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GHS Classification Results by the Japanese Government

GENERAL INFORMATION

Item	Information
CAS RN	153719-23-4
Chemical Name	3-[(2-Chloro-1,3-thiazol-5-yl)methyl]-5-methyl-N-nitro-1,3,5-oxadiazinan-4-imine; Thiamethoxam
Substance ID	R02-A-026-METI, MOE
Classification year (FY)	FY2020
Ministry who conducted the classification	Ministry of Economy, Trade and Industry (METI)/Ministry of the Environment (MOE)
New/Revised	New
Classification result in other fiscal year
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)
Model SDS by MHLW (External link)
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	Classification not possible	- -	-	-	There is a chemical group associated with explosive properties (nitro group) present in the molecule, and the oxygen balance is -99, higher than the criteria: -200, but the classification is not possible due to no data.
2	Flammable gases	Not classified (Not applicable)	- -	-	-	Solid (GHS definition)
3	Aerosols	Not classified (Not applicable)	- -	-	-	Not aerosol products.
4	Oxidizing gases	Not classified (Not applicable)	- -	-	-	Solid (GHS definition)
5	Gases under pressure	Not classified (Not applicable)	- -	-	-	Solid (GHS definition)
6	Flammable liquids	Not classified (Not applicable)	- -	-	-	Solid (GHS definition)
7	Flammable solids	Classification not possible	- -	-	-	No data available.
8	Self-reactive substances and mixtures	Classification not possible	- -	-	-	There is a chemical group associated with explosive properties (nitro group) present in the molecule, but the classification is not possible due to no data.
9	Pyrophoric liquids	Not classified (Not applicable)	- -	-	-	Solid (GHS definition)
10	Pyrophoric solids	Classification not possible	- -	-	-	No data available.
11	Self-heating substances and mixtures	Classification not possible	- -	-	-	Classification is not possible because 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 classified (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 classified (Not applicable)	- -	-	-	Solid (GHS definition)
14	Oxidizing solids	Classification not possible	- -	-	-	The substance is an organic compound containing chlorine and oxygen (but not fluorine), and the oxygen is chemically bonded to the element other than carbon or hydrogen (N). However, the classification is not possible due to no data.
15	Organic peroxides	Not classified (Not applicable)	- -	-	-	Organic compounds containing no bivalent -O-O- structure in the molecule.
16	Corrosive to metals	Classification not possible	- -	-	-	Classification is not possible because test methods applicable to solid substances are not available.
17	Desensitized explosives	Classification not possible	- -	-	-	There is a chemical group associated with explosive properties (nitro group) present in the molecule, but the classification is not possible due to no data.

HEALTH HAZARDS

Hazard class		Classification	Pictogram Signal word	Hazard statement (code)	Precautionary statement (code)	Rationale for the classification
1	Acute toxicity (Oral)	Category 4	Warning	H302	P301+P312 P264 P270 P330 P501	[Rationale for the Classification] It was classified in Category 4 from (1). [Evidence Data] (1) LD50 for rats: 1,560 mg/kg (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2012), JMPR (2010), ECHA RAC Opinion (2019)) [Reference Data, etc.] (2) LD50 for mice (males): 783 mg/kg (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2012), JMPR (2010), ECHA RAC Opinion (2019)) (3) LD50 for mice (females): 964 mg/kg (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2012), JMPR (2010), ECHA RAC Opinion (2019))
1	Acute toxicity (Dermal)	Not classified	- -	-	-	[Rationale for the Classification] It was classified as "Not classified" from (1). [Evidence Data] (1) LD50 for rats: > 2,000 mg/kg (OECD TG 402) (ECHA RAC Opinion (2018), AICIS (formerly, NICNAS IMAP) (2018)) [Reference Data, etc.] (2) LD50 for rabbits: > 652 mg/kg (OECD TG 402, purity: 32.6% (medium: xylene)) (ECHA RAC Opinion (2018))
1	Acute toxicity (Inhalation: Gases)	Not classified	- -	-	-	[Rationale for the Classification] Solid (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)	Classification not possible	- -	-	-	[Rationale for the Classification] The classification is not possible because effects are unknown at a dose near the upper limit for Category 4 from (1). [Evidence Data] (1) LC50 for rats (4 hours): > 3.72 mg/L (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2012), JMPR (2010), ECHA RAC Opinion (2019))
2	Skin corrosion/irritation	Not classified	- -	-	-	[Rationale for the Classification] It was classified as "Not classified" from (1). [Evidence Data] (1) It is reported that in a skin irritation test with rabbits (n = 6) (OECD TG 404, GLP, 4-hour application, 72-hour observation), no skin reactions were seen in any animal (erythema/eschar score: 0/0/0/0/0/0, edema score: 0/0/0/0/0/0) (EU CLH report (2018), RAC Opinion (2019), Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2012), JMPR (2010), A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2018)).
