GHS Classification Result

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GENERAL INFORMATION
Item Information
CAS RN 97-77-8
Chemical Name Tetraethylthiuram disulfide (Disulfiram)
Substance ID H30-B-003-MHLW, MOE
Classification year (FY) FY2018
Ministry who conducted the classification Ministry of Health, Labour and Welfare (MHLW)/Ministry of the Environment (MOE)
New/Revised Revised
Classification result in other fiscal year FY2006  
Download of Excel format Excel file

REFERENCE INFORMATION
Item Information
Guidance used for the classification (External link) GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
UN GHS document (External link) UN GHS document
Definitions/Abbreviations (Excel file) Definitions/Abbreviations
Model Label by MHLW (External link) MHLW Website (in Japanese Only)
Model SDS by MHLW (External link) MHLW Website (in Japanese Only)
OECD/eChemPortal (External link) eChemPortal

PHYSICAL HAZARDS
Hazard class Classification Pictogram
Signal word
Hazard statement
(code)
Precautionary statement
(code)
Rationale for the classification
1 Explosives Not applicable
-
-
- - There are no chemical groups associated with explosive properties present in the molecule.
2 Flammable gases (including chemically unstable gases) Not applicable
-
-
- - Solid (GHS definition)
3 Aerosols Not applicable
-
-
- - Not aerosol products.
4 Oxidizing gases Not applicable
-
-
- - Solid (GHS definition)
5 Gases under pressure Not applicable
-
-
- - Solid (GHS definition)
6 Flammable liquids Not applicable
-
-
- - Solid (GHS definition)
7 Flammable solids Classification not possible
-
-
- - There is information that it is flammable (HSDB (Accessed Jun. 2018)), but the classification is not possible due to no data.
8 Self-reactive substances and mixtures Not applicable
-
-
- - There are no chemical groups present in the molecule associated with explosive or self-reactive properties.
9 Pyrophoric liquids Not applicable
-
-
- - Solid (GHS definition)
10 Pyrophoric solids Classification not possible
-
-
- - No data available.
11 Self-heating substances and mixtures Classification not possible
-
-
- - Test methods applicable to solid (melting point <= 140 deg C) substances are not available.
12 Substances and mixtures which, in contact with water, emit flammable gases Not applicable
-
-
- - The chemical structure of the substance does not contain metals or metalloids (B, Si, P, Ge, As, Se, Sn, Sb, Te, Bi, Po, At).
13 Oxidizing liquids Not applicable
-
-
- - Solid (GHS definition)
14 Oxidizing solids Not applicable
-
-
- - Organic compounds containing no oxygen, fluorine or chlorine.
15 Organic peroxides Not applicable
-
-
- - Organic compounds containing no bivalent -O-O- structure in the molecule.
16 Corrosive to metals Classification not possible
-
-
- - Test methods applicable to solid substances are not available.

HEALTH HAZARDS
Hazard class Classification Pictogram
Signal word
Hazard statement
(code)
Precautionary statement
(code)
Rationale for the classification
1 Acute toxicity (Oral) Not classified
-
-
- - [Rationale for the Classification]
According to (1) -(6), one case corresponds to Category 4, three cases to "Not classified" (Category 5 in UN GHS classification), and two cases to "Not classified." Therefore, it was classified as "Not classified" (Category 5 in UN GHS classification) with more cases.

[Evidence Data]
(1) LD50 value for rats: 8,600 mg/kg (ACGIH (7th, 2001), NTP TR166 (1979))
(2) LD50 value for rats: 4,573 mg/kg (female) (NICNAS IMAP (Accessed Jun. 2018))
(3) LD50 value for rats: >5,200 mg/kg (male) (NICNAS IMAP (Accessed Jun. 2018))
(4) LD50 value for rats: 1,300 mg/kg (DFGOT vol. 5 (1993))
(5) LD50 value for rats: 2,500 mg/kg (DFGOT vol. 5 (1993))
(6) LD50 value for rats: 3,100 mg/kg (DFGOT vol. 5 (1993))
1 Acute toxicity (Dermal) Not classified
-
-
- - [Rationale for the Classification]
From (1), it was classified as "Not classified."

