of method if other than guideline:

Multicase
MCASE/MC4PC is a knowledge-based system designed by MultiCASE, Inc. and further developed with the Informatics and Computational Safety Analysis Staff (ICSAS) of the US FDA to reveal the relationship between the structure of a chemical and its activity in a specific biological assay (Klopman et al., 2005). MC4PC, and the predecessor software CASE (Computer Automated Structure Evaluation), were designed to find structural fragments that discriminate between active and inactive molecules, and the backbone of the software is based on the hypothesis that a relationship does exist between chemical structure and activity. Together with the ICSAS, human expert rules were developed to enhance the performance of the MC4PC quantitative structure activity relationship (SAR) software program, which reduces chemicals to 2 - 10 atom fragments and sorts the fragments in relation to biological activity or toxicity (structural alerts), lists the structural alerts linked to a query compound, and lists the structures, names, and activity of compounds in the database that are related to the query substance. The program automatically identifies molecular substructures that have a high probability of being relevant or responsible for an observed toxicological effect from a learning set containing both active and inactive molecules of diverse structure. The program selects its own descriptors from a number of possible sub-structural units and creates a dictionary of molecular descriptors. The selected descriptors are characterized either as activating (biophore) or inactivating (biophobe).

GLP compliance:

no

Remarks:

not applicable. QSAR model

Limit test:

no

Species:

other: rodent, rat and mouse

Strain:

other: QSAR model

Sex:

male

Route of administration:

other: QSAR model

Vehicle:

other: QSAR model

Analytical verification of doses or concentrations:

not specified

Remarks:

Doses / Concentrations:

Basis:
other: QSAR model

Control animals:

not specified

Clinical signs:

no effects observed

Description (incidence and severity):

QSAR model

Body weight and weight changes:

no effects observed

Description (incidence and severity):

QSAR model

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

QSAR model

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

QSAR model

Other effects:

no effects observed

Description (incidence and severity):

Test substance intake: QSAR model

Reproductive function: oestrous cycle:

no effects observed

Description (incidence and severity):

QSAR model

Reproductive function: sperm measures:

no effects observed

Description (incidence and severity):

QSAR model

Reproductive performance:

no effects observed

Description (incidence and severity):

QSAR model

The tested molecule does not contain any confirmed alerts and is assumed to be inactive.
The Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation and therefore SodiumO-ethyl dithiocarbonate does not cause reproductive toxicity.The probability that the prediction is accurate is 80%.

Dose descriptor:

other: RP_AQ1,RP_AQ4,RP_AQ9

Effect level:

80 other: % The probability that the prediction is accurate is 80%.

Based on:

other: RP_AQ1 Newborn behavioral toxicity, rodent,RP_AQ4 Newborn behavioral toxicity, rat,RP_AQ9 Newborn behavioral toxicity, mouse

Sex:

not specified

Basis for effect level:

other: see 'Remark'

Remarks on result:

other: Generation: QSAR model (migrated information)

Clinical signs:

no effects observed

Description (incidence and severity):

QSAR model

Mortality / viability:

no mortality observed

Description (incidence and severity):

QSAR model

Body weight and weight changes:

no effects observed

Description (incidence and severity):

QSAR model

Sexual maturation:

no effects observed

Description (incidence and severity):

QSAR model

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

QSAR model

Gross pathological findings:

no effects observed

Description (incidence and severity):

QSAR model

Histopathological findings:

no effects observed

Description (incidence and severity):

QSAR model

The tested molecule does not contain any confirmed alerts and is assumed to be inactive.
The Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation and therefore SodiumO-ethyl dithiocarbonate does not cause reproductive toxicity.The probability that the prediction is accurate is 80%.

Remarks on result:

other: The tested molecule does not contain any confirmed alerts and is assumed to be inactive.

Reproductive effects observed:

not specified

Table 10.Newborn behavioral toxicity, rodent

Compound	AQ1	AQ2	AQ3	RCA Method Expert Call (Overall)	Review expert
O-ethyld ithiocarbonic acid	-	-	-	-*	-

 

Table 11.Newborn behavioral toxicity, rat

Compound	AQ4	AQ5	AQ6	RCA Method Expert Call (Overall)	Review expert
O-ethyld ithiocarbonic acid	-	-	-	-*	-

 

Table 12.Newborn behavioral toxicity, mouse

Compound	AQ7	RCA Method Expert Call (Overall)	Review expert
O-ethyld ithiocarbonic acid	-	-*	-

The probability that the prediction is accurate is 80%.

Conclusions:

The tested molecule does not contain any confirmed alerts and is assumed to be inactive.
The Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation and therefore Sodium O-ethyl dithiocarbonate does not cause reproductive toxicity.The probability that the prediction is accurate is 80%.

