GHS Classification Results by the Japanese Government
GENERAL INFORMATION
REFERENCE INFORMATION
PHYSICAL HAZARDS
HEALTH HAZARDS
ENVIRONMENTAL HAZARDS
NOTE:
GENERAL INFORMATION
| Item | Information |
|---|---|
| CAS RN | 121-75-5 |
| Chemical Name | O,O-Dimethyl-S-1,2-bis(ethoxycarbonyl)ethyl dithiophosphate; Malathion |
| Substance ID | R02-B-057-MHLW, MOE |
| Classification year (FY) | FY2020 |
| 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 FY2016 |
| Download of Excel format | Excel file |
REFERENCE INFORMATION
| Item | Information |
|---|---|
| Guidance used for the classification (External link) | GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0)) |
| 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 |
| Hazard class | Classification | Pictogram Signal word |
Hazard statement (code) |
Precautionary statement (code) |
Rationale for the classification | |
|---|---|---|---|---|---|---|
| 1 | Explosives | Not classified (Not applicable) |
- |
- | - | There are no chemical groups associated with explosive properties present in the molecule. It was classified as "Not classified." |
| 2 | Flammable gases | Not classified (Not applicable) |
- |
- | - | Liquid (GHS definition). It was classified as "Not classified." |
| 3 | Aerosols | Not classified (Not applicable) |
- |
- | - | Not aerosol products. It was classified as "Not classified." |
| 4 | Oxidizing gases | Not classified (Not applicable) |
- |
- | - | Liquid (GHS definition). It was classified as "Not classified." |
| 5 | Gases under pressure | Not classified (Not applicable) |
- |
- | - | Liquid (GHS definition). It was classified as "Not classified." |
| 6 | Flammable liquids | Not classified |
- |
- | - | It was classified as "Not classified" from a flash point of 163 deg C (closed cup) (ICSC (2019)). |
| 7 | Flammable solids | Not classified (Not applicable) |
- |
- | - | Liquid (GHS definition). It was classified as "Not classified." |
| 8 | Self-reactive substances and mixtures | Not classified (Not applicable) |
- |
- | - | There are no chemical groups present in the molecule associated with explosive or self-reactive properties. It was classified as "Not classified." |
| 9 | Pyrophoric liquids | Classification not possible |
- |
- | - | No data available. |
| 10 | Pyrophoric solids | Not classified (Not applicable) |
- |
- | - | Liquid (GHS definition). It was classified as "Not classified." |
| 11 | Self-heating substances and mixtures | Classification not possible |
- |
- | - | Classification is not possible because test methods applicable to liquid substances are not available. |
| 12 | Substances and mixtures which, in contact with water, emit flammable gases | Not classified |
- |
- | - | It contains a metalloid (P), but it was classified as "Not classified" because it is estimated that it does not react vigorously with water from water solubility data of 143 mg/L (20 deg C) (HSDB (Access on May 2020)). |
| 13 | Oxidizing liquids | Classification not possible |
- |
- | - | The substance is an organic compound containing oxygen (but not fluorine or chlorine), which is chemically bonded to the element other than carbon or hydrogen (P). However, the classification is not possible due to no data. |
| 14 | Oxidizing solids | Not classified (Not applicable) |
- |
- | - | Liquid (GHS definition). It was classified as "Not classified." |
| 15 | Organic peroxides | Not classified (Not applicable) |
- |
- | - | Organic compounds containing no bivalent -O-O- structure in the molecule. It was classified as "Not classified." |
| 16 | Corrosive to metals | Classification not possible |
- |
- | - | No data available. Besides, there is information that it attacks iron and other metals (HSDB (Access on May 2020)). |
| 17 | Desensitized explosives | Not classified (Not applicable) |
- |
- | - | There are no chemical groups associated with explosive properties present in the molecule. It was classified as "Not classified." |
| 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] It was classified as "Not classified" from (1) - (5). [Evidence Data] (1) LD50 for rats: 8,000 mg/kg (purity: 98.2%) (Canada Pesticides (2010)) (2) LD50 for rats: 8,200 mg/kg (purity: 99.1%) (Canada Pesticides (2010)) (3) LD50 for rats: 8,227 mg/kg (purity: 99.1%) (JMPR (2016)) (4) LD50 for rats: 9,500 mg/kg (purity: 99.3%) (ATSDR (2003), OEL Documentations (Japan Society For Occupational Health (JSOH), 1989)) (5) LD50 for rats: 10,700 mg/kg (recrystalized) (OEL Documentations (Japan Society For Occupational Health (JSOH), 1989)) [Reference Data, etc.] (6) LD50 for rats: 2,100 mg/kg (IPCS PIM G001 (1989)) (7) LD50 for rats: 2,800 mg/kg (EHC 63 (1986), OEL Documentations (Japan Society For Occupational Health (JSOH), 1989)) (8) LD50 for rats: 2,830 mg/kg (ACGIH (7th, 2003)) |
| 1 | Acute toxicity (Dermal) | Not classified |
- |