[Evidence Data]
(1) LD50 value for rabbits: >2,000 mg/kg (NICNAS IMAP (Accessed Jun. 2018))
1 Acute toxicity (Inhalation: Gases) Not applicable
-
-
- - [Rationale for the Classification]
Solid (GHS definition)
1 Acute toxicity (Inhalation: Vapours) Classification not possible
-
-
- - [Rationale for the Classification]
Classification not possible due to lack of data. Besides, the vapor pressure is 0.116 Pa (Howard (1997), estimated value), and it is slightly sublimable.
1 Acute toxicity (Inhalation: Dusts and mists) Classification not possible
-
-
- - [Rationale for the Classification]
Classification not possible due to lack of data.
2 Skin corrosion/irritation Not classified
-
-
- - [Rationale for the Classification]
Based on evidence (1)-(4) that this substance is not skin irritating, it was classified as "Not classified."

[Evidence Data]
(1) There is a report that a drunken-like effect was seen due to exposure with workers at a manufacturing plant, but it is also known that skin irritation is generally seen at the time of perspiration, and minimal skin irritation was observed in only 9% of the overall. In addition, exposure concentrations were not determined (ACGIH (7th, 2001)).
(2) There is a report that in a skin irritation test (corresponds to OECD TG 404, n=6) with rabbits, when this substance was applied for 4 hours, PII (skin primary irritation index) was 0.13 (maximum 8) (NICNAS IMAP (Accessed Jun. 2018), REACH registration dossier (Accessed Jun. 2018))
(3) There is a report that in a skin irritation test (corresponds to OECD TG 404, GLP-compliant) with rabbits, when this substance was applied for 24 hours, the erythema score was 0.25, but recovery was complete in 3 days, and the edema score was 0 (NICNAS IMAP (Accessed Jun. 2018), REACH registration dossier (Accessed Jun. 2018)).
(4) There is a report that in a skin irritation test (corresponds to OECD TG 404, GLP-compliant) with rabbits, when this substance was applied for 24 hours, the erythema score was 0.96, but recovery was complete in 7 days, and the edema score was 0 (NICNAS IMAP (Accessed Jun. 2018), REACH registration dossier (Accessed Jun. 2018)).
3 Serious eye damage/eye irritation Not classified
-
-
- - [Rationale for the Classification]
Based on (1) and (2), it was classified as "Not classified" (Category 3 in UN GHS classification). Besides, the category was changed from the previous classification by use of the new information sources.

[Evidence Data]
(1) There is a report that in an eye irritation test (corresponds to OECD TG405, n=6, GLP-compliant) with rabbits, when this substance was applied, the average scores for 24-72 hours were 0 (6/6 animals) for corneal opacity and 0.33 (2/6 animals) for iritis, and recovery was complete in 7 days (NICNAS IMAP (Accessed Jun. 2018), REACH registration dossier (Accessed Jun. 2018)).
(2) There is a report that in an eye irritation test (corresponds to OECD TG405, n=6) with rabbits, when this substance was applied, the average scores for 24-72 hours were 0.17 for corneal opacity, 0.17 for iritis, 0.94 for conjunctival redness and 0.67 for conjunctival edema, and recovery was complete in 7 days (NICNAS IMAP (Accessed Jun. 2018), REACH registration dossier (Accessed Jun. 2018)).
4 Respiratory sensitization Classification not possible
-
-
- - [Rationale for the Classification]
Classification not possible due to lack of data.
4 Skin sensitization Category 1


Warning
H317 P302+P352
P333+P313
P362+P364
P261
P272
P280
P321
P501
[Rationale for the Classification]
Based on (1)-(5), it is considered that this substance is a skin sensitizer in humans, therefore, it was classified in Category 1. Besides, the category was changed from the previous classification by using new information sources.

