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GHS Classification Results by the Japanese Government

GENERAL INFORMATION

Item	Information
CAS RN	51235-04-2
Chemical Name	3-Cyclohexyl-6-(dimethylamino)-1-methyl-1,3,5-triazine-2,4(1H,3H)-dione (synonym: hexazinone)
Substance ID	R03-A-001-MHLW, MOE
Classification year (FY)	FY2021
Ministry who conducted the classification	Ministry of Health, Labour and Welfare (MHLW)/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	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. Besides, there is information that it is combustible (GESTIS (Accessed Sep. 2021)).
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	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 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)	Category 4	Warning	H302	P301+P312 P264 P270 P330 P501	[Rationale for the Classification] Based on (1) and (2), it was classified in Category 4. [Evidence Data] (1) LD50 for rats: 1,200 mg/kg (Risk Assessment Report (Pesticide) (Food Safety Commission of Japan, 2008), FAO (2012), EPA Pesticides RED (1994)) (2) LD50 for rats (males): 1,690 mg/kg (ACGIH (2020))
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 rabbits: > 5,000 mg/kg (OECD TG 402) (FAO (2012)) (2) LD50 for rabbits: > 5,280 mg/kg (Risk Assessment Report (Pesticide) (Food Safety Commission of Japan, 2008), EPA Pesticides RED (1994))
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)	Not classified	- -	-	-	[Rationale for the Classification] Based on (1), it was classified as "Not classified." [Evidence Data] (1) LC50 (4 hours, dust) for rats: > 7.48 mg/L (ACGIH (2020), Patty (2012))
2	Skin corrosion/irritation	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) and (2), it was classified as "Not classified" (Category 3 in UN GHS classification) in accordance with the GHS Classification Guidance for the Japanese Government. [Evidence Data] (1) This substance was found to be mildly irritating to the skin in rabbits (Risk Assessment Report (Pesticide) (Food Safety Commission of Japan, 2008)). (2) This substance was a mild skin irritant (EPA Pesticides RED (1994)).
3	Serious eye damage/eye irritation	Category 1	Danger	H318	P305+P351+P338 P280 P310	[Rationale for the Classification] Based on (1) to (3), it was classified in Category 1. [Evidence Data] (1) This substance induced irreversible corneal opacity in the eye of rabbits (Risk Assessment Report (Pesticide) (Food Safety Commission of Japan, 2008)). (2) This substance was a severe eye irritant (EPA Pesticides RED (1994)). (3) In an eye irritation test with rabbits (n=3), corneal opacity, iritis, conjunctival redness, and chemosis were observed, and the effects resolved in 2 animals within 21 days (Patty (2012)).
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] Based on (1) and (2), it was classified as "Not classified" in accordance with the GHS Classification Guidance for the Japanese Government. [Evidence Data] (1) It was reported that, in a Buehler test with guinea pigs, negative results were obtained (Risk Assessment Report (Pesticide) (Food Safety Commission of Japan, 2008)). (2) This substance was not a skin sensitizer (EPA Pesticides RED (1994)).
5	Germ cell mutagenicity	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) and (2), it was classified as "Not classified." [Evidence Data] (1) As for in vivo, negative results were obtained in all of a micronucleus test using the bone marrow cells of mice (single oral dose, up to 3,000 mg/kg) and a chromosome aberration assay with the bone marrow cells of rats (single oral dose, up to 1,000 mg/kg) (Risk Assessment Report (Pesticide) (Food Safety Commission of Japan, 2008), FAO (2012), ACGIH (8th, 2020), EPA Pesticides (1994), Patty (6th, 2012)). (2) As for in vitro, negative results in a bacterial reverse mutation test, negative results in a gene mutation assay with the cultured mammalian cells (Chinese hamster ovary cells (CHO)), and positive results in a chromosome aberration assay using CHO were reported (Risk Assessment Report (Pesticide) (Food Safety Commission of Japan, 2008), FAO (2012), ACGIH (2020), EPA Pesticides (1994)).
6	Carcinogenicity	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) to (3), it was classified as "Not classified." [Evidence Data] (1) As for the classification results by domestic and international organizations, the EPA classified this substance in Group D (Not Classifiable As To Human Carcinogenicity) (EPA OPP Annual Cancer Report 2020 (Accessed Sep. 2021)), the ACGIH classified it in A4 (ACGIH (8th, 2020)). (2) In a 2-year carcinogenicity study with rats dosed by feeding, no evidence of carcinogenicity was observed (Risk Assessment Report (Pesticide) (Food Safety Commission of Japan, 2008), EPA Pesticides (1994), ACGIH (8th, 2020)). (3) In a 2-year carcinogenicity study with mice dosed by feeding, increases in hepatocellular adenomas were observed in females of a group treated at the highest dose of 10,000 ppm. As preneoplastic lesions, an increase in foci of altered hepatocytes was observed in males at or above 2,500 ppm and in females at 10,000 ppm (Risk Assessment Report (Pesticide) (Food Safety Commission of Japan, 2008)). The assessment by the EPA finally judged that, even though cell adenoma in females showed a significant increase in a trend test, there was no significant difference in pairwise comparison test with controls, and liver tumor in mice was equivocal evidence (it was not possible to conclude whether the results were negative or positive) (EPA Pesticides (1994)). The assessment by the ACGIH also concluded that an increase in hepatocellular neoplastic nodules (males), and increases in the incidences of hepatocellular adenomas (males and females) and combined hepatocellular adenomas and carcinomas (males and females) were observed, but they were equivocal evidence for carcinogenicity (ACGIH (2020)).