Reference 10

Endpoint:

screening for reproductive / developmental toxicity

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Reproductive effects observed:

not specified

Reference 11

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

QSAR prediction:MCASE/MC4PC is a knowledge-based system designed by MultiCASE, Inc. and further developed with the Informatics and Computational Safety Analysis Staff (ICSAS) of the US FDA to reveal the relationship between the structure of a chemical and its activity in a specific biological assay. This method is relevant for reproductive toxicity endpoints in rodentss.

Qualifier:

according to guideline

Guideline:

other: MULTICASE AO1-AO7 FDA Reproductive toxicity in adult males

Principles of method if other than guideline:

Multicase
MCASE/MC4PC is a knowledge-based system designed by MultiCASE, Inc. and further developed with the Informatics and Computational Safety Analysis Staff (ICSAS) of the US FDA to reveal the relationship between the structure of a chemical and its activity in a specific biological assay (Klopman et al., 2005). MC4PC, and the predecessor software CASE (Computer Automated Structure Evaluation), were designed to find structural fragments that discriminate between active and inactive molecules, and the backbone of the software is based on the hypothesis that a relationship does exist between chemical structure and activity. Together with the ICSAS, human expert rules were developed to enhance the performance of the MC4PC quantitative structure activity relationship (SAR) software program, which reduces chemicals to 2 - 10 atom fragments and sorts the fragments in relation to biological activity or toxicity (structural alerts), lists the structural alerts linked to a query compound, and lists the structures, names, and activity of compounds in the database that are related to the query substance. The program automatically identifies molecular substructures that have a high probability of being relevant or responsible for an observed toxicological effect from a learning set containing both active and inactive molecules of diverse structure. The program selects its own descriptors from a number of possible sub-structural units and creates a dictionary of molecular descriptors. The selected descriptors are characterized either as activating (biophore) or inactivating (biophobe).

GLP compliance:

no

Remarks:

not applicable. QSAR model

Limit test:

no

Species:

other: rodent, rat and mouse

Strain:

other: QSAR model

Sex:

male

Route of administration:

other: QSAR model

Vehicle:

other: QSAR model

Analytical verification of doses or concentrations:

not specified

Remarks:

Doses / Concentrations:

Basis:
other: QSAR model

Control animals:

not specified

Clinical signs:

no effects observed

Description (incidence and severity):

QSAR model

Body weight and weight changes:

no effects observed

Description (incidence and severity):

QSAR model

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

QSAR model

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

QSAR model

Other effects:

no effects observed

Description (incidence and severity):

Test substance intake: QSAR model

Reproductive function: oestrous cycle:

no effects observed

Description (incidence and severity):

QSAR model

Reproductive function: sperm measures:

no effects observed

Description (incidence and severity):

QSAR model

Reproductive performance:

no effects observed

Description (incidence and severity):

QSAR model

The tested molecule does not contain any confirmed alerts and is assumed to be inactive.
The Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation and therefore SodiumO-ethyl dithiocarbonate does not cause reproductive toxicity.The probability that the prediction is accurate is 80%.

Dose descriptor:

other: RP_AO1 , RP_AO4 , RP_AO7

Effect level:

80 other: % The probability that the prediction is accurate is 80%.

Based on:

other: RP_AO1 Fertility in males, rodent, RP_AO4 Fertility in males, rat, RP_AO7and Fertility in males, mouse

Sex:

not specified

Basis for effect level:

other: see 'Remark'

Remarks on result:

other: Generation: QSAR model (migrated information)

Clinical signs:

no effects observed

Description (incidence and severity):

QSAR model

Mortality / viability:

no mortality observed

Description (incidence and severity):

QSAR model

Body weight and weight changes:

no effects observed

Description (incidence and severity):

QSAR model

Sexual maturation:

no effects observed

Description (incidence and severity):

QSAR model

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

QSAR model

Gross pathological findings:

no effects observed

Description (incidence and severity):

QSAR model

Histopathological findings:

no effects observed

Description (incidence and severity):

QSAR model

The tested molecule does not contain any confirmed alerts and is assumed to be inactive.
The Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation and therefore Sodium O-ethyl dithiocarbonate does not cause reproductive toxicity.The probability that the prediction is accurate is 80%.

Remarks on result:

other: The tested molecule does not contain any confirmed alerts and is assumed to be inactive.

Reproductive effects observed:

not specified

Table 1. Reproductive toxicity in male adult rodents

Compound	AO1	AO2	AO3	RCA Method Expert Call (Overall)	Review expert
O-ethyld ithiocarbonic acid	-	-	-	-*	-

 

Table 2. Reproductive toxicity in male adult rats

Compound	AO4	AO5	AO6	RCA Method Expert Call (Overall)	Review expert
O-ethyld ithiocarbonic acid	-	-	-	-*	-

 

Table 3. Reproductive toxicity in male adult mice

Compound	AO7	RCA Method Expert Call (Overall)	Review expert
O-ethyld ithiocarbonic acid	+	?*	-

The probability that the prediction is accurate is 80%.

