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GHS Classification Results by the Japanese Government

GENERAL INFORMATION

Item	Information
CAS RN	33089-61-1
Chemical Name	3-methyl-1,5-di(2,4-xylyl)-1,3,5-triazapenta-1,4-diene; Amitraz
Substance ID	R02-B-103-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
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. It was classified as "Not classified."
2	Flammable gases	Not classified (Not applicable)	- -	-	-	Solid (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)	- -	-	-	Solid (GHS definition). It was classified as "Not classified."
5	Gases under pressure	Not classified (Not applicable)	- -	-	-	Solid (GHS definition). It was classified as "Not classified."
6	Flammable liquids	Not classified (Not applicable)	- -	-	-	Solid (GHS definition). It was classified as "Not classified."
7	Flammable solids	Classification not possible	- -	-	-	No data available. Besides, there is information that it is combustible (HSDB (Access on June 2020)).
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	Not classified (Not applicable)	- -	-	-	Solid (GHS definition). It was classified as "Not classified."
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). It was classified as "Not classified."
13	Oxidizing liquids	Not classified (Not applicable)	- -	-	-	Solid (GHS definition). It was classified as "Not classified."
14	Oxidizing solids	Not classified (Not applicable)	- -	-	-	Organic compounds containing no oxygen, fluorine or chlorine. 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	- -	-	-	Classification is not possible because 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. It was classified as "Not classified."