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 reproduction toxicity study with rats dosed by feeding, only lower body weight was observed in F1/F2 offspring at the mid-dose (2,000 ppm) at which general toxicity (P females: decreased body weight gain, F1 females: decreased food consumption) appeared in parent animals, and a decrease in lactation index was observed in the second litter of F2 at the high dose (5,000 ppm) at which decreased body weight was added in F1 male and female parent animals. It was reported that there were no effects on fertility of parent animals, and there were no significant findings in offspring either to provide a rationale for the classification (Risk Assessment Report (Pesticide) (Food Safety Commission of Japan, 2008), ACGIH (8th, 2020), EPA Pesticides (1994), Patty (6th, 2012)). (2) It was reported that, in a developmental toxicity study with female rats dosed by gavage (days 7 to 16 of gestation), only lower body weight was observed in fetuses even at the highest dose (900 mg/kg/day) at which death (1/25 animals) and decreased final body weight were observed in dams (Risk Assessment Report (Pesticide) (Food Safety Commission of Japan, 2008), ACGIH (8th, 2020), EPA Pesticides (1994), Patty (6th, 2012)). (3) In a developmental toxicity study with female rabbits dosed by gavage (days 7 to 28 of gestation), at the highest dose (175 mg/kg/day), 21/22 animals died in dams, and developmental effects could not be assessed. It was reported that, at the one-level lower dose (125 mg/kg/day), marked toxicity, such as decreased body weight gain, decreased food consumption, abortion, death, and other symptoms (diarrhea, etc.), was observed in dams, while only lower body weight was observed in fetuses (Risk Assessment Report (Pesticide) (Food Safety Commission of Japan, 2008)).
8	Specific target organ toxicity - Single exposure	Category 3 (Narcotic effects)	Warning	H336	P304+P340 P403+P233 P261 P271 P312 P405 P501	[Rationale for the Classification] Based on (1), it was classified in Category 3 (narcotic effects). [Evidence Data] (1) It was reported that, in an acute oral toxicity test with rats and guinea pigs, lethargy, ataxia, salivation, prostration, chewing motions, and ruffled fur were observed in rats at 1,200 mg/kg (within the range for Category 2) and in guinea pigs at 860 mg/kg (within the range for Category 2) (ACGIH (2020)). [Reference Data, etc.] (2) It was reported that, in an acute oral toxicity test with dogs, vomiting, tremors, salivation, and rapid respiration were observed at 1,000 mg/kg (within the range for Category 2), but they disappeared the following day (ACGIH (2020)).
9	Specific target organ toxicity - Repeated exposure	Category 2 (liver)	Warning	H373	P260 P314 P501	[Rationale for the Classification] Based on (1), it was classified in Category 2 (liver). [Evidence Data] (1) It was reported that, in a 1-year chronic toxicity study with dogs dosed by feeding, an increase in ALP, wasting (males), a decrease in Alb (males), hepatocellular vacuolation (males), bodies in a concentric pattern in the liver (females), and hepatocellular pigmentation (females) were observed at 1,500 ppm (37.5 mg/kg/day, within the range for Category 2); and macrocytic anemia (moderate), a decrease in T.Chol, increases in AST and ALT, an increase in relative liver weight, centrilobular single cell necrosis, bodies in a concentric pattern in the liver, a decrease in absolute testis weight (males), hepatocellular pigmentation (males), and wasting (females) were observed at 6,000 ppm (150 mg/kg/day, in the range corresponding to "Not classified") (Risk Assessment Report (Pesticide) (Food Safety Commission of Japan, 2008), ACGIH (2020), EPA Pesticides RED (1994)). [Reference Data, etc.] (2) It was reported that, in a 2-year combined chronic toxicity/carcinogenicity study with rats dosed by feeding, decreased body weight gain, decreased food efficiency, and a decrease in body weight (males) were observed at 1,000 ppm (50 mg/kg/day, within the range for Category 2) (Risk Assessment Report (Pesticide) (Food Safety Commission of Japan, 2008), ACGIH (2020), FAO (2012), EPA Pesticides RED (1994)). (3) It was reported that, in a 2-year combined chronic toxicity/carcinogenicity study with mice dosed by feeding, foci of altered hepatocytes (males) and centrilobular hepatocellular hypertrophy (males) were observed at 2,500 ppm (366 mg/kg/day (males), 450 mg/kg/day (females), in the range corresponding to "Not classified") (Risk Assessment Report (Pesticide) (Food Safety Commission of Japan, 2008), ACGIH (2020), FAO (2012), EPA Pesticides RED (1994)).
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 72-hour ErC50 = 0.041 mg a.i./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, 2013). (a.i.: active ingredient)
11	Hazardous to the aquatic environment Long term (Chronic)	Category 1	Warning	H410	P273 P391 P501	If chronic toxicity data are used, then it is classified in Category 1 due to being not rapidly degradable (BIOWIN) and 72-hour NOErC = 0.0093 mg a.i./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, 2013). 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 3 due to being not rapidly degradable and 96-hour LC50 = 78 mg/L for crustacea (Palaemonetes pugio) (HSDB, 2021, OPP Pesticide Ecotoxicity Database). By drawing a comparison between the above results, it was classified in Category 1. (a.i.: active ingredient)
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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