- | - | [Rationale for the Classification] It was classified as "Not classified" from (1) - (6). [Evidence Data] (1) LD50 for rats: > 2,000 mg/kg (JMPR (2016), EPA Pesticides RED (2009), Canada Pesticides (2010)) (2) LD50 for rats: > 4,444 mg/kg (ATSDR (2003)) (3) LD50 for rats: > 5,000 mg/kg (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2014), OEL Documentations (Japan Society For Occupational Health (JSOH), 1989)) (4) LD50 for rabbits: 4,100 mg/kg (EHC 63 (1986), GESTIS (Access on May 2020), HSDB (Access on May 2020)) (5) LD50 for rabbits: 8,790 mg/kg (JMPR (2016)) (6) LD50 for rabbits: 8,900 mg/kg (Canada Pesticides (2010)) |
| 1 | Acute toxicity (Inhalation: Gases) | Not classified |
- |
- | - | [Rationale for the Classification] Liquid (GHS definition). It was classified as "Not classified." |
| 1 | Acute toxicity (Inhalation: Vapours) | Classification not possible |
- |
- | - | [Rationale for the Classification] Classification not possible due to lack of data. |
| 1 | Acute toxicity (Inhalation: Dusts and mists) | Not classified |
- |
- | - | [Rationale for the Classification] It was classified as "Not classified" from (1). Besides, because an exposure concentration was higher than the saturated vapor pressure concentration (7.1E-004 mg/L), a reference value in the unit of mg/L was applied as mist. [Evidence Data] (1) LC50 for rats (4 hours): > 5.2 mg/L (JMPR (2016), Canada Pesticides (2010), US AEGL (2009), Patty (6th, 2012)) (2) Vapor pressure of this substance: 4.0E-005 mmHg (30 deg C) (HSDB (Access on May 2020)) (converted value for the saturated vapor pressure concentration: 7.1E-004 mg/L) |
| 2 | Skin corrosion/irritation | Not classified |
- |
- | - | [Rationale for the Classification] It was classified as "Not classified" from (1) - (5). The classification result was changed due to new data obtained. [Evidence Data] (1) This substance was reported to be slightly irritating or not irritating in skin irritation tests with rabbits (JMPR (2016)). (2) In a skin irritation test with rabbits, very slight irritation was observed (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2014)). (3) In a skin irritation test with rabbits according to EPA OPPTS 870.2500, it was reported to be slightly irritating (EPA Pesticides (2009)). (4) In a skin irritation test with rabbits, slight irritation was observed (ACGIH (7th, 2003), Canada Pesticides (2010), Patty (6th, 2012)). (5) The skin-irritating potential of this substance and its formulations was low (GESTIS (Access on May 2020)). |
| 3 | Serious eye damage/eye irritation | Category 2B |
Warning |
H320 | P305+P351+P338 P337+P313 P264 |
[Rationale for the Classification] It was classified in Category 2B from (1) - (5). [Evidence Data] (1) This substance was reported to be slightly irritating in eye irritation tests with rabbits (JMPR (2016)). (2) In an eye irritation test with rabbits, slight irritation was observed (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2014), ACGIH (7th, 2003), Canada Pesticides (2010), Patty (6th, 2012)). (3) It is reported that in an eye irritation test with rabbits according to EPA OPPTS 870.2400, slight conjunctival irritation was observed and cleared within 7 days (EPA Pesticides RED (2009)). (4) It is reported that in an experiment by exposure of 16 volunteers to the aerosol of this substance, conjunctival irritation was seen (ATSDR (2003)). (5) Exposure to this substance triggered immediate irritations, conjunctivitis, and eyelid edema in rabbits (GESTIS (Access on May 2020), HSDB (Access on May 2020)). |
| 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] It was classified in Category 1 from (1) - (4). [Evidence Data] (1) In an experiment in 87 volunteers, this substance (10%) induced sensitization responses in almost half of the subjects (ATSDR (2003)). (2) It was reported to be positive in a skin sensitization test with guinea pigs (maximization test) (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2014)). (3) In skin sensitization tests with guinea pigs, this substance was reported to be negative in a Buehler test and positive in a maximization test. And it was reported to be negative in a mouse local lymph node assay (LLNA) (JMPR (2016)). (4) This substance caused sensitization reactions in 13/24 animals (positive rate 54%) at high concentrations in a skin sensitization test with guinea pigs (maximization test) (GESTIS (Access on May 2020)). [Reference Data, etc.] (5) This substance was not sensitizing in guinea pigs (ACGIH (7th, 2003), Canada Pesticides (2010), Patty (6th, 2012)). (6) In a skin sensitization test with guinea pigs according to EPA OPPTS 870.2600, it was reported to be negative (EPA Pesticides RED (2009)). (7) It was classified in Skin Sens. 1 (H317) in EU-CLP classification (EU CLP classification (Access on July 2020)). |
