Sodium O-ethyl dithiocarbonate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Reference 1

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

other: MC4PC version 2.4.1.5

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Principles of method if other than guideline:

AN1-AN9 FDA Reproductive toxicity in females set

GLP compliance:

no

Species:

other: rodents

Dose descriptor:

other:

Basis for effect level:

other: see 'Remark'

Remarks on result:

not measured/tested

Remarks:

Effect level not specified Generation not specified (migrated information)

Remarks on result:

other: (Q)SAR

Remarks:

Effect level not specified Generation not specified (migrated information)

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-ethyl dithiocarbonic acid	-	-	-	-	-*	-

 

Table 9. Reproductive toxicity in female adult mice

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

The probability that the prediction is accurate is 80%.

QPRF and QMRF forms are included.

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.The unknown structural features, which were detected in all test batteries, do not resemble the main structural units of well known developmental toxicant CS2. The tested substance was reported in NICNAS Priority existing chemical assessment report (1995, Vol.6, 66p) and it was not listed there as developmental toxicant for humans, as long as it is used in the conditions, preventing its decomposition, producing carbon disulfide.

Reference 2

Endpoint:

fertility, other

Remarks:

based on test type (migrated information)

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Principles of method if other than guideline:

Sperm toxicity

Species:

other: rodents

Dose descriptor:

other:

Basis for effect level:

other: see 'Remark'

Remarks on result:

not measured/tested

Remarks:

Effect level not specified Generation not specified (migrated information)

Remarks on result:

other: QSAR

Remarks:

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. The unknown structural features, which were detected in all test batteries, do not resemble the main structural units of well known developmental toxicant CS2. The tested substance was reported in NICNAS Priority existing chemical assessment report (1995, Vol.6, 66p) and it was not listed there as developmental toxicant for humans, as long as it is used in the conditions, preventing its decomposition, producing carbon disulfide.

Remarks on result:

other: (Q)SAR

Remarks:

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.

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-ethyl dithiocarbonic acid	-	-	-	-*	-

 

Table 6. Sperm toxicity in male adult mice

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

The probability that the prediction is accurate is 80%.QPRF and QMRF forms are included.

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.The unknown structural features, which were detected in all test batteries, do not resemble the main structural units of well known developmental toxicant CS2. The tested substance was reported in NICNAS Priority existing chemical assessment report (1995, Vol.6, 66p) and it was not listed there as developmental toxicant for humans, as long as it is used in the conditions, preventing its decomposition, producing carbon disulfide.

Reference 3

Endpoint:

toxicity to reproduction

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Guideline:

other:

Principles of method if other than guideline:

ACD/Labs Predicted Values-Estrogen Receptor Binding Affinity. Algorithm Version:v5.0.0.184

Dose descriptor:

other:

Basis for effect level:

other: No binding to Estrogen Receptor Alpha (Log RBA <-3) for the sodium ethyl xanthate (CAS# 140-90-9),

Remarks on result:

not measured/tested

Remarks:

Effect level not specifiedGeneration not specified (migrated information)

Reproductive effects observed:

not specified

No binding to Estrogen Receptor Alpha (Log RBA <-3) for the following compounds:

- sodium ethyl xanthate (CAS# 140-90-9),

- sodium isopropyl xanthate (CAS# 140-93-2),

- sodium isobutyl xanthate (CAS# 25306-75-6)

Conclusions:

No binding to Estrogen Receptor Alpha (Log RBA <-3) for the following compounds:- sodium ethyl xanthate (CAS# 140-90-9),- sodium isopropyl xanthate (CAS# 140-93-2),- sodium isobutyl xanthate (CAS# 25306-75-6)

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Effect on fertility: via inhalation route

Endpoint conclusion:

no adverse effect observed

Effect on fertility: via dermal route

Endpoint conclusion:

no adverse effect observed

Additional information

The results should be considered together with the results of test with the 3FDA Reprotox sets, designed from the FDA archives and openly published results of reproductive toxicity tests date for:

Reproductive toxicity in adult males

• Rodents, full set (AO1, 791 records)
• Rodents part A (AO2, 608 records)
• Rodents part B (AO3,607 records)
• Rat, full set (AO4,721 records)
• Rat, part A (AO5,553 records)
• Rat, part B (AO6,553 records)
• Mouse, full set (AO7,146 records)

Sperm toxicity

• Mammal, full set (AP1,917 records)
• Mammal, part A (AP2,575 records)
• Mammal, part B (AP3,574 records)
• Rat, full set (AP4,730 records)
• Rat, part A (AP5,452 records)
• Rat, part B (AP6,452 records)
• Mouse, full set (AP7,262 records)

Reproductive

• toxicity in females
• Rodents, full set (AN1, 968 records)
• Rodents part A (AN2, 424 records)
• Rodents part B (AN3, 424 records)
• Rodents part C (AN4, 39 records)v
• Rat, full set (AN5,902 records)
• Rat, part A (AN6,455 records)
• Rat, part B (AN7,455 records)
• Rat, part C (AN8,454 records)
• Mouse, full set (AN9,151 records)

 

The results of tests with theFDA ReproTOXsets are summarized in the following tables.

 

Important notice:The RCA method expert call is a computer-generated output that is considered, along with other available information, in formulating the final conclusion.The Final Conclusion is a conclusion made by the reviewer, taking into account all the available evidence, including thein-silicoand available experimental results.

Table 1. Reproductive toxicity in male adult rodents

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

 

Table 2. Reproductive toxicity in male adult rats

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

 

Table 3. Reproductive toxicity in male adult mice

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

 

 

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-ethyl dithiocarbonic acid	-	-	-	-*	-

 

Table 6. Sperm toxicity in male adult mice

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

 

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-ethyl dithiocarbonic acid	-	-	-	-	-*	-

 

Table 9. Reproductive toxicity in female adult mice

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

 

Table 10. Summary of the results and overall conclusions for the reproductive toxicity tests

Compound	Fertility males			Sperm toxicity			Fertility females			The FINAL conclusion
	Rodnts	Rats	Mice	Rodnts	Rats	Mice	Rodnts	Rats	Mice
O-ethyl dithiocarbonic acid	-	-	-	-	-	-	-	-	-	-

 

The RCA paradigm, implemented in the RCA decision support system, requires the following criteria for a chemical to be designated as POSITIVE:

1.     To be active in more than one test assay within a test battery

2.     To be active in a test assay, there must be two or more structurally similar fragments across the modules of the test assay.

Tables 1 - 10 reveal these conditions were not met by test compound in FDA Reproductive Toxicity Set. The unknown structural features, which were detected in all test batteries, do not resemble the main structural units of well known developmental toxicant CS₂. The tested substance was reported in NICNAS Priority existing chemical assessment report (1995, Vol.6, 66p) and it was not listed there as developmental toxicant for humans, as long as it is used in the conditions, preventing its decomposition, producing carbon disulfide. The Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation.

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

The RCA reasoning tool, based on the weight of evidence approach, should be applied. This set of rules was developed and refined to assist the U.S. Food and Drug Administration (FDA) in utilizing categorical model predictions in a regulatory setting for drug safety evaluation, since 1998._(Unpublished internal documents, available upon request from the ICSAS office or MultiCASE. See alsoMatthews EJ, Contrera JF. A new highly specific method for predicting the carcinogenic potential of pharmaceuticals in rodents using enhanced MCASE QSAR-ES software. Regul Toxicol Pharmacol 1998; 28(3):242–264.)According to the RCA rules based evaluation which is summarized in the table above, an alert in order to be relevant and confirmed basing on the weight of evidence approach has to appear in a structurally similar form in more than 2 test modules within a test battery.

The RCA reasoning system based on the results of MC4PC generated predictions are routinely used the ICSAS office of CDER FDA for the research and regulatory support activities. 

 Conclusion:.

 It is concluded that the MultiCASE model/RCA weight of evidence approach is valid for prediction of sodium O-ethyl dithiocarbonate’s effect on reproductive toxicity to humans.

Final conclusion is that the tested chemical is considered to be nonthreatening to humans from this evaluation.