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) - (5). [Evidence Data] (1) LD50 for rats: 400-938 mg/kg (Canada Pesticides (2017), EU EMEA (1997)) (2) LD50 for rats: 400 mg/kg (GESTIS (Access on June 2020), HSDB (Access on June 2020)) (3) LD50 for rats: females: 515 mg/kg, males: 531 mg/kg (EPA Pesticides RED (1995)) (4) LD50 for rats: 600 mg/kg (JMPR (1999), Risk Assessment Report (Pesticides and Veterinary Medicinal Products) (Food Safety Commission of Japan, 2007), HSDB (Access on June 2020)) (5) LD50 for rats: males: 800 mg/kg (HSDB (Access on June 2020))
1	Acute toxicity (Dermal)	Classification not possible	- -	-	-	[Rationale for the Classification] The category could not be specified from (1), (2), and it was classified as "Classification not possible." [Evidence Data] (1) LD50 for rabbits: > 200 mg/kg (JMPR (1999), EPA Pesticides RED (1995), Risk Assessment Report (Pesticides and Veterinary Medicinal Products) (Food Safety Commission of Japan, 2007), GESTIS (Access on June 2020), HSDB (Access on June 2020)) (2) LD50 for rats: > 1,600 mg/kg (Canada Pesticides (2017), Risk Assessment Report (Pesticides and Veterinary Medicinal Products) (Food Safety Commission of Japan, 2007), HSDB (Access on June 2020))
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] It was classified as "Not classified" from (1). Besides, because an exposure concentration was higher than the saturated vapor pressure concentration (3.2E-005 mg/L), a reference value in the unit of mg/L was applied as dust. [Evidence Data] (1) LC50 for rats (6 hours): 65 mg/L (converted 4-hour equivalent value: 98 mg/L) (JMPR (1999), EU EMEA (1997), Risk Assessment Report (Pesticides and Veterinary Medicinal Products) (Food Safety Commission of Japan, 2007)) (2) Vapor pressure of this substance: 2.0E-006 mmHg (25 deg C) (HSDB (Access on May 2020)) (converted value for the saturated vapor pressure concentration: 3.2E-005 mg/L) [Reference Data, etc.] (3) LC50 for rats (exposure time: unkonwn): 2.4 mg/L (Canada Pesticides (2017), EPA Pesticides RED (1995))
2	Skin corrosion/irritation	Not classified	- -	-	-	[Rationale for the Classification] It was classified as "Not classified" from (1) - (4). [Evidence Data] (1) This substance was not irritating to the skin and eye of rabbits (JMPR (1999), Canada Pesticides (2017)). (2) This substance was minimally irritating to the eyes and skin of rabbits (Canada Pesticides (2017)). (3) It was not irritating in a skin irritation test with rabbits according to EPA OPP 81-5 (EPA Pesticides RED (1995)). (4) No irritation was observed in a skin irritation test with rabbits (Risk Assessment Report (Pesticides and Veterinary Medicinal Products) (Food Safety Commission of Japan, 2007), HSDB (Access on June 2020)).
3	Serious eye damage/eye irritation	Not classified	- -	-	-	[Rationale for the Classification] It was classified as "Not classified" from (1) - (4). [Evidence Data] (1) This substance was not irritating to the skin and eye of rabbits (JMPR (1999), Canada Pesticides (2017)). (2) This substance was minimally irritating to the eyes and skin of rabbits (Canada Pesticides (2017)). (3) It was not irritating in an eye irritation test with rabbits according to EPA OPP 81-4 (EPA Pesticides RED (1995)). (4) It was minimally to slightly irritating in an eye irritation test with rabbits (Risk Assessment Report (Pesticides and Veterinary Medicinal Products) (Food Safety Commission of Japan, 2007)).
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). Besides, positive and negative results were mixed in guinea pig tests, but by considering differences in the sensitivity of test methods, it was classified in Category 1. [Evidence Data] (1) This substance was not a sensitizer in a skin sensitization test with guinea pigs (Buehler test) (JMPR (1999), Canada Pesticides (2017)). (2) This substance was a sensitizer in a skin sensitization test with guinea pigs (maximization test) (Canada Pesticides (2018)). (3) It was reported to be negative in a skin sensitization test with guinea pigs according to EPA OPP 81-6 (EPA Pesticides RED (1995)). (4) In skin sensitization tests with guinea pigs, marked positive responses were seen in a maximization test, but it was negative in a Buehler test (Risk Assessment Report (Pesticides and Veterinary Medicinal Products) (Food Safety Commission of Japan, 2007)). [Reference Data, etc.] (5) It was classified in Skin Sens. 1 (H317) in EU-CLP classification (EU CLP classification (Access on August 2020)).
5	Germ cell mutagenicity	Not classified	- -	-	-	[Rationale for the Classification] It was classified as "Not classified" from (1) - (3). [Evidence Data] (1) As for in vivo, it was reported to be negative in a dominant lethal test by oral administration to mice and an unscheduled DNA synthesis test using rat liver (Risk Assessment Report (Pesticides and Veterinary Medicinal Products) (Food Safety Commission of Japan, 2007), JMPR (1998)). (2) As for in vitro, it was reported to be negative in a bacterial reverse mutation test and a chromosomal aberration test with cultured mammalian cells (same as the above). (3) It is reported that it was considered that this substance that did not have genotoxicity that could pose a problem in vivo (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2007)).
6	Carcinogenicity	Category 2	Warning	H351	P308+P313 P201 P202 P280 P405 P501	[Rationale for the Classification] It was classified in Category 2 based on classification results by other organizations in (1) and tumor formation observed in (2), (3). There was also an assessment that carcinogenicity was denied because it was due to large exposure, but a decision was made based on hazard. [Evidence Data] (1) As for classification results by domestic and international organizations, EPA classified it in S (Suggestive Evidence of Carcinogenic Potential) (EPA Annual Cancer Report 2019 (Access on September 2020): classified in 2006). (2) In a test by 2-year diet administration of this substance to rats, no carcinogenicity was observed. And in a test by 2-year diet administration of this substance to male and female mice, the incidences of hepatocellular adenoma and carcinoma in females and lung adenoma in males increased at the highest dose. Besides, based on reductions in body weight gains noted after 18 months of dosing, it was concluded that the highest dose exceeded the maximum tolerated dose. Therefore, the tumor response observed at the highest dose was not considered to be toxicologically significant, and it was concluded that this substance was not carcinogenic (Canada Pesticides (2017)). (3) In carcinogenicity tests by 18-month or 2-year diet administration of this substance to male and female mice, increased incidences of lymphoreticular tumors and hepatocellular carcinoma and adenoma were observed in females, but they were found only at doses where apparent toxicity was shown, and no genotoxicity was observed (Risk Assessment Report (Pesticides and Veterinary Medicinal Products) (Food Safety Commission of Japan, 2007)). [Reference Data, etc.] (4) In the latest assessment to set a residue limit for this substance, EPA stated that the tumors in the liver and lung found in a carcinogenicity test in mice were commonly seen in the mouse and were only found at a dose that appears to have been excessive given the other adverse effects seen in the animals (Federal Register Vol.78, No.54 (2013)). (5) In combined chronic toxicity/carcinogenicity tests by 2-year diet administration of this substance to male and female rats and mice, no carcinogenicity was observed (Risk Assessment Report (Pesticides and Veterinary Medicinal Products) (Food Safety Commission of Japan, 2007)).
7	Reproductive toxicity	Category 2, Additional category for effects on or via lactation	Warning	H361	P308+P313 P201 P202 P280 P405 P501	[Rationale for the Classification] Based on (1) to (4), effects on fertility, offspring, and fetuses were observed at a dose of parental toxicity, and therefore, it was classified in Category 2, and based on (1) and (2), effects on lactation were considered, and therefore, "effects on or via lactation" was added. A new information source