| 5 | Germ cell mutagenicity | Not classified |
- |
- | - | [Rationale for the Classification] From (1) - (4), it was classified as "Not classified" based on expert judgment. [Evidence Data] (1) As for in vivo, it was reported to be negative in a dominant lethal test with mice, negative in a micronucleus test with mouse bone marrow cells, and negative in a UDS test in the rat liver (IARC 112 (2017), JMPR (2016), ATSDR (2003), Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2014)). (2) As for in vitro, it was reported to be positive in chromosomal aberration tests and gene mutation tests using human peripheral blood lymphocytes or cultured mammalian cells and negative in a bacterial reverse mutation test (same as the above). (3) Many tests were conducted using this substance or its formulations, and many positive results were found. However, negative knowledge was obtained in in-vivo tests performed using a substance with less impurities according to test guidelines and GLP (JMPR (2016), Canada pesticide (2010), EPA Pesticides RED (2009), ATSDR (2003), Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2014)). (4) It is described by the Food Safety Commission of Japan, JMPR, Canada, and EPA that malathion did not have genotoxicity that could pose a problem in vivo (JMPR (2016), Canada pesticide (2010), EPA Pesticides RED (2009), Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2014)). |
| 6 | Carcinogenicity | Category 1B |
 Danger |
H350 | P308+P313 P201 P202 P280 P405 P501 |
[Rationale for the Classification] It was classified in Category 1B based on results in (2) - (4) and IARC's classification in (1). [Evidence Data] (1) As for classification results by domestic and international organizations, it was classified in Group 2A by IARC (IARC 112 (2017)), Group 2B by the Japan Society for Occupational Health (JSOH) (Recommendation of Occupational Exposure Limits (Japan Society For Occupational Health (JSOH), proposed in 2018)), A4 by ACGIH (ACGIH (7th, 2003)), and S (Suggestive Evidence of Carcinogenicity, but not Sufficient to Assess Human Carcinogenic Potential) by EPA (EPA Annual Cancer Report 2019 (Access on July 2020): classified in 2000). (2) IARC concluded that positive associations of exposure to this substance were observed with non-Hodgkin lymphoma and cancer of the prostate in humans, and there was limited evidence for carcinogenicity in humans (IARC 112 (2017)). (3) In two carcinogenicity tests by diet administration of this substance to male and female mice, increases in the incidences of hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined) (increases only in males in one test and both males and females in the other one) were observed (IARC 112 (2017)). (4) In two carcinogenicity tests by diet administration of this substance to male and female rats, significant increases in the incidences of liver tumors (hepatocellular adenoma, hepatocellular adenoma or carcinoma (combined)), fibroadenoma of the mammary gland, and uterine polyps were observed in females. And two very rare tumors of the nasal pharyngeal cavity were identified in males (IARC 112 (2017)). |
| 7 | Reproductive toxicity | Not classified |
- |
- | - | [Rationale for the Classification] Based on (1) to (3), it was classified as "Not classified." [Evidence Data] (1) In a two-generation reproductive study with rats dosed by feeding, no effect was observed in a parent generation, and only a slight effect (lower body weight at weaning) was observed in F1 and F2 offspring (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2014)). (2) In a three-generation reproductive study with rats dosed by feeding, low body weight at mating in P, F1, and F2 parent animals, dyspnea and death (3/16 males and 1/16 females) in P parent animals, dyspnea and death (1/16) in females in F3 parent animals, decreases in fertility index and gestation index in P parent animals, low body weight at weaning in F1 and F3 offspring, and a decrease in lactation index in F3 offspring were observed. The decreases in fertility index, gestation index, and lactation index were due to maternal toxicity, and were not considered to be direct effects of the test substance on fertility (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2014)). (3) In a developmental toxicity study with rats and rabbits of gestation dosed by gavage, no effect was observed in fetuses even at a dose at which maternal toxicity was observed (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2014)). [Reference Data, etc.] (4) In a developmental neurotoxicity test with rats (dose by gavage to dams on day 6 of gestation to post-delivery day 10, and to offspring on postnatal days 11-21), no maternal toxicity was observed; and in offspring, tremor and hypoactivity on postnatal days 11-21, and delayed surface righting on postnatal day 11 were observed, but it was considered that these symptoms were direct effects of the test substance, and not developmental neurotoxicity effects (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2014)). |
