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Direct observations: clinical cases, poisoning incidents and other

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Administrative data

Endpoint:
direct observations: clinical cases, poisoning incidents and other
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: A published study containing sufficient details to regard it as reliable for use in hazard assessment. Limited experimental detail provided.

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Metabolism of xanthates in man and guinea pig
Author:
Merlevede E and Peters
Year:
1965
Bibliographic source:
Archives of the Belgian Medical Society, 23(8): 513-551
Reference Type:
study report
Title:
Unnamed
Year:
2000

Materials and methods

Study type:
study with volunteers
Endpoint addressed:
basic toxicokinetics
acute toxicity: oral
Test guideline
Qualifier:
no guideline available
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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
solid: compact
Details on test material:
- Name of test material (as cited in study report):sodium ethyl xanthate

Method

Type of population:
occupational
Subjects:
human volunteers
Ethical approval:
confirmed, but no further information available
Route of exposure:
oral
Reason of exposure:
intentional
Exposure assessment:
measured
Details on exposure:
Following oral intake in human volunteers, of 150 and 250 mg sodium ethyl xanthate, a maximum rate (13 – 57 μg/m3/h) of CS2 elimination in breath was seen between 1-2 h, with complete elimination by 6 h (total recovery of CS2 wasnot reported).
Examinations:
Humans and guinea pigs were dosed with various xanthate compounds, including sodium and potassium isobutyl xanthate, and the amount of expired CS2 monitored.

Results and discussion

Results of examinations:
Following oral intake in human volunteers, of 150 and 250 mg sodium ethyl xanthate, a maximum rate (13 – 57 μg/m3/h) of CS2 elimination in breath was seen 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 alcohol resulted in an increased rate of elimination, together with a greater total recovery of 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 (in humans and animals) are associated with CS2 toxicity. It is not known whatcontribution 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 profilesmight be expected for animals and humans.

Any other information on results incl. tables

Metabolism

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 sodium isobutyl xanthate in humans and 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.

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).
Executive summary:

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

Following sub-cutaneous injection (70-200 mg/kg) of potassium ethyl xanthate in guinea pigs, up to 7% of the dose was expired as CS2 after 8 h, with maximum elimination between 1 - 2 h in most animals. The rate of elimination was dose related,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 ethyl xanthate, 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 250mg sodium ethyl xanthate, following intake of 200 ml of alcohol (approximately18% by volume), however, the lack of a suitable control group preventedquantitative assessment.