[Evidence Data]
(1) There is a report that dermatitis was seen intermittently for 10 months on the forearm and face of a 40-year-old female nurse who handled disulfiram tablets, and it worsened even after wearing rubber gloves, but she recovered on holidays and weekends, and when a patch test was conducted, she showed a positive reaction to this substance and a thiuram mixture (DFGOT (1997, Accessed Jun. 2018), Initial Risk Assessment Report (Ministry of Health, Labour and Welfare, 2018)).
(2) There is a report that this substance not only has skin sensitizing ability but also cross-reacts with dithiocarbamate (DFGOT (1997, Accessed Jun. 2018), Initial Risk Assessment Report (Ministry of Health, Labour and Welfare, 2018)).
(3) There is a report that in 408 workers suspected of contact dermatitis, reactions were seen in 185 workers at patch tests against rubber chemicals, of whom 92 workers showed reactions to this substance (DFGOT (1997, Accessed Jun. 2018), Initial Risk Assessment Report (Ministry of Health, Labour and Welfare, 2018)).
(4) There is a report that in a sensitization test with 2,260 people, 108 subjects (4.8%) showed a response to this substance, 78 of them also showed a response to components of the thiuram preparation (DFGOT (1997, Accessed Jun. 2018), Initial Risk Assessment Report (Ministry of Health, Labour and Welfare, 2018)).
(5) There is a report that in a patch test with 3,851 contact dermatitis patients, 145 patients (3.8%) had a response to thiuram preparations and 9 of 35 patients (29%) had a response to this substance (DFGOT (1997, Accessed Jun. 2018), Initial Risk Assessment Report (Ministry of Health, Labour and Welfare, 2018)).

[Reference Data, etc.]
(6) The Ministry of Health, Labor and Welfare concluded that the substance is skin sensitizing (Initial Risk Assessment Report (Ministry of Health, Labour and Welfare, 2018)).
(7) This substance was classified as "Skin Sens. 1" by EU CLP.
5 Germ cell mutagenicity Classification not possible
-
-
- - [Rationale for the Classification]
Based on (1)-(3), it was classified as "Classification not possible" in accordance with the GHS Classification Guidance for the Japanese Government.

[Evidence Data]
(1) As for in vivo somatic cell mutagenicity tests, it was negative in a chromosomal aberration test with rats and a micronucleus test with mice (Initial Risk Assessment Report (Ministry of Health, Labour and Welfare, 2018)).
(2) As for in vivo genotoxicity tests, an increase in the number of sister chromatid exchanges was reported in a sister chromatid exchange assay in sister chromatid exchange (SCE) assays with mouse bone marrow and spermatogonial cells (NICNAS IMAP (Accessed Jun. 2018), Initial Risk Assessment Report (Ministry of Health, Labour and Welfare, 2018)).
(3) As for in vitro somatic cell mutagenicity tests, a chromosomal aberration test with human peripheral blood lymphocytes was negative and a mouse lymphoma assay was positive (Initial Risk Assessment Report (Ministry of Health, Labour and Welfare, 2018), DFGOT vol. 5 (1993), ACGIH (7th, 2001), NICNAS IMAP (Accessed Jun. 2018)).

[Reference Data, etc.]
(4) As for other in vitro tests, bacterial reverse mutation tests were negative, and a sister chromatid exchange test and a DNA strand break test with cultured mammalian cells were positive (Initial Risk Assessment Report (Ministry of Health, Labour and Welfare, 2018), DFGOT vol. 5 (1993), ACGIH (7th, 2001), NICNAS IMAP (Accessed Jun. 2018)).
(5) The Ministry of Health, Labor and Welfare concluded that it is not possible to judge the genotoxicity of this substance (Initial Risk Assessment Report (Ministry of Health, Labour and Welfare, 2018)).
6 Carcinogenicity Classification not possible
-
-
- - [Rationale for the Classification]
As for carcinogenicity, there is no available report on humans.
Since the reliability of the initial test results of (2)-(4) were judged to be insufficient, it was classified as "Classification not possible" also based on classifications by other organizations in (1). Besides, the Ministry of Health, Labor and Welfare concluded that it is not possible to judge the carcinogenicity of this substance in humans (Initial Risk Assessment Report (Ministry of Health, Labour and Welfare, 2018)).

[Evidence Data]
(1) As for classification results by domestic and international organizations, it was classified in Group 3 by IARC (IARC 12 (1976)) and in A4 by ACGIH (ACGIH (7th, 2001)).

