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GHS Classification Results by the Japanese Government

GENERAL INFORMATION

Item	Information
CAS RN	23564-05-8
Chemical Name	Dimethyl 4,4'-(o-phenylene)bis(3-thioallophanate) (synonym: Thiophanate-methyl)
Substance ID	R03-B-017-METI, MOE
Classification year (FY)	FY2021
Ministry who conducted the classification	Ministry of Economy, Trade and Industry (METI)/Ministry of the Environment (MOE)
New/Revised	Revised
Classification result in other fiscal year	FY2008
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

PHYSICAL HAZARDS

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.
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	Not classified (Not applicable)	- -	-	-	There are no chemical groups present in the molecule associated with explosive or self-reactive properties.
9	Pyrophoric liquids	Not classified (Not applicable)	- -	-	-	Solid (GHS definition)
10	Pyrophoric solids	Not classified	- -	-	-	It is estimated that it does not ignite at normal temperatures because it can be estimated that it does not decompose up to 165 deg C from the information that it decomposes at 165 deg C (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, 2015).
11	Self-heating substances and mixtures	Classification not possible	- -	-	-	No data 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	Not classified (Not applicable)	- -	-	-	The substance is an organic compound containing oxygen (but not fluorine or chlorine) which is chemically bonded only to carbon or hydrogen.
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	- -	-	-	Test methods applicable to solid substances are not available.
17	Desensitized explosives	Not classified (Not applicable)	- -	-	-	There are no chemical groups associated with explosive properties present in the molecule.

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] Based on (1), it was classified as "Not classified." [Evidence Data] (1) LD50 for rats: > 5,000 mg/kg (JMPR (2017), EPA Pesticides RED (2005), CLH Report (2018))
1	Acute toxicity (Dermal)	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) and (2), it was classified as "Not classified." [Evidence Data] (1) LD50 for rats: > 2,000 mg/kg (JMPR (2017)) (2) LD50 for rabbits: > 2,000 mg/kg (EPA Pesticides RED (2005), CLH Report (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)	Category 4	Warning	H332	P304+P340 P261 P271 P312	[Rationale for the Classification] Based on (1) and (2), it was classified in Category 4. [Evidence Data] (1) LC50 (4 hours) for rats (males): 1.7 mg/L (CLH Report (2018), REACH registration dossier (Accessed July 2021)) (2) LC50 (4 hours) for rats (males): 1.9 mg/L (CLH Report (2018), REACH registration dossier (Accessed July 2021))
2	Skin corrosion/irritation	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) and (2), it was classified as "Not classified." [Evidence Data] (1) It was reported that, in an acute dermal irritation/corrosion test (equivalent to OECD TG 404, GLP, semiocclusive, 4-hour application, 72-hour observation) with rabbits (n=6), no skin irritation reactions were observed in any animals (erythema and scab score: 0/0/0/0/0/0, edema score: 0/0/0/0/0/0) (ECHA RAC Opinion (2019), CLH Report (2018), REACH registration dossier (Accessed Aug. 2021)). (2) This substance was not a skin irritant substance (EFSA (2018), JMPR (2017), EPA Pesticides (2005)).
3	Serious eye damage/eye irritation	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) to (4), it was classified as "Not classified." [Evidence Data] (1) It was reported that, in an acute eye irritation/corrosion test (equivalent to OECD TG 405, GLP, 72-hour observation) with rabbits (n=9), mild conjunctival redness was observed in 1 out of 6 animals of a group without eye washing after 24 hours, but it disappeared after 48 hours (CLH Report (2018), ECHA RAC Opinion (2019), REACH registration dossier (Accessed Aug. 2021)). (2) This substance was not an eye irritant substance (EFSA (2018)). (3) In an eye irritation test with rabbits, no eye irritation was observed (JMPR (2017)). (4) In an eye irritation test with rabbits, mild eye irritation was observed (EPA Pesticides (2005)).
4	Respiratory sensitization	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
4	Skin sensitization	Category 1B	Warning	H317	P302+P352 P333+P313 P362+P364 P261 P272 P280 P321 P501	[Rationale for the Classification] Based on (1) to (4), it was classified in Category 1B. Also, based on the new findings, classification results were changed. [Evidence Data] (1) It was reported that, in a Maximization test (GLP, intradermal administration: 3.5% solution) with guinea pigs (n=10), a 42% solution was locally administered, and animals were challenged twice, and as a result, the sensitization rate was 100% (10/10 animals) in both cases (ECHA RAC Opinion (2019), CLH Report (2018)). (2) This substance may cause an allergic skin reaction (EFSA (2018)). (3) This substance was a skin sensitizing substance (EPA Pesticides (2005)). (4) It was a skin sensitizer in a Maximization test with guinea pigs, but not in a Buehler test (JMPR (2017)).