| 8 | Specific target organ toxicity - Single exposure | Category 1 (nervous system, respiratory organs, cardiovascular system) |
Danger |
H370 | P308+P311 P260 P264 P270 P321 P405 P501 |
[Rationale for the Classification] Based on (1) to (5), effects on the nervous system, cardiovascular system, and respiratory organs were observed in humans. Based on (6), effects on the nervous system at doses within the range for Category 1 were also observed in experimental animals. Therefore, it was classified in Category 1 (nervous system, respiratory organs, cardiovascular system). After a review of the information, the classification results were changed from the previous classification. [Evidence Data] (1) Common signs and symptoms were abdominal cramps, diarrhea, nausea, vomiting, miosis, blurred vision, salivation, lacrimation, dyspnea, and muscle fasciculations, which were typically observed by parasympathetic autonomic stimulation, and it was also reported that inhibition of erythrocyte and plasma cholinesterase (ChE) activity was observed (ATSDR (2003)). (2) It was reported that in a case of death due to poisoning from this substance, dilatation of the pericardial blood vessels and noticeable hemorrhage in the surrounding tissues, interstitial edema, inflammatory cells, hemosiderin-laden macrophages and fatty infiltration of the myocardium, and damage to the myocardium were observed. It was reported that in acute poisoning at a high dose level, changes in the electroencephalogram (EEG) were also observed as in repeated exposures at a low dose level, and these symptoms got worse by a small amount of additional exposure (ACGIH (7th, 2001)). (3) It was reported that in almost all cases of poisoning from this substance (estimated dose amount: 214-2,117 mg/kg), effects on the cardiovascular system, such as bradycardia and low blood pressure by vagal stimulation, and atrio-ventricular conduction disturbances appearing within a few days after exposure, were observed (ATSDR (2003)). (4) In multiple cases of poisoning from this substance (the exposure amount was 214-1,071 mg/kg in the cases in which doses could be estimated), respiratory difficulties were reported. Even at the lower dose estimates, respiratory distress and bronchitis were common, and most patients required ventilatory support. In two cases, development of pulmonary fibrosis was observed within 2 weeks of the poisoning incident (ATSDR (2003)). As the effects on the respiratory organs associated with the administration of this substance, histopathologic lesions of the nasal cavity and larynx after inhalation were reported (EPA Pesticides RED (2009)). (5) Four male volunteers per group were exposed for 1 hour twice a day for 42 days to aerosol containing this substance at a concentration of 0, 5.3, 21, or 85 mg/m3, and there were complaints of nasal irritation in a group of 85 mg/m3 within 5-10 minutes after the start of each exposure (ATSDR (2003)). (6) It was reported that in an oral toxicity test with rats using this substance with a purity of 95%, an erythrocyte ChE inhibitory effect was observed at or above 12 mg/kg (within the range for Category 1), and in another test using this substance with unknown purity, severe respiratory distress was observed at about 411 mg/kg (within the range for Category 2) (ATSDR (2003)). [Reference Data, etc.] (7) It was reported that, in humans, several impurities in commercial products manufactured for use as pesticides inhibited the normal metabolism of this substance, resulting in increased toxicity. This was considered to be due to the carboxylesterase inhibitory effect of impurities. It was reported that isomalathion (CAS RN 3344-12-5) contained in the formulation of this substance affected the increase of toxicity, but effects of other impurities were also suggested (EHC 63 (1986)). (8) This substance was converted to malaoxon (CAS RN 1634-78-2) by the metabolism in insects and mammals. Malaoxon was known to be a more potent ChE inhibitor than this substance (EPA Pesticides RED (2006)). |
| 9 | Specific target organ toxicity - Repeated exposure | Category 1 (nervous system), Category 2 (respiratory organs) |
Danger Warning |
H372 H373 |
P260 P264 P270 P314 P501 |