Conclusions:

The tested molecule does not contain any confirmed alerts and is assumed to be inactive.
The Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation and therefore SodiumO-ethyl dithiocarbonate does not cause reproductive toxicity.The probability that the prediction is accurate is 80%.

Reference 12

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

QSAR model,Estrogen Receptor Binding method, relevant for reproductive toxicity endpoints in fish and mammals.

Type of information:

(Q)SAR

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

QSAR prediction: Accepted Estrogen Receptor Binding QSAR method for chemicals properties assessment.. This method is relevant for reproductive toxicity endpoints in fish and mammals.

Qualifier:

according to guideline

Guideline:

other: QSAR Toolbox Version 3.3.5.17

Principles of method if other than guideline:

This grouping method contains simple categories for estrogen receptor (ER) binding. This method is relevant for reproductive toxicity endpoints in fish and mammals.

GLP compliance:

no

Remarks:

not applicable. QSAR model,Estrogen Receptor Binding method, relevant for reproductive toxicity endpoints in fish and mammals.

Limit test:

no

Species:

other: fish (trout) and mammals.

Strain:

other: QSAR model

Sex:

not specified

Route of administration:

other: QSAR model

Vehicle:

other: QSAR model

Details on exposure:

Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .

Remarks:

Doses / Concentrations:

Basis:
other: QSAR model

Control animals:

not specified

Parental animals: Observations and examinations:

Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .

Clinical signs:

no effects observed

Description (incidence and severity):

QSAR model

Body weight and weight changes:

no effects observed

Description (incidence and severity):

QSAR model

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

QSAR model

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

QSAR model

Other effects:

no effects observed

Description (incidence and severity):

Test substance intake: QSAR model

Reproductive function: oestrous cycle:

no effects observed

Description (incidence and severity):

QSAR model

Reproductive function: sperm measures:

no effects observed

Description (incidence and severity):

QSAR model

Reproductive performance:

no effects observed

Description (incidence and severity):

QSAR model

Sodium O-ethyl dithiocarbonate have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore Sodium O-ethyl dithiocarbonate (SEX) does not cause reproductive toxicity.

1.1. CAS number: 140-90-9
1.2. Chemical name(s):
carbonodithioic acid, o-ethyl ester, sodium salt
sodium o-ethyl dithiocarbonate
sodium o-ethyl carbonodithioate
carbonic acid, dithio-, o-ethyl ester, sodium salt
sodium ethyl xanthate
1.3. Structure codes:
a. SMILES: CCOC(=S)S{-}.[Na]{+}
1.4. Profiling results:
-DNA binding by OECD -No alert found
-Est rogen Receptor Binding-Non binder, non cyclic structure
-OECD HPV Chemical Categories-Not categorized
-Protein binding by OECD-No alert found

Dose descriptor:

other: Relative ERBA (Estrogen Receptor Binding Affinity)

Effect level:

< -3 other: Log RBA(Relative Binding Affinities )

Based on:

other: Estrogen receptor (ER) binding

Sex:

not specified

Basis for effect level:

other: see 'Remark'

Remarks on result:

other: Generation: QSAR model (migrated information)

Clinical signs:

no effects observed

Description (incidence and severity):

QSAR model

Mortality / viability:

no mortality observed

Description (incidence and severity):

QSAR model

Body weight and weight changes:

no effects observed

Description (incidence and severity):

QSAR model

Sexual maturation:

no effects observed

Description (incidence and severity):

QSAR model

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

QSAR model

Gross pathological findings:

no effects observed

Description (incidence and severity):

QSAR model

Histopathological findings:

no effects observed

Description (incidence and severity):

QSAR model

Sodium O-ethyl dithiocarbonate have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore Sodium O-ethyl dithiocarbonate (SEX) does not cause reproductive toxicity.

1.1. CAS number: 140-90-9
1.2. Chemical name(s):
carbonodithioic acid, o-ethyl ester, sodium salt
sodium o-ethyl dithiocarbonate
sodium o-ethyl carbonodithioate
carbonic acid, dithio-, o-ethyl ester, sodium salt
sodium ethyl xanthate
1.3. Structure codes:
a. SMILES: CCOC(=S)S{-}.[Na]{+}
1.4. Profiling results:
-DNA binding by OECD -No alert found
-Est rogen Receptor Binding-Non binder, non cyclic structure
-OECD HPV Chemical Categories-Not categorized
-Protein binding by OECD-No alert found

Remarks on result:

other: Substance have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore Sodium O-ethyl dithiocarbonate (SEX) does not cause reproductive toxicity.