5	Germ cell mutagenicity	Category 2	Warning	H341	P308+P313 P201 P202 P280 P405 P501	[Rationale for the Classification] Based on (1) and (2), this substance was considered to be an in vitro and in vivo aneugen, and therefore, it was classified in Category 2. With the additional new information sources, classification results were changed. [Evidence Data] (1) As for in vivo, positive results were obtained in a micronucleus test using the bone marrow cells of mice (B6D2F1) (dosed once by gavage, OECD TG 474, GLP); negative results were obtained in a micronucleus test using the bone marrow cells of mice (ICR) of a different strain (dosed twice by gavage, OECD TG 474, GLP) and a chromosomal aberration test of mice (B6D2F1) (dosed once by gavage, OECD TG 475, GLP); and negative results were obtained in either of a mammalian chromosomal aberration test using the spermatogonia of mice (ICR) and a micronucleus test using the testis cells of mice (ICR) (OECD TG 474, GLP). All of the above are the GLP conforming guideline test results (REACH registration dossier (Accessed July 2021), CLH Report (2018)). (2) As for in vitro, negative results were obtained in a bacterial reverse mutation test, a mammalian chromosomal aberration test, and a gene mutation test; and positive (-S9) results were obtained in a micronucleus test using human lymphocytes. All of the above are the GLP conforming guideline test results (REACH registration dossier (Accessed July 2021), CLH Report (2018)). [Reference Data, etc.] (3) In the EU CLP classification, this substance was classified as Muta. 2. The ECHA RAC rejected the proposal for the change to Muta. 1B by the CLH Report (2018) and concluded that Muta. 2 should be kept (ECHA RAC Opinion (2019)).
6	Carcinogenicity	Category 2	Warning	H351	P308+P313 P201 P202 P280 P405 P501	[Rationale for the Classification] Based on (1) to (3), the tumors observed in some tests were mainly benign tumors, and therefore, it was classified in Category 2. With the additional new information sources, classification results were changed. [Evidence Data] (1) In a carcinogenicity study with rats (Fischer 344) dosed by feeding for two years, an increase in the incidence of thyroid follicular cell adenoma was observed in males of a group at the highest dose of 6,000 ppm (281 to 335 mg/kg/day) (CLH Report (2018), EPA OPP Human Health Risk Assessment (2009), JMPR (2017)). The RAC of the ECHA stated that the incidence of thyroid follicular cell adenoma significantly increased in two groups at a high dose of 1,200 ppm (54.4 to 63.5 mg/kg/day) or higher (ECHA RAC Opinion (2019)). (2) In a carcinogenicity study with mice (CD-1) dosed by feeding for 18 months, an increase in the incidence of hepatocellular adenoma was observed in males and females in two groups at a high dose of 3,000 ppm (468 to 558 mg/kg/day) or higher (CLH Report (2018), EPA OPP Human Health Risk Assessment (2009), JMPR (2017)). (3) It was also reported that, in other carcinogenicity study with rats (SD) and mice (ICR-SLC) dosed by feeding for two years (rats: up to 640 ppm (30 to 34 mg/kg/day), mice: up to 640 ppm (82 mg/kg/day)), there was no incidence of tumor (CLH Report (2018), EPA OPP Human Health Risk Assessment (2009)). [Reference Data, etc.] (4) As for the classification results by domestic and international organizations, the EPA classified this substance in L (Likely To Be Carcinogenic To Humans) (EPA OPP Annual Cancer Report 2020 (Accessed July 2021): Classification in 1999)). (5) This substance causes an increase in the incidence of thyroid adenoma in rats and hepatocellular adenoma in mice. Regarding the mechanism of thyroid tumor formation, a mixed mode of actions through induction of drug metabolizing enzymes (cytochrome P450, UDPGT, etc.) of the liver and inhibition of thyroid peroxidase (TPO) has been proposed as a hypothesis (JMPR (2017), EFSA (2018)). (6) As for this substance, the CLP classification as Carc. 2 was proposed, and the RAC of the ECHA agreed with this proposal (ECHA RAC Opinion (2019)). (7) As for the results of an increase in the incidence of thyroid adenoma in rats and hepatocellular adenoma in mice, the substance is unlikely to pose a carcinogenic risk to humans (JMPR (2017).