[Reference Data, etc.]
(2) In studies in which two strains of mice were administered by feeding at 100 mg/kg/day up to 4 weeks old and then at 323 ppm up to about 78 weeks old, increases in lung adenoma and liver tumors (hepatoma) in males of one strain and an increase in subdermal fibrosarcoma in males of the other strain were observed. IARC pointed out that the subdermal fibrosarcoma after oral administration of chemicals are extremely unusual, therefore, the above findings are questionable (IARC 12 (1976), Initial Risk Assessment Report (Ministry of Health, Labour and Welfare, 2018)).
(3) In a study in which this substance was administered by gavage to male rats twice a week (500 mg/kg/week, unspecified administration period), the mean survival period was 65 weeks, and benign interstitial cell tumors of the testis were observed in two animals. However, the IARC working group pointed out that the duration of this study was inadequate (IARC 12 (1976), Initial Risk Assessment Report (Ministry of Health, Labour and Welfare, 2018)).
(4) In carcinogenicity studies by feeding male and female rats at 300 or 600 ppm for 107 weeks, and male mice at 500 or 2,000 ppm and female mice at 100 or 500 ppm for 108 weeks, although dose-related low body weight was observed throughout the study period in the dose groups of males and females of rats and mice, no carcinogenicity was observed (NTP TR166 (1979), Initial Risk Assessment Report (Ministry of Health, Labour and Welfare, 2018)).
7 Reproductive toxicity Category 2


Warning
H361 P308+P313
P201
P202
P280
P405
P501
[Rationale for the Classification]
From the report on humans in (1) and the reports on animal experiments in (2), it is judged that conclusive judgement on the teratogenicity is difficult, and there is no finding which should be considered as evidence of the classification for other developmental effects. On the other hand, since according to (3), in the two-generation study with rats, the decrease in the number of pups was observed at the general toxic dose of parental animals, it was classified in Category 2. Besides, The Ministry of Health, Labor and Welfare concluded that it is not possible to judge the reproductive toxicity of this substance as an evaluation with emphasis on teratogenicity and fetotoxicity (Initial Risk Assessment Report (Ministry of Health, Labour and Welfare, 2018)).

[Evidence Data]
(1) Although there are multiple reports on malformations of offspring (clubfoot, facial malformations, phocomelia, etc.) associated with ingestion of this substance, it is pointed out that it is not possible to judge this substance is teratogenic in humans because it is difficult to exclude the effects of other substances (Initial Risk Assessment Report (Ministry of Health, Labour and Welfare, 2018), DFGOT (1997, Accessed Jun. 2018)).
(2) Although there are data showing fetotoxicity such as reduced fetal weight and delayed ossification in many developmental toxicity tests with pregnant rats or pregnant mice, there is no report suggesting an increased incidence in malformations (Initial Risk Assessment Report (Ministry of Health, Labour and Welfare, 2018), DFGOT (1997, Accessed Jun. 2018)).
(3) In a two-generation study with rats administered by feeding, decreased body weight gain and decreases in both the litter size and the number of births per mating pair were observed in parental animals by administration of 500 or 1,000 ppm (Initial Risk Assessment Report (Ministry of Health, Labour and Welfare, 2018), DFGOT (1997, Accessed Jun. 2018)).

[Reference Data, etc.]
(4) This substance is used as an anti-alcohol drug against chronic alcoholism but is contraindicated for pregnant women or women who may be pregnant because safety in pregnant women has not been established (Ethical Pharmaceuticals 2018 (2017)).
(5) In the tests with pregnant hamsters and pregnant guinea pigs dosed orally, a development of malformations was observed, but interpretation of the results is difficult for reasons such as reviews of solvent effects or dose relationship were inadequate (Initial Risk Assessment Report (Ministry of Health, Labour and Welfare, 2018)).
8 Specific target organ toxicity - Single exposure Category 1 (nervous system, kidney)


Danger
H370 P308+P311
P260
P264
P270
P321
P405
P501
[Rationale for the Classification]
Based on (1)-(3), since the target organs (findings) by acute exposure of this substance are considered to be the nervous system (depression, areflexia/analgesia, neuropathy, etc.) and kidney (albuminuria) observed in plural cases, it was classified in Category 1 (nervous system, kidney). Besides, gastrointestinal tract (vomiting, etc.) was not adopted as a target organ because it was reported in only one case. Kidney was added as a target organ by using a different information source than the previous classification.