Reproductive effects observed:

not specified

This grouping method contains simple categories for estrogen receptor (ER) binding. This method is relevant for reproductive toxicity endpoints in fish and mammals.

 

Non-binder, impaired OH or NH2 group

Non-binder without OH or NH2 group

Non-binder, non-cyclic structure

Non-binder, MW > 500

Non-binder, non-cyclic structure– chemicals without cycles and MW =<500

Non-ER binder due to non-cyclic molecular structure.

 

Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .

Popular among these are the “four phase” assessment that includes Comparative Molecular Field Analysis (CoMFA) and the Common Reactivity Pattern Approach (COREPA)

Since the RE-binding is a receptor mediated event, particular organic functional groups, size and shape are critical to binding potency.

Sodium O-ethyl dithiocarbonate have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore SodiumO-ethyl dithiocarbonate (SEX) does not cause reproductive toxicity.

Conclusions:

Non-ER binder due to non-cyclic molecular structure. SodiumO-ethyl dithiocarbonate have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore Sodium O-ethyl dithiocarbonate (SEX) does not cause reproductive toxicity.

Executive summary:

Sodium O-ethyl dithiocarbonate have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore Sodium O-ethyl dithiocarbonate (SEX) does not cause reproductive toxicity.

 

1.1. CAS number: 140-90-9

 1.2. Chemical name(s):

carbonodithioic acid, o-ethyl ester, sodium salt

sodium o-ethyl dithiocarbonate

sodium o-ethyl carbonodithioate

carbonic acid, dithio-, o-ethyl ester, sodium salt

sodium ethyl xanthate

 1.3. Structure codes:

a. SMILES: CCOC(=S)S{-}.[Na]{+}

 1.4. Profiling results:

-DNA binding by OECD -No alert found

-Est rogen Receptor Binding-Non binder, non cyclic structure

-OECD HPV Chemical Categories-Not categorized

-Protein binding by OECD-No alert found

 

Reference 13

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

(Q)SAR

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

QSAR prediction: Accepted Estrogen Receptor Binding QSAR method for chemicals properties assessment.. This method is relevant for reproductive toxicity endpoints in fish and mammals.

Qualifier:

according to guideline

Guideline:

other: Estrogen Receptor Binding method

Principles of method if other than guideline:

This grouping method contains simple categories for estrogen receptor (ER) binding. This method is relevant for reproductive toxicity endpoints in fish and mammals.

GLP compliance:

no

Remarks:

not applicable. QSAR model

Limit test:

no

Species:

other: fish and mammals.

Strain:

other: QSAR model

Sex:

not specified

Route of administration:

other: QSAR model

Vehicle:

other: QSAR model

Details on exposure:

Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .

Remarks:

Doses / Concentrations:

Basis:
other: QSAR model

Control animals:

not specified

Parental animals: Observations and examinations:

Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .

Clinical signs:

no effects observed

Description (incidence and severity):

QSAR model

Body weight and weight changes:

no effects observed

Description (incidence and severity):

QSAR model

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

QSAR model

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

QSAR model

Other effects:

no effects observed

Description (incidence and severity):

Test substance intake: QSAR model

Reproductive function: oestrous cycle:

no effects observed

Description (incidence and severity):

QSAR model

Reproductive function: sperm measures:

no effects observed

Description (incidence and severity):

QSAR model

Reproductive performance:

no effects observed

Description (incidence and severity):

QSAR model

No binding to Estrogen Receptor Alpha (Log RBA <-3) for the sodium O-ethyl dithiocarbonate (SEX) and therefore Sodium O-ethyl dithiocarbonate (SEX) does not cause reproductive toxicity.

Dose descriptor:

other: QSAR model

Effect level:

< -3 other: Log RBA(Relative Binding Affinities )

Based on:

other: Estrogen receptor (ER) binding

Sex:

not specified

Basis for effect level:

other: No binding to Estrogen Receptor Alpha (Log RBA <-3) for the sodium O-ethyl dithiocarbonate (SEX)

Remarks on result:

other: Generation: QSAR model (migrated information)

Clinical signs:

no effects observed

Description (incidence and severity):

QSAR model

Mortality / viability:

no mortality observed

Description (incidence and severity):

QSAR model

Body weight and weight changes:

no effects observed

Description (incidence and severity):

QSAR model

Sexual maturation:

no effects observed

Description (incidence and severity):

QSAR model

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

QSAR model

Gross pathological findings:

no effects observed

Description (incidence and severity):

QSAR model

Histopathological findings:

no effects observed

Description (incidence and severity):

QSAR model

No binding to Estrogen Receptor Alpha (Log RBA <-3) for the sodium O-ethyl dithiocarbonate (SEX) and therefore Sodium O-ethyl dithiocarbonate (SEX) does not cause reproductive toxicity.

