Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

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-isobutil dithiocarbonic acid

-

-

-

-*

-

 

Table 2. Reproductive toxicity in male adult rats

Compound

AO4

AO5

AO6

RCA Method Expert Call (Overall)

Review expert

O-isobutil dithiocarbonic acid

-

-

-

-*

-

 

Table 3. Reproductive toxicity in male adult mice

Compound

AO7

RCA Method Expert Call (Overall)

Review expert

O-isobutil dithiocarbonic acid

-

-*

-

 

 

Table 4. Sperm toxicity in male adult rodents

Compound

AP1

AP2

AP3

RCA Method Expert Call (Overall)

Review expert

O-isobutil dithiocarbonic acid

-

-

-

-*

-

 

Table 5. Sperm toxicity in male adult rats

Compound

AP4

AP5

AP6

RCA Method Expert Call (Overall)

Review expert

O-isobutil dithiocarbonic acid

-

-

-

-*

-

 

Table 6. Sperm toxicity in male adult mice

Compound

AP7

RCA Method Expert Call (Overall)

Review expert

O-isobutil dithiocarbonic acid

-

-*

-

 

Table 7. Reproductive toxicity in female adult rodents

Compound

AN1

AN2

AN3

AN4

RCA Method Expert Call (Overall)

Review expert

O-isoButil dithiocarbonic acid

-

-

-

-

-*

-

 

Table 8. Reproductive toxicity in female adult rats

Compound

AN5

AN6

AN7

AN8

RCA Method Expert Call (Overall)

Review expert

O-isobutil dithiocarbonic acid

-

-

-

-

-*

-

 

Table 9. Reproductive toxicity in female adult mice

Compound

AN9

RCA Method Expert Call (Overall)

Review expert

O-isobutil 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-isobutil 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 mentioned 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.

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

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.

Justification for classification or non-classification