7	Reproductive toxicity	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) to (5), it was classified as "Not classified." Besides, in (5), a decrease in the number of live fetuses was observed, but it was a mild effect. [Evidence Data] (1) It was reported that, in a two-generation reproduction toxicity study (OECD TG 416, GLP) with rats dosed by feeding, effects on the thyroid (weight increase/hypertrophy/hyperplasia, increased TSH and decreased T4 (only in males at 2,000 ppm)) and the liver (weight increase/hepatocellular hypertrophy) in parent animals, and reduced body weight gain in offspring were observed, but no effects on fertility were observed in each treated group from 200 ppm (14.6 to 18.0 mg/kg/day) to 2,000 ppm (147.1 to 172.9 mg/kg/day) (CLH Report (2018), EPA OPP Human Health Risk Assessment (2009), JMPR (2017)). (2) It was reported that, in a three-generation reproductive toxicity study (GLP) with rats dosed by feeding, no reproductive toxicity was observed (CLH Report (2018), EPA OPP Human Health Risk Assessment (2009)). (3) It was reported that, in a developmental toxicity study (OECD TG 414, GLP, days 6-19 of gestation) with rats dosed by gavage, no developmental toxicity was observed (CLH Report (2018), EPA OPP Human Health Risk Assessment (2009), JMPR (2017)). (4) In one of two developmental toxicity studies (OECD TG 414, GLP, days 6-28 of gestation) with rabbits dosed by gavage, reduced body weight gain, reduced food consumption, etc. were observed in parent animals at or above the middle dose (20 mg/kg/day), but in offspring, only skeletal variations (supernumerary thoracic ribs) were observed at the highest dose (40 mg/kg/day) (CLH Report (2018), EPA OPP Human Health Risk Assessment (2009), JMPR (2017)). Also in the other study, at or above the middle dose at which reduced body weight gain was observed in parent animals, skeletal variations (supernumerary ribs, thickened ribs, incomplete/asymmetrical ossification of costal elements of sacral vertebrae, and asymmetric pelvis) were observed in offspring, but since some parent animals had suffered from infections, the findings were considered to be support data (CLH Report (2018), EPA OPP Human Health Risk Assessment (2009)). (5) It was reported that, in a developmental toxicity study (OECD TG 414, GLP, days 1 to 15 of gestation) with mice dosed by gavage, a mild decrease in the number of live pups per litter (9.7 animals, control group (10.9 animals)) was observed at 1,000 mg/kg/day (CLH Report (2018)). [Reference Data, etc.] (6) Carbendazim (CAS RN 10605-21-7), which is a metabolite of this substance, is classified as Repr. 1B (GHS classification by the Japanese Government: Category 1B) according to the CLP classification, and therefore, a concern about reproductive toxicity of this substance cannot be completely excluded, but based on the results of reproductive and developmental toxicity studies of this substance, it was agreed that it is not necessary to propose the classification for reproductive toxicity of this substance (EFSA (2018)).
8	Specific target organ toxicity - Single exposure	Not classified	- -	-	-	[Rationale for the Classification] Based on (1), neurological symptoms were observed in the inhalation route, but based on (2), neurological toxicity was denied, and therefore, the nervous system was not adopted as the target organ. In other routes, there were no effects for which the target organs could be identified, and therefore, it was classified as "Not classified." Also, based on the new findings, classification results were changed. [Evidence Data] (1) It was reported that, in an acute inhalation toxicity test (GLP, 4 hours, mist) with rats, in a 1.9 mg/L group at 1.0 to 1.9 mg/L (within the range for Category 2), deaths (males: 5/5, females: 3/5) were observed, and as symptoms, decreased motor activity, low sensitivity, muscular hypotonia, ventral position, incontinence of urine, ataxia, ptosis, tremor, and convulsion were observed (REACH registration dossier (Accessed July 2021), CLH Report (2018)). (2) It was reported that, in an acute neurotoxicity study with rats, no symptoms were observed at 2,000 mg/kg (within the range for Category 2), and JMPR concluded that the substance was not neurotoxic (JMPR (2017), REACH registration dossier (Accessed July 2021), CLH Report (2018)). (3) It was reported that, in an acute oral toxicity test with rats (GLP), no symptoms were observed at 5,000 mg/kg (in the range corresponding to "Not classified") (REACH registration dossier (Accessed July 2021)). (4) It was reported that, in an acute dermal toxicity test with rabbits (GLP), reddening of the application area was observed at 2,000 mg/kg (within the range for Category 2) (REACH registration dossier (Accessed July 2021)).