Remarks on result:

other: No binding to Estrogen Receptor Alpha (Log RBA <-3) for the sodium O-ethyl dithiocarbonate (SEX) and therefore Sodium O-ethyl dithiocarbonate (SEX) does not cause reproductive toxicity.

Reproductive effects observed:

not specified

No binding to Estrogen Receptor Alpha (Log RBA <-3) for the sodium O-ethyl dithiocarbonate (SEX) and therefore Sodium O-ethyl dithiocarbonate (SEX) does not cause reproductive toxicity.

Conclusions:

No binding to Estrogen Receptor Alpha (Log RBA <-3) for the sodium O-ethyl dithiocarbonate (SEX) and therefore Sodium O-ethyl dithiocarbonate (SEX) does not cause reproductive toxicity.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

89.36 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

 The inhalation dose for the rat is converted to the oral dose using a standard breathing volume for the rat (1.15 m3/kg for 24 hours exposure.The resulting air concentration needs to be firstly corrected for 24 hlight activity (20 m3), assuming 100 % absorption for both routes.
 corrected oral NOAEL=   inhalationNOAEL
  (1554 mg/m3  ÷20m3/rat) x 1.15 m3/kg bw =89.36 mg/kg bw/day
  NOAELrat  = 89.36 mg/kg bw/day

Effect on fertility: via inhalation route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

1 554 mg/m³

Study duration:

subacute

Species:

rat

Effect on fertility: via dermal route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

2.23 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

For dermal exposure we taken that:
-the average weight of rats is 250g (200-300g),
-the dose is applied over an area which is approximately 10% of the total body surface=0.025 kg
 corrected dermal NOAEL=   oral NOAEL
89.36 mg/kg bw/day x 0.025 kg =                  
 NOAELrat  = 2.23 mg/kg bw/day

Additional information

Oral exposure

 The inhalation dose for the rat is converted to the oral dose using a standard breathing volume for the rat (1.15 m3/kg for 24 hours exposure.The resulting air concentration needs to befirstly corrected for 24 hlight activity (20 m³), assuming 100 % absorption for both routes.

 

corrected oral NOAEL=   inhalationNOAEL

  (1554 mg/m³  ÷20m3/rat) x 1.15 m3/kg bw =89.36 mg/kg bw/day

            

 NOAELrat  = 89.36 mg/kg bw/day

Dermal exposure:

For dermal exposure we taken that:

-the average weight of rats is 250g (200-300g),

-the dose is applied over an area which is approximately 10% of the total body surface=0.025 kg

 corrected dermal NOAEL=   oral NOAEL

89.36 mg/kg bw/day x 0.025 kg =                  

 NOAELrat  = 2.23 mg/kg bw/day

Inhalation exposure:

Based on the results in the study of WIL Research Laboratories, Inc. 1992, 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).

 

Short description of key information:
There are conclusive but not suffcient data for the classification of substance SEX with regard to reproduction.
Non-ER binder due to non-cyclic molecular structure. Sodium O-ethyl dithiocarbonate have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore Sodium O-ethyl dithiocarbonate (SEX) does not cause reproductive toxicity.
It is concluded that the substance SEX does not meet the criteria to be classified for human health hazards for Reproductive toxicity

Effects on developmental toxicity

Description of key information

There are conclusive but not suffcient data for the classification of substance SEX with regard to Developmental toxicity / teratogenicity 

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

other: published data

Adequacy of study:

weight of evidence

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:

Dithiocarbamates are related compounds to xanthates. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium or potassium hydroxide: They arise from the reaction of the amine with CS2. Well-conducted and reported study, published in peer-reviewed literature, minor restrictions in design and reporting, but otherwise adequate for assessment.

Qualifier:

no guideline followed

Principles of method if other than guideline:

The test substance was administered at dose levels of 31.25, 64.2, 125 and 250 mg/kg bw/day as suspension in olive oil to groups of pregnant Wistar rats (21-23 animals/group) during days 7 to 15 of gestation. On gestation day 20, 14 rats from the control and high dose groups and 15 rats from the other test groups were opened under anesthesia to inspect the uterus, number of corpora lutea, number of inplants, sex ratio and number of live and dead fetuses. The other rats from each group were allowed to give natural birth, and post-natal development of the pups was examined. The assessed parameters were number of pups, mortality rate, outward abnormalities, skeletal and soft tissue abnormalities and body weight, as well as ear auricle extension, tooth bud collapse or emergence, fur emergence, eyelid opening and timing for testes descent and vagina opening. Pups were allowed to wean and the observation continued till age 10 weeks, after which animals were sacrificed and gross pathological and organ weight examinations were performed.