3	Serious eye damage/eye irritation	Not classified	- -	-	-	[Rationale for the Classification] It was classified as "Not classified" from (1). [Evidence Data] (1) It is reported that in an eye irritation test with rabbits (n = 9) (OECD TG 405, GLP, 3-day observation), all the animals in the unwashed eye group (6) showed slight conjunctival redness 1 hour after application but fully recovered within 24 hours (corneal opacity score: 0/0/0/0/0/0, iritis score: 0/0/0/0/0/0, conjunctival redness score: 0/0/0/0/0/0, chemosis score: 0/0/0/0/0/0) (EU CLH report (2018), RAC Opinion (2019), Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2012), JMPR (2010), A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2018)).
4	Respiratory sensitization	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
4	Skin sensitization	Not classified	- -	-	-	[Rationale for the Classification] Because a positive rate was less than 30% in (1), it was classified as "Not classified." [Evidence Data] (1) It is reported that in a maximization test with guinea pigs (n = 20) (OECD TG 406, GLP, intradermal administration: 1% solution), a positive rate was 0% (0/20), 5% (1/20) at 24, 48 hours after challenge (CLH Report (2018), RAC Opinion (2019), Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2012), JMPR (2010), A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2018)).
5	Germ cell mutagenicity	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) to (5), it was classified as "Not classified." [Evidence Data] (1) In a micronucleus test with mice bone marrow cells (OECD TG474, GLP), negative results were obtained (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2012), A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2013), JMPR (2010)). (2) In a bacterial reverse mutation test, negative results were obtained (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2012), JMPR (2010)). (3) In an in vitro mammalian cell gene mutation test, negative results were obtained (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2012), JMPR (2010)). (4) In an in vitro mammalian cell chromosome aberration test, negative results were obtained (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2012), JMPR (2010)). (5) In two UDS tests using primary cultured hepatocytes of rats and mice, negative results were obtained (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2012), JMPR (2010)).
6	Carcinogenicity	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) to (7), it was classified as "Not classified." In the animal studies of (2) and (3), negative results in rats and positive results in mice were obtained, and an increase in the incidence of liver tumors in mice was apparent. Therefore, it was considered that there was a possibility of classification in Category 2. [Evidence Data] (1) As for the classification results by domestic and international organizations, EPA classified this substance in NL (Not Likely to be Carcinogenic to Humans) (EPA Annual Cancer Report (2018): Classification in 2005). (2) In a two-year combined chronic toxicity/carcinogenicity study with rats, a significant increase in malignant brain glial cell tumors (2/50 cases) and skin/hypodermis lipomas (3/50 cases) was observed in males in the highest dose group, but it was close to or within the historical data. In addition, no early-onset of tumorigenesis as spontaneous tumor was observed. Therefore, it was considered that the findings were not treatment-related (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2012)). (3) In an 18-month carcinogenicity study with mice, an increased incidence of hepatocellular adenomas was observed in males and females in three high-dose groups, and an increased incidence of hepatocellular carcinomas was observed in the highest-dose group of males and in two high-dose groups of females (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2012)). [Reference Data, etc.] (4) Concerning carcinogenicity of this substance, EPA initially classified it in L (Likely to be Carcinogenic to Humans) based on the findings of liver tumors in mice (EPA Pesticide Review (2000)) but reclassified it in NL in 2005 as described in (1). The bases of the reclassification as NL were that this substance had no genotoxicity and liver tumors in mice were caused by a nongenotoxic mechanism and that since it was known that mice produced a more metabolite having hepatotoxicity (produced via clothianidin (CGA 322704) which was a main metabolite of this substance) compared to rats and humans, the results of the carcinogenicity test with mice could not be applied to humans (US Federal Register vol. 77 No.42 (2012)). (5) EU has been conducting the CLP classification work for this substance. There is a possibility that this substance is classified in Category 2 for carcinogenicity based on the test results with mice. An independent team of experts examined in detail the mode of action by which liver tumors arise in mice and concluded that liver tumors in mice were produced via regenerative hyperplasia induced by the metabolite of this substance having sustained cytotoxicity and sustained cytotoxicity to liver cells (it is known that compared to rats and humans, mice produce more hepatotoxic metabolite [CGA 265307 (desmethylclothianidin); produced via clothianidin (CGA 322704) which is a main metabolite of this substance]). They considered that relevance of the mode of action to humans could reasonably be excluded on the basis of marked quantitative differences in metabolism between mice and humans and concluded that it was classified as "Not classified (conclusive but not sufficient for classification)" for carcinogenicity (ECHA RAC Opinion (2019)). (6) JMPR concluded that on the bases of the absence of genotoxicity, the absence of carcinogenicity in rats and the mode of action by which liver tumors arise in mice, this substance is unlikely to pose a carcinogenic risk at human dietary exposure levels (JMPR (2010)). (7) In a carcinogenicity study, an increase in hepatocellular adenoma and hepatocellular carcinoma was observed in male and female mice. Based on the study result about the mode of action for liver tumor formation, it was considered that this substance induced hepatic enzyme activity and accelerated cell division, and furthermore it had cytotoxicity. It was considered that the mode of action for liver tumor formation by this substance was attributed to the promotion action produced as a result of secondary cell proliferation due to cellular injury (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2012)).
