Registration Dossier

Administrative data

Endpoint:
biotransformation and kinetics
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)

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1965
Reference Type:
review article or handbook
Title:
Priority existing chemical Report No. 5s
Author:
Dep. of Health and Ageing, Australian Government
Year:
2000
Bibliographic source:
National Industrial Chemicals Notification and Assessment Scheme

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Xanthates are metabolised in humans and animals to CS2.Carbon disulfide and/or its metabolite 2-thiothiazolidine-4-carboxylic acid (TTCA) have been measured at part-per-billion levels in virtually all samples of breath, blood, urine or breast milk of subjects.
GLP compliance:
not specified
Type of medium:
other: animal and human

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
solid: compact

Results and discussion

Any other information on results incl. tables

Biotransformation to CS2

Sodium isobutyl 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 sodium isobutyl xanthate.

 

Xanthates are metabolised in humans and animals to CS2. Animal data for xanthates indicate that up to 7% of dose may be eliminated as CS2 in breath. The elimination vs time curves for sodiumisobutylxanthate in humansand guinea pigs indicate that biotransformation to CS2 is not saturated at dosesstudied (250 mg or 3.5 mg/kg in humans).

 

It is known that sodium isobutyl xanthate is metabolised to CS2 due to the presenceof the CS2/cysteine (glutathione) conjugation product, 2-thiothiazolidine-4-carboxylic acid (TTCA) in urine of exposed workers.

 

Carbon disulfide and/or its metabolite 2-thiothiazolidine-4-carboxylic acid (TTCA) have been measured at part-per-billion levels in virtually all samples of breath, blood, urine or breast milk of subjects with no known occupational exposure in a number of studies (Pellizzari et al., 1982; Phillips, 1992; Brugnone et al., 1994). This provides support for the data on levels in environmental media, which indicate that humans have environmental exposure to carbon disulfide.

 

A single metabolism study (in French) published by Merlevede and Peters (1965)was identified.In this study, humans and guineapigs were dosed with various xanthate compounds, including sodium andpotassiumisobutylxanthate, and the amount of expired CS2 monitored.

 

Following sub-cutaneous injection (70-200 mg/kg) of potassium ethyl xanthate inguinea pigs, up to 7% of the dose was expired as CS2 after 8 h, with maximumelimination between 1 - 2 h in most animals. The rate of elimination was doserelated,however the total percentage recovered was independent of dose. A morerapid rate of elimination was seen following sub-cutaneous injection (50 and 100mg/kg) of sodium ethyl xanthate, with CS2 expiration complete after 6 h, withmaximum elimination at 1 h (total recovery of CS2 was not reported).

 

Following oral intake in human volunteers, of 150 and 250 mg sodium ethylxanthate, a maximum rate (13 – 57 μg/m3/h) of CS2 elimination in breath wasseen between 1-2 h, with complete elimination by 6 h (total recovery of CS2 wasnot reported).

 

The effect of alcohol on xanthate metabolism was also studied. In guinea pigs,concomitant sub-cutaneous injection of sodium diethyl xanthate and alcoholresulted in an increased rate of elimination, together with a greater total recoveryof CS2. These increases were directly related to the dose of alcohol.

An increased rate of elimination was also apparent in humans administered 250 mg sodium ethyl xanthate, following intake of 200 ml of alcohol (approximately18% by volume), however, the lack of a suitable control group preventedquantitative assessment.

 

 

 

It is generally considered that adverse effects from exposure to xanthates (inhumans and animals) are associated with CS2 toxicity. It is not known what contribution to human toxicity is likely from inhalation/dermal absorption of CS2per se, as a xanthate decomposition product, and CS2 as a xanthate metabolite.

Effects due to the parent xanthate compound or other metabolites might also contribute to overall toxicity.

If metabolism to CS2 is associated with critical effects, then the limited data available on xanthate metabolism indicates that similar toxicological profiles might be expected for animals and humans.

Animal and human studies indicate that the nervous system is the critical targetorgan for CS2 from inhalation exposure. Apparently only one chronic inhalation study has been carried out in animals for CS2 and there are no chronic animal orhuman data pertaining to neurological effectsfollowing dermal exposure(ATSDR 1996).

Notwithstanding the available epidemiological data, it has generally been considered that chronic adverse effects in humans from inhalation exposure toCS2 are associated with levels in excess of 10 ppm2, although further, morerefined dose-response data is required in order to fully characterise chronicNOAELs or LOAELs.

Applicant's summary and conclusion

Conclusions:
Xanthates are metabolised in humans and animals to CS2. Animal data for xanthates indicate that up to 7% of dose may be eliminated as CS2 in breath. The elimination vs time curves for sodium isobutyl xanthate in humans and guinea pigs indicate that biotransformation to CS2 is not saturated at doses studied (250 mg or 3.5 mg/kg in humans).