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Japan
- Age at study initiation: females 12 weeks, males 14 weeks
- Housing: singly in aluminum pregnancy cages (Natsume Seisakusho)
- Diet: solid feed pellets (Oriental Yeast Co., MF), ad libitum
- Water: tap water, ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 25±1
- Humidity (%): 55±5
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light):

Route of administration:

oral: gavage

Vehicle:

olive oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: using an ultrasonic disintegrator (360W, 5 minutes) as a 20% suspension fluid in olive oil (The Japanese Pharmacopoeia).

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

- Impregnation procedure: cohoused
- M/F ratio per cage: 2 / 5
- Length of cohabitation: overnight
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

During days 7-15 of gestation

Frequency of treatment:

Once daily

Duration of test:

Until gestation day 20 or natural labor; naturally born pups were observed until age of 10 weeks

No. of animals per sex per dose:

21-23 females/dose

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: based on the dose-range finding study

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: daily

FOOD CONSUMPTION : Yes / No / No data
- Time schedule for examinations: daily


OTHER: spleen weights of pregnant dams were examined

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: sex ratio

Fetal examinations:

- External examinations: Yes: [all per litter ]
- Soft tissue examinations: Yes: [ca. 1/3 per litter ]
- Skeletal examinations: Yes: [ca. 2/3 per litter ]
- Head examinations: No

Statistics:

x2 test (death rate of dams), the t test (dam body weight, feed intake volume, number of corpora lutea, implant number and spleen weight, fetus number and weight, and the newborn number, body weight, and weight of important organs), and the rank sum test (fetus death rate, frequency of malformations, number of bone variations, delivery rate, suckling rate, and survival rate of newborns)

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
The 31.25 and 62.5mg/kg groups showed the same body weight increases as the control group, and no abnormalities in the normal state were seen, nor were there any examples of deaths. In the 125mg/kg group, while no change in the average weight trend was seen, minor cases of diarrhea were observed in 5 rats out of 22 rats from the 6th day after start of administration (gestation day 12) through the 8th day (gestation day 14). In the 250 mg/kg group, minor suppression of body weight increase was seen from the 2nd day after start of administration (gestation day 8), and in all cases piloerection, diarrhea, bleeding around the eyes, and debilitation were observed, with 7 rats out of 21 dying between gestation day 9 and day 13. The pregnant rats that avoided death continued to show minor suppression of body weight increase even after administration was ended.
A drop in feed intake volume was seen for the control group and for each of the ZDEC groups on the 2nd day after the start of administration (gestation day 8). The feed intake volume during the gestation period for the groups at 125 mg/kg and lower showed no major difference when compared with the control group. In the 250 mg/kg group, the feed intake volume was lower than the control group from the 2nd day after start of administration (gestation day 8) through the 6th day (gestation day 12). From the 7th day of administration, however, it showed generally the same trend as the control group.

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No significant differences were found in the number of corpora lutea, implantations sites, implantation rates, live and dead fetuses, sex ratio and fetus weights between the controls and the test groups. In the external abnormality test, no abnormal fetuses were observed in the control group, and in the ZDEC groups of 125 mg/kg or less. In the 250 mg/kg group, one case of a fetus with a cleft palate was found. However, this occurrence rate was 0.6%, and was not a significant difference when compared with the control group. In the internal organs test, no abnormal fetuses were observed among the surviving fetuses. Abnormalities thought to be skeletal malformations were not observed in the control group and in the ZDEC groups of 125 mg/kg or less. In the 250 mg/kg group, one case of a fetus with a cleft palate was found (0.8%). However, this occurrence frequency of skeletal malformation fetuses was low, and was not a significant difference when compared with the control group.
Abnormalities that could be considered skeletal deformations were observed in all groups, including the control group. Cervical ribs were observed in 1.5 to 8.9% of all groups. Fetuses with shortened or split cervical arches were observed in 1.7% of the 62.5 mg/kg group and 4.2% of the 250 mg/kg group. Deformations (vestigial conditions, dual sphere conditions) of the thoracic centra were observed in 3.0 to 11.0% of all groups, split thoracic centra was observed in 2.7% of the control group, 1.6% of the 31.25 mg/kg group, 0.7% of the 62.5 mg/kg group, and 2.2% of the 250 mg/kg group. Fetuses with sternebrae abnormalities (deformation, splitting, fusion, deficiency) included 64.0% of the control group, 59.7% of the 31.25 mg/kg group, 63.6% of the 62.5 mg/kg group, 64.1% of the 125 mg/kg group, and 81.4% of the 250 mg/kg group. Lumbar ribs were observed in 31.1 to 58.5% of all groups, including the control group. Shortened pubic bones were observed in 0.8% of the 31.25 mg/kg group. Nevertheless, the occurrence rates for these skeletal deformations did not show significant differences between the control group and the ZDEC dosage groups.
For the ossification state, the bone number for the metacarpal bone, metatarsal bone, and sacro-cardal vertebrae was determined. In every case, there was no significant difference in bone number between the target group and the ZDEC dosage groups.
No significant differences in body weight were observed between the test groups and control groups up till the age of 10 weeks, when the study was terminated. For the ear auricle extension, tooth bud collapse or emergence, fur emergence, eyelid opening, and timing for testes descent and vagina opening of newborn pups, each measurement period showed no significant difference between the control group and the ZDEC dosage groups.