[Rationale for the Classification] Based on (1) to (3), it was reported that effects on the nervous system, including deaths, were observed in humans, and based on (4) and (5), it was reported that effects on the nervous system and respiratory organs were observed in test animals at doses within the range for Category 2, and therefore, it was classified in Category 1 (nervous system) and Category 2 (respiratory organs). By examination with the newly added information, the classification result were changed from the previous classification. [Evidence Data] (1) Large-scale occupational poisoning occurred among 5,350 sprayers, 1,070 mixers, and 1,070 supervisors involved in a mosquito control program that utilized water-soluble formulations of this substance, and at least 5 persons died. The exposure route was primarily dermal, and the exposure concentration was estimated to be 1-200 microg/cm3. The cholinesterase (ChE) inhibitory effect progressed with the working period, and symptoms were blurred vision, giddiness, nausea, vomiting, abdominal cramps etc. which were consistent with organophosphate intoxication. The severest symptoms were observed in formulations containing high levels of isomalathion (CAS RN 3344-12-5) and other impurities, and erythrocyte ChE activity decreased by 11-20% and 39-47% at the end of the workday for workers using the formulations containing 2-3% isomalathion, but only by 0.8-3.0% for workers using the formulation not containing isomalathion (ACGIH (7th, 2001), ACGIH (7th, 2003), EHC 63 (1986)). (2) An 18-month-old child was exposed dermally and by inhalation to this substance from a garden spray every day for 6 weeks, and as a result, the child developed cholinergic toxicity symptoms with prolonged weakness, including several days of extensive flaccid paralysis. These symptoms disappeared within 4 weeks by the administration of atropine and a rest (ATSDR (2003)). (3) Five male volunteers were administered by capsules containing this substance (the purity was not known) at about 0.11 mg/kg/day for 32 days, then, at about 0.23 mg/kg/day for 47 days, and as a result, plasma and erythrocyte ChE activity did not decrease, and no clinical symptoms were induced. It was reported that another five volunteers were administered at about 0.34 mg/kg/day for 56 days, and no clinical symptoms were observed, but in about 3 weeks after the end of the administration, plasma ChE activity decreased by up to 25%, then, a decrease in erythrocyte ChE activity was also observed (ATSDR (2003)). (4) It was reported that in a 90-day oral toxicity test with rats, at 75 mg/kg (within the range for Category 2), changes indicating increased excitability were observed in the electroencephalogram (EEG) and electromyogram (EMG) (ATSDR (2003)). (5) It was reported that in a 13-week aerosol inhalation exposure test with rats, at or above 0.1 mg/L (converted guidance value: 0.0722 mg/L, within the range for Category 2), erythrocyte ChE activity inhibition, and histopathologic lesions of the nasal cavity and larynx were observed; and at 2.01 mg/L (converted guidance value: 1.45 mg/L, within the range exceeding Category 2), salivation was observed (ACGIH (7th, 2003)). [Reference Data, etc.] (6) It was reported that, in humans, several impurities in commercial products manufactured for use as pesticides inhibited the normal metabolism of this substance, resulting in increased toxicity. This was considered to be due to the carboxylesterase inhibitory effect of impurities. It was reported that isomalathion contained in the formulation of this substance affected the increase of toxicity, but effects of other impurities were also suggested (EHC 63 (1986)). (7) This substance was converted to malaoxon (CAS RN 1634-78-2) by the metabolism in insects and mammals. Malaoxon was known to be a more potent ChE inhibitor than this substance (EPA Pesticides RED (2006)). |
| 10 | Aspiration hazard | Classification not possible |
- |
- | - | [Rationale for the Classification] Classification not possible due to lack of data. |
| Hazard class | Classification | Pictogram Signal word |
Hazard statement (code) |
Precautionary statement (code) |
Rationale for the classification | |
|---|---|---|---|---|---|---|
| 11 | Hazardous to the aquatic environment Short term (Acute) | Category 1 |
 Warning |
H400 | P273 P391 P501 |
It was classified in Category 1 from 48-hour EC50 = 0.00070 mg/L for crustacea (Daphnia magna) (Document for registration standards for agricultural chemicals set by the Minister of Environment to prevent harm to animals and plants in areas of public waters, 2018). |
| 11 | Hazardous to the aquatic environment Long term (Chronic) | Category 1 |
Warning |
H410 | P273 P391 P501 |
It was classified in Category 1 because it was not rapidly degradable (a 4-week degradation rate by BOD: 22% (Biodegradation and Bioconcentration Results of Existing Chemical Substances under the Chemical Substances Control Law, METI, 2002)) and due to 21-day NOEC = 0.00006 mg/L for crustacea (Daphnia magna) (EPA RED, 2006, 2009). |
| 12 | Hazardous to the ozone layer | Classification not possible |
- |
- | - | This substance is not listed in the Annexes to the Montreal Protocol. |
NOTE:
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