Potassium O-ethyl dithiocarbonate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

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

Link to relevant study records

Reference

Endpoint:

one-generation reproductive toxicity

Remarks:

based on test type (migrated information)

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Carbon disulphide is both a reagent in the manufacture, as well as a decomposition product of xanthates. Potassium ethyl xanthate readily decomposes to carbon disulphide, especially in the presence of moisture/water. Therefore, the health effects of carbon disulphide (CS2) need to be considered in the assessment of Potassium ethyl xanthate.

Qualifier:

no guideline followed

Principles of method if other than guideline:

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

GLP compliance:

not specified

Limit test:

no

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. Potassium ethyl xanthate readily decomposes to carbon disulphide, especially in the presence of moisture/water. Therefore, the health effects of carbon disulphide (CS2) need to be considered in the assessment of Potassium ethyl xanthate.

Executive summary:

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

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 Potassium ethyl xanthate with regard to reproduction.
It is concluded that the substance Potassium ethyl xanthate 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 Potassium ethyl xanthate with regard to Developmental toxicity / teratogenicity 

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

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

Remarks:

Doses / Concentrations:
31.25, 62.5, 125 and 250 mg/kg bw/day
Basis:
actual ingested

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.

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:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Carbon disulphide is both a reagent in the manufacture, as well as a decomposition product of xanthates. Potassium ethyl xanthate readily decomposes to carbon disulphide, especially in the presence of moisture/water. Therefore, the health effects of carbon disulphide (CS2) need to be considered in the assessment of Potassium ethyl xanthate.

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

Remarks:

Doses / Concentrations:
0, 60, 100, 300, 600, 1200 ppm (0, 190, 316, 948, 1896, 3792 mg/m3)
Basis:
nominal conc.

No. of animals per sex per dose:

24

Control animals:

yes

Details on study design:

- Dose selection rationale: based on dose range finding study were 100, 300, 1000 or 3000 ppm were tested. Exposure to 3000 ppm was lethal to rabbits. Surviving animals in the remaining exposure levels were euthanitized on gestation day 29, cesarean sections were performed, and uterine contents were evaluated. Exposure to 1000 ppm of carbon disulfide did not produce overt maternal toxicity, and only a transient exposure-related anoxia was suggested. However, it produced significant embryo and fetal toxicity. From these data, concentrations of carbon disulfide were selected for the main study.

Maternal examinations:

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

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

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

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29; cesarian sections were performed

Ovaries and uterine content:

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

Fetal examinations:

All fetuses were examined for gross visceral , skeletal and cephalic malformations. Enhanced fetal evaluations included a double stain to evaluate skeletal and cartilaginous malformations. In addition, cephalic evaluations were conducted on all viable fetuses based on results from the dosage range-finding study.

Statistics:

ANOVA, Dunett's test, Fischer's exact test, Chi-Square test, Kruskal- Wallis test

Details on maternal toxic effects:

Maternal toxic effects:yes

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

Dose descriptor:

NOAEC

Effect level:

300 ppm

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Dose descriptor:

NOAEC

Effect level:

600 ppm

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOAEC

Effect level:

948 mg/m³ air

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Dose descriptor:

NOAEC

Effect level:

1 896 mg/m³ air

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

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.

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. Potassium ethyl xanthate readily decomposes to carbon disulphide, especially in the presence of moisture/water. Therefore, the health effects of carbon disulphide (CS2) need to be considered in the assessment of Potassium ethyl xanthate.

Executive summary:

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

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

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. Potassium ethyl xanthate readily decomposes to carbon disulphide, especially in the presence of moisture/water. Therefore, the health effects of carbon disulphide (CS2) need to be considered in the assessment of Potassium ethyl xanthate.

Justification for classification or non-classification

Based on the hazard assessment of Potassium ethyl xanthate in section 2.1 and 2.2. in IUCLID 5.4., 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 Potassium ethyl xanthate does not meet the criteria to be classified for human health hazards for Reproductive toxicity