7	Reproductive toxicity	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) to (5), it was classified as "Not classified." [Evidence Data] (1) It was reported that in a two-generation reproduction toxicity study with rats dosed by feeding, an increase in hyaline droplet deposition in the renal tubules, reduced body weight gain, increases in relative weight of the spleen and liver, increased incidences of renal tubular casts, decreased food consumption, an increase in relative heart weight (males) were observed in parental animals and reduced body weight gain (F1 males and females and F2 males) was observed in pups at 2,500 ppm, but no effects on fertility were observed (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2012), JMPR (2010)). (2) It was reported that in a two-generation reproduction toxicity study with rats dosed by feeding, no effects on fertility were observed (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2012), JMPR (2010)). (3) It was reported that in a developmental toxicity study with rats dosed by gavage, at 750 mg/kg/day, reduced body weight gain, decreased food consumption, transient hypoactivity, piloerection, regurgitation, and reduced carcass weight were observed in parental animals, and lower body weight and skeletal anomalies, such as irregular ossification of the occipital bone, shortened 13th rib and poor or absent ossification of the sternebra, metatarsal or phalanges were observed in pups (males and females), but no teratogenicity was observed (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2012), JMPR (2010)). (4) It was reported that in a developmental toxicity study with rabbits dosed by gavage, at 150 mg/kg/day, decreased food consumption, reduced body weight gain, bloody discharge in the perineal area or vagina, and a decrease in body weight were observed in parental animals, and a decrease in body weight and increased incidences of fused sternebrae and non-ossification of phalanges were observed in pups (males and females), and no teratogenicity was observed (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2012), JMPR (2010)). (5) It was reported that in a developmental neurotoxicity test with rats dosed by gavage, at 4,000 ppm, reduced body weight gain and lower food consumption were observed in parental animals; lower weight at birth and lower weight on days after birth, a decrease in absolute brain weight (males and females), a delay in the day of age when preputial separation occurred (males), lower values of the thickness of the molecular layer of the cerebellar prepyramidal fissure and cerebellum width (males) on day 12 after birth, lower values of dorsal cortex thickness, thalamus and cortex overall width and hippocampus overall width (males and females) on day 63 after birth were observed in pups; and no developmental neurotoxicity was observed. However, in a histopathological examination of the brains and nervous tissues, no abnormalities were observed, and in a functional test, no treatment-related effects were observed (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2012), JMPR (2010)).
8	Specific target organ toxicity - Single exposure	Category 2 (nervous system)	Warning	H371	P308+P311 P260 P264 P270 P405 P501	[Rationale for the Classification] Based on (1) to (3), it was classified in Category 2 (nervous system). Presuming from the LD50 values, the findings of (1) and (2) were considered to be effects within the range for Category 2. [Evidence Data] (1) It was reported that in an acute oral toxicity test with rats, ptosis, reduced spontaneous activity and tonic convulsion were observed and LD50 was 1,560 mg/kg (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2012), JMPR (2010)). (2) It was reported that in an acute oral toxicity test with mice, reduced spontaneous activity, clonic convulsion, and prostration were observed and LD50 was 783 mg/kg (males) and 964 mg/kg (females) (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2012), JMPR (2010)). (3) It was reported that in an acute neurotoxicity test with rats dosed orally, effects on righting reflex, reduction of rectal temperature, palpebral closure, gait abnormality, reduced rearing behaviors, hypoarousal, and tremors were observed at 500 to 1,500 mg/kg (within the range for Category 2) (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2012), JMPR (2010)).