[Evidence Data]
(1) There is a report that in the case of a 10-year-old girl who developed acute toxic symptoms after ingesting 3 g of this substance, drowsiness and mydriasis after 20 hours, vomiting, anxiety, and depression on the second day, ataxia and pyelonephritis with albuminuria on the fourth day, and memory loss on the 3-6th day were observed (DFGOT (1993, Accessed Jun. 2018), Initial Risk Assessment Report (Ministry of Health, Labour and Welfare, 2018)).
(2) There is a report of a case of a 3-year-and-7-month-old child who showed loss of consciousness, cyanosis, dyspnea, areflexia and analgesia 10 hours after ingesting 10 g of this substance, and there is a report that a 24-year-old woman who ingested 10 g of this substance showed nausea, vomiting, gastroenteritis, headache, ataxia and increased albuminuria (DFGOT (1993, Accessed Jun. 2018), Initial Risk Assessment Report (Ministry of Health, Labour and Welfare, 2018)).
(3) There is a report that neuropathy such as nystagmus, convulsions, coma and memory/cognitive impairment were observed in a 15-year-old boy who ingested 10 g of this substance (DFGOT (1993, Accessed Jun. 2018), Initial Risk Assessment Report (Ministry of Health, Labour and Welfare, 2018)).
9 Specific target organ toxicity - Repeated exposure Category 1 (nervous system, cardiovascular system, thyroid, gastrointestinal tract, liver)


Danger
H372 P260
P264
P270
P314
P501
[Rationale for the Classification]
It can be classified in Category 1 (nervous system, cardiovascular vascular system, gastrointestinal tract, liver) from human findings (1)-(2) and in Category 1 (thyroid) from (3). Therefore, it was classified in Category 1 (nervous system, cardiovascular system, thyroid, gastrointestinal tract, liver). Besides, as a result of reviewing the classification results using information sources different than the previous classification, some target organs were added (cardiovascular system, gastrointestinal tract) or deleted (endocrine system: fluctuations in hormone levels such as some thyroid-related hormones and gonadotropins have been reported in humans, but no effect on endocrine system organs other than the thyroid gland of rats was observed).

[Evidence Data]
(1) This substance is an anti-alcohol drug for chronic alcoholism. The severe adverse reaction was psychoneurotic disorder, and there is a report that in rare cases, serious encephalopathy (disorders of orientation, memory disorders, confusion, etc.) appeared. In addition, liver dysfunction accompanied by elevations in AST (GOT), ALT (GPT), gamma-GTP, LDH, ALP, bilirubin etc., and jaundice may appear (Ethical Pharmaceuticals 2018 (2017)).
(2) As for other side effects, gastrointestinal tract disorders (nausea, vomiting, abdominal cramps, diarrhea, constipation), nervous system disorders (drowsiness, headache, polyneuropathy, peripheral neuritis), cardiovascular disorders (pallor, hypotension, vasodilation, tachycardia, arrhythmia, myocardial infarction), in addition, although very rare, cases are reported who developed hepatic dysfunction, hepatitis, jaundice, and, in severe cases, hepatic coma and death (Initial Risk Assessment Report (Ministry of Health, Labour and Welfare, 2018)).
(3) As a result of oral administration to rats at 25 mg/kg/day of this substance for 30 days (converted guidance value: 8.3 mg/kg/day, within the range of Category 1), the weight increase and hyperplasia of the thyroid were observed (DFGOT (1997, Accessed Jun. 2018), Initial Risk Assessment Report (Ministry of Health, Labour and Welfare, 2018)).
10 Aspiration hazard Classification not possible
-
-
- - [Rationale for the Classification]
Classification not possible due to lack of data.

ENVIRONMENTAL HAZARDS
Hazard class Classification Pictogram
Signal word
Hazard statement
(code)
Precautionary statement
(code)
Rationale for the classification
11 Hazardous to the aquatic environment (Acute) Classification not possible
-
-
- - Reliable acute toxicity data were not obtained.
11 Hazardous to the aquatic environment (Long-term) Classification not possible
-
-
- - No data available.
12 Hazardous to the ozone layer Classification not possible
-
-
- - No data available.


NOTE:
  • GHS Classification Result by the Japanese Government is intended to provide a reference for preparing a GHS label or SDS for users. To include the same classification result in a label or SDS for Japan is NOT mandatory.
  • Users can cite or copy this classification result when preparing a GHS label or SDS. Please be aware, however, that the responsibility for a label or SDS prepared by citing or copying this classification result lies with users.
  • This GHS classification was conducted based on the information sources and the guidance for classification and judgement which are described in the GHS Classification Guidance for the Japanese Government etc. Using other literature, test results etc. as evidence and including different content from this classification result in a label or SDS are allowed.
  • Hazard statement and precautionary statement will show by hovering the mouse cursor over a code in the column of "Hazard statement" and "Precautionary statement," respectively. In the excel file, both the codes and statements are provided.
  • A blank or "-" in the column of "Classification" denotes that a classification for the hazard class was not conducted in the year.

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