9	Specific target organ toxicity - Repeated exposure	Category 2 (liver, thyroid, blood system)	Warning	H373	P260 P314 P501	[Rationale for the Classification] Based on (1) to (4), effects on the blood and thyroid were observed in the oral route, and based on (3), effects on the liver were observed, and therefore, it was classified in Category 2 (liver, thyroid, blood system). Also, (6) and (7) were not used for the classification because they were the studies before establishment of the guidelines, and the evaluation items were limited. [Evidence Data] (1) It was reported that, in a repeated dose 3-month oral toxicity study with dogs dosed by gavage, hypertrophy of the thyroid follicular cells was observed at or above 50 mg/kg/day (within the range for Category 2), and reduced body weight gain, reduced food consumption, increased liver and thyroid weight, a decrease in T3 (males), hematological changes (decreases in Hct, Hb, and RBC) (females), and decreases in T3 and T4 (females) were observed at or above 200 mg/kg/day (JMPR (2017), CLH Report (2018)). (2) It was reported that, in 1-year chronic toxicity studies with dogs dosed by gavage, increased thyroid weight (females) was observed at 8 mg/kg/day (within the range for Category 1), and tremor, hypertrophy and hyperplasia of the thyroid, a decrease in T4 (males), and hematological changes (decreases in RBC, Hb, and Hct) (males) were observed at 200 mg/kg/day (JMPR (2017), CLH Report (2018)). (3) It was reported that, in an 18-month combined chronic toxicity/carcinogenicity studies with mice, increased liver and thyroid weight, centrilobular hepatocellular hypertrophy (females), and hepatocellular adenoma (females) were observed at 640 ppm (99 mg/kg/day (males), 123 mg/day (females), within the range for Category 2), and increased liver and thyroid weight, and hepatocellular adenoma were observed at or above 3,000 ppm (468 mg/kg/day (males), 558 mg/kg/day (females)) (JMPR (2017), CLH Report (2018)). (4) It was reported that, in a 2-year combined chronic toxicity/carcinogenicity study with rats, increased liver, thyroid, and kidney weight, hematological changes (decreases in RBC, MCV, MCH, and MCHC) were observed at 1,200 ppm (54 mg/kg/day (males), 64 mg/kg/day (females), within the range for Category 2), and hyperplasia and hypertrophy of the thyroid follicular cells, centrilobular hepatocellular hypertrophy, occurrence of lipofuscin pigment, decreased levels of chloride and potassium (males), decreases in T4 and T3 (males), an increase in TSH (males), urinary protein (males), and granular kidneys (males) were observed at or above 1,200 ppm (54 mg/kg/day (males), 64 mg/kg/day (females), within the range for Category 2) (JMPR (2017), CLH Report (2018), REACH registration dossier (Accessed Aug. 2021)). (5) It was reported that, in a repeated dose 21-day dermal toxicity study with rabbits, no symptoms were observed at 100 mg/kg/day (converted guidance value: 23.3 mg/kg/day, within the range for Category 2) (CLH Report (2018)). [Reference Data, etc.] (6) It was reported that, in 2-year chronic toxicity studies with dogs, increased thyroid weight, and moderate hypertrophy of the thyroid were observed at 50 mg/kg/day (within the range for Category 2) (JMPR (2017), CLH Report (2018)). (7) It was reported that, in a 2-year combined chronic toxicity/carcinogenicity study with mice, reduced body weight gain and histopathological changes in testes (males) were observed at 640 ppm (82 mg/kg/day (males), 84 mg/kg/day (females), within the range for Category 2) (JMPR (2017)).
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	It was classified in Category 1 from 96-hour LC50 = 0.03 mg/L for fish (Ictalurus punctatus) (HSDB (2021), OPP Pesticide Ecotoxicity Database). The classification result was changed from the previous classification by using new information.
11	Hazardous to the aquatic environment Long term (Chronic)	Category 1	Warning	H410	P273 P391 P501	If chronic toxicity data are used, then it was classified as "Not classified" due to being not rapidly degradable (BIOWIN), and 72-hour NOErC= 4.3 mg/L for algae (Raphidocelis subcapitata) (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, 2015). If acute toxicity data are used for a trophic level for which chronic toxicity data are not obtained (crustacea, fish), then it is classified in Category 1 because it is not rapidly degradable and due to 96-hour LC50 = 0.03 mg/L for fish (Ictalurus punctatus) (HSDB (2021), OPP Pesticide Ecotoxicity Database). By drawing a comparison between the above results, it was classified in Category 1. The classification result was revised from the previous classification by changing how to classify it in chronic toxicity and using new information.
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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