9	Specific target organ toxicity - Repeated exposure	Classification not possible	- -	-	-	[Rationale for the Classification] Based on (1) to (5), no target organ could be identified in the oral route and it was considered to be classified as "Not classified." However, there was no information on toxicity in the other routes, and classification was not possible due to lack of data. Based on (4), liver effects were observed, but the findings (precancerous lesions) on the liver of mice could not be extrapolated to humans. Therefore, the liver was excluded from the target organs. [Evidence Data] (1) It was reported that in a repeated dose 90-day oral toxicity study with rats by feeding, kidney effects (deposit of hyaline droplets in renal tubules, chronic lesions of the renal tubules, increased Cre (males)) were observed at 1,250 ppm (84.9 mg/kg/day (males), 92.5 mg/kg/day (females), within the range for Category 2), and chronic lesions of the renal tubules (females) were observed at 2,500 ppm (168 mg/kg/day (males), 182 mg/kg/day (females), in the range corresponding to "Not classified"). However, it was found by immunohistological staining that the alterations in the renal tubular cells of males were caused by alpha 2mu-globulin deposition, and it was concluded that the findings were not applicable to humans. Concerning renal tubule lesions in females, it was concluded that since the findings had not been replicated in longer-term studies, it was an incidental finding (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2012), JMPR (2010)). (2) It was reported that in a repeated dose 90-day oral toxicity study with dogs dosed by feeding, hematological effects (a reduction in red blood cells, hemoglobin and hematocrit (females); and a reduction in MCH and monocyte counts and prolonged PT (males and females)), a decrease in testicular weight and a reduction in spermatogenesis (males) were observed at 1,000 to 2,500 ppm (32.0 to 54.8 mg/kg/day (males), within the range for Category 2) and at 1,000 to 2,000 ppm (33.9 to 50.5 mg/kg/day (females), within the range for Category 2) (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2012), JMPR (2010)). (3) It was reported that in a one-year chronic toxicity study with dogs dosed by feeding, hematological effects (an increase in BUN/Cre, increases in red blood cell distribution width and neutrophil percentage, reductions in basophil percentage and lymphocyte percentage) were observed at 750 to 1,500 ppm (21.0 to 42.0 mg/kg/day (males), 24.6 to 45.1 mg/kg/day (females), within the range for Category 2) (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2012)). (4) It was reported that in an 18-month carcinogenicity study with mice dosed by feeding, liver effects (hepatocellular hypertrophy, necrosis of single hepatocytes, inflammatory cell infiltration, hepatocellular fatty changes (males)) were observed at 500 to 2,500 ppm (63.8 to 354 mg/kg/day (males), 87.6 to 479 mg/kg/day (females), from the range for Category 2 through the range corresponding to "Not classified") (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2012), JMPR (2010)). (5) It was reported that in a two-year combined chronic toxicity/carcinogenicity studies with rats dosed by feeding, kidney effects (an increase in chronic nephropathy, an increase in renal lymphocytic infiltration, an increase in BUN) were observed at 500 ppm (21.0 mg/kg bw per day (males), within the range for Category 2). However, as was the case with (1), it was reported that these effects were alpha 2mu-globulin mediated and specific to male rats and could not be extrapolated to humans (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2012), JMPR (2010)).
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 Short term (Acute)	Category 1	Warning	H400	P273 P391 P501	This substance is a neonicotinoid pesticide known to have a specific efficacy profile. By the expert judgment, it was classified in Category 1 from 48-hour EC50 = 0.035 mg/L for crustacea (larvae of Chironomus riparius) (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, 2016).
11	Hazardous to the aquatic environment Long term (Chronic)	Category 1	Warning	H410	P273 P391 P501	This substance is a neonicotinoid pesticide known to have a specific efficacy profile. It was not rapidly degradable (a degradation rate by BOD: 7% (EU CLP CLH, 2018)), and by the expert judgment, it was classified in Category 1 from 35-day NOEC = 0.0003 mg/L for crustacea (Cloeon dipterum) (REACH registration dossier, 2021).
12	Hazardous to the ozone layer	Classification not possible	- -	-	-	This substance is not listed in the Annexes to the Montreal Protocol.

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.
An asterisk “*” in the column of “Classification” denotes that “Not classified (or No applicable)” and/or “Classification not possible” is applicable. Details are described in the column of “Rationale for the classification”. If no English translation is available for “Rationale for the classification,” please refer to the Japanese version of the results.

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