Other QSAR predictions:

ACD/Labs

(http://weblab.acdlabs.com/iLab2/index.php)

CEASAR QSAR model for Developmental Toxicity

 (http://www.ceasar-project.eu)

QSAR TOOLBOX

(QSAR Toolbox Version 2.2 , Client - Server)

The mentioned above QSAR predictions do not indicate reproductive toxicity of xanthates.

Effects on developmental toxicity

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

not specified

Species:

rat

Route of administration:

oral: unspecified

Duration of treatment / exposure:

10 daysgestation day 6-15

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day

Basis for effect level:

other: effect type not specified

Remarks on result:

other: not specified

Remarks:

not specified

Abnormalities:

not specified

Developmental effects observed:

not specified

Reference 2

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

not specified

Species:

rat

Route of administration:

inhalation

Duration of treatment / exposure:

6 hours/day, 6 - 20 day of gestation

No. of animals per sex per dose:

20-23

Dose descriptor:

NOAEL

Effect level:

200 ppm

Basis for effect level:

other: maternal toxicity

Remarks on result:

other: not specified

Abnormalities:

not specified

Developmental effects observed:

not specified

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

chronic

Species:

rat

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

622 mg/m³

Study duration:

chronic

Species:

rat

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

There is no human available information concerning developmental effect for xanthaes.

Reproductive effects of carbon disulfide should be consider because it is a metabolite and decomposition product of xanthates.

Birth defects have been reported in newborns of women workers exposed to carbon disulfide and increased rate of menstrual disorder, toxemia of pregnancy were also reported in case of exposition to 12-18 ppm carbon disulfide.

Decreased sperm count and decreased libido in men and menstrual irregularities in women exposed at the workplace, possible disruptions of the neuro-hormonal-endocrine balance necessary for normal ovarian and uterine cycles may lead to amenorrhea, abnormal menstrual cycles and even to sterility. However, community and workplace studies have not shown a decrease fertility rate , an increase in the time between live births, or an effect on semen quality with carbon disulfide exposure.(“Toxicological Profile for Carbon Disulfide” , U.S. Department of Health and Human Services, Agency for Toxic Substances and Disease Registry, August 2000)

Developmental effect of carbon disulfide (CAS# 75-15-0) have been noticed in the case of women exposed to the chemical at workplace but the data are inadequate to draw any conclusion. Pharmacokinetic studies indicate that carbon disulfide and its metabolites pass the placenta at all stages of gestation and localize in brain, blood, liver, and eyes, but is not identifiable at what level the exposure could produce effects in humans.(“Toxicological Profile for Carbon Disulfide” , U.S. Department of Health and Human Services, Agency for Toxic Substances and Disease Registry, August 2000)

 

Repeated exposure to carbon disulphide vapour can adversely affect the central and peripheral nervous systems, including weakening of the muscles of the legs and damage to the peripheral and cerebral arteries. Carbon disulphide has been shown to contribute towards coronary heart disease in exposed workers, and severe effects on the retina of the eye have been observed. Hearing defects in workers exposed to carbon disulphide have also been reported. Adverse effects on the reproductive system of workers have been noted, including menstrual abnormalities in females and decreased libido and changes in sperm morphology in males.(Sodium Ethyl

Xanthate PRIORITY EXISTING CHEMICAL NO. 5 MAY 1995 AUSTRALIAN GOVERNMENT PUBLISHING SERVICE

CANBERRA)

Summary and discussion of reproductive toxicity

 

There is no human information available concerning reproductive toxicity for xanthates(, CHEMINFO ,2004, ,Chemical Profiles Created by CCOHS , www.ccohs.ca).

According to Horst Spielmann(Environmental HealthPerspectives: Vol. 106, Sup.2 April 1998)a direct influence on the developing organism has not only a given chemical but also its active metabolites. Toxicokinetic and metabolism studies are very important for the interpretation of the developmental toxicity.

Carbon disulfide (CAS# 75-15-0) is the main metabolite of xanthates, and it is consider as an active reproductive and developmental toxicant.