Remarks on result:

other: Embryotoxic / teratogenic effects:no effects

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

In the present study, the NOAEL for maternal toxicity of zinc bis(diethyldithiocarbamate) was 125 mg/kg bw/day (Based on clinical signs of toxicity and mortality at the next dose level) and the NOAEL for developmental toxicity was 250 mg/kg bw/day (No adverse effects on the highest dose tested)
Dithiocarbamates are related compounds to xanthates. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium or potassium hydroxide: They arise from the reaction of the amine with CS2.

Reference 2

Endpoint:

developmental toxicity

Type of information:

other: published data

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 is both a reagent in the manufacture, as well as a decomposition product of xanthates. SEX 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 SEX.

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

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:

maternal abnormalities

Remarks on result:

other: developmental toxicity

Dose descriptor:

NOAEC

Effect level:

600 ppm

Based on:

test mat.

Basis for effect level:

maternal abnormalities

other: maternal toxicity

Remarks on result:

other: maternal toxicity

Dose descriptor:

NOAEC

Effect level:

948 mg/m³ air

Based on:

test mat.

Basis for effect level:

maternal abnormalities

other: developmental toxicity

Remarks on result:

other: developmental toxicity

Dose descriptor:

NOAEC

Effect level:

1 896 mg/m³ air

Based on:

test mat.

Basis for effect level:

maternal abnormalities

Remarks on result:

other: maternal toxicity

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:

600 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

fetal/pup body weight changes

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. SEX 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 SEX.

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

250 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

948 mg/m³

Study duration:

subacute

Species:

rabbit

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

6.25 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

For dermal exposure we taken that:
-the average weight of rats is 250g (200-300g),
-the dose is applied over an area which is approximately 10% of the total body surface=0.025 kg
 corrected dermal NOAEL=   oral NOAEL
250 mg/kg bw/dayx0.025 kg =                  
 NOAELrat  = 6.25 mg/kg bw/day

Additional information

Oral exposure

In the study of Nakaura S, et al. 1984, the NOAEL for maternal toxicity of zinc bis(diethyldithiocarbamate) was 125 mg/kg bw/day (Based on clinical signs of toxicity and mortality at the next dose level) and the NOAEL for developmental toxicity was 250 mg/kg bw/day (No adverse effects on the highest dose tested)

Dithiocarbamates are related compounds to xanthates. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium or potassium hydroxide: They arise from the reaction of the amine with CS2.

Dermal exposure:

For dermal exposure we taken that:

-the average weight of rats is 250g (200-300g),

-the dose is applied over an area which is approximately 10% of the total body surface=0.025 kg

 corrected dermal NOAEL=   oral NOAEL

250 mg/kg bw/dayx0.025 kg =                  

 NOAELrat  = 6.25 mg/kg bw/day

Inhalation exposure:

In the study of PAI (Pathology Associates, Inc.). 1991, the substance was embryotoxic, developmentally toxic at exposure levels of 300 ppm (948mg/m3) and above, while overt maternal toxicity was observed only at the 1200 ppm exposure level.

Toxicity to reproduction: other studies

Link to relevant study records

Reference

Endpoint:

toxicity to reproduction: other studies

Type of information:

other: published data

Adequacy of study:

supporting 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 is both a reagent in the manufacture, as well as a decomposition product of xanthates. SEX 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 SEX.

Qualifier:

no guideline followed

Principles of method if other than guideline:

CS2 was administer intraperitoneally to male rats in order to examine alterations in reproductive hormones, testicular tissue and epididymis.

GLP compliance:

not specified

Type of method:

in vivo

Species:

rat

Strain:

other: Charles-Foster

Sex:

male

Route of administration:

intraperitoneal

Vehicle:

cotton seed oil

Details on exposure:

Different dosages of CS2 dissolved in maruti micro reined cotton seed oil viz. 25,50,100 and 200 mg/kg body weight daily were administered intraperitoneally over a period of 30 days

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

30 days

Frequency of treatment:

daily

Duration of test:

30 days

Remarks:

Doses / Concentrations:
0, 25, 50, 100 mg
Basis:
nominal conc.

No. of animals per sex per dose:

10

Control animals:

yes, concurrent no treatment

yes, concurrent vehicle

Details on study design:

Different dosages of CS2 dissolved in maruti micro reined cotton seed oil viz. 25,50,100 and 200 mg/kg body weight daily were administered intraperitoneally over a period of 30 days. Pathomorphological changes and functional impairments were observed in male reproductive organs. Significant decrease in serum testosterone levels and marked degenerative changes in testicular tissue were observed specially in 100 and 200 mg/kg CS2 treated rats.

Dose descriptor:

LOAEC

Effect level:

25 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

other: decreased serum testosterone levels, histologic findings

decreased serum testosterone levels, histologic findings

Table 1: Effects of different doses of CS2 on serum testosterone levels

and tissue weights of rats.

Dose (mg/kg bw)	Testosterone (ng/dl)	Testis (mg)	Epididymis (mg)
Control	540±37.32	1.35±0.08	33±2
Vehicle control	504.5±52.22	1.32±0.07	36.4±1.4
25	224.3±17.35*	1.27±0.07	35.3±2.2
50	207.77±23.32*	1.32±0.13	33.2±2.3
100	84±29.88*	1.37±0.12	32.7±2.4
200	31.6±3.09*	1.34±0.06	33.3±0.3

*p < 0.001

CS2 exposure exerted reductions in body weights, that were remarkable after treatment with the 2 highest doses. Exposure to all concentrations resulted in a significant dose-dependent decline in serum testorone levels, while no alterations were recorded in the testicular and epididymal weights. The histologic examinations revealed no changes in the epididymis. The testis were evidently affected with ' thickening of peritubular membrane, rupturing of seminiferous basement membrane, degeneration and disorganization of spermatogonial cells and less number or absence of sperms in the lumen'. Such effects were much more pronounced at the last two groups.

 

Conclusions:

The present observations clearly indicate effects of CS2 on the male reproduction system. Nonetheless, the relevance of the study is questionable due to the invasive route of exposure.
Carbon disulphide is both a reagent in the manufacture, as well as a decomposition product of xanthates. SEX 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 SEX.

Executive summary:

Deleterious effects of short term exposure of CS2 were investigated on reproductive organs of male albino rats. Different dosages of CS2 dissolved in maruti micro reined cotton seed oil viz. 25,50,100 and 200 mg/kg body weight daily were administered intraperitoneally over a period of 30 days. Pathomorphological changes and functional impairments were observed in male reproductive organs. Significant decrease in serum testosterone levels and marked degenerative changes in testicular tissue were observed specially in 100 and 200 mg/kg CS2 treated rats. Diminution of serum testosterone levels and degeneration in Leydig ceils indicate a definite alterations in the process of steroidogenesis after CS2treatment. Pronounced changes in testicular structure indicated plausible effect on sper­matogenesis. Further, androgenic deficiency, evident by decrease in testosterone level after CS2 treatment produced alterations in epididymis.

Additional information

Deleterious effects of short term exposure of CS2 were investigated on reproductive organs of male albino rats. Different dosages of CS2 dissolved in maruti micro reined cotton seed oil viz. 25,50,100 and 200 mg/kg body weight daily were administered intraperitoneally over a period of 30 days. Pathomorphological changes and functional impairments were observed in male reproductive organs. Significant decrease in serum testosterone levels and marked degenerative changes in testicular tissue were observed specially in 100 and 200 mg/kg CS2 treated rats. Diminution of serum testosterone levels and degeneration in Leydig ceils indicate a definite alterations in the process of steroidogenesis after CS2treatment. Pronounced changes in testicular structure indicated plausible effect on sper­matogenesis. Further, androgenic deficiency, evident by decrease in testosterone level after CS2 treatment produced alterations in epididymis.

The present observations clearly indicate effects of CS2 on the male reproduction system. Nonetheless, the relevance of the study is questionable due to the invasive route of exposure.

Carbon disulphide is both a reagent in the manufacture, as well as a decomposition product of xanthates. SEX 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 SEX.

Justification for classification or non-classification

Based on the hazard assessment of SEX in section 2.1 and 2.2. in IUCLID 6, available data for the substance and following the “Guidance on Information Requirement and Chemical Safety Assessment R.8. Characterisation of dose [concentration]- response for human health” and according to the criteria described in Directive 67/548 and in the CLP Regulation:

Directive 67/548

Toxicity to reproduction/development Repr. Cat. 1; R61 May cause harm to the unborn child. Repr. Cat. 2; R61 May cause harm to the unborn child. Repr. Cat. 3; R63 Possible risk of harm to the unborn child. Toxicity to reproduction/fertility  Repr. Cat. 1; R60 May impair fertility. Repr. Cat. 2; R60 May impair fertility. Repr. Cat. 3; R62 Possible risk of impaired fertility

CLP

Reproductive toxicity Repr. 1A Repr. 1B Repr. 2 H360: May damage fertility or the unborn child <state specific effect if known > <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>. H361: Suspected of damaging fertility or the unborn child <state specific effect if known> <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>.

 

It is concluded that the substance SEX does not meet the criteria to be classified for human health hazards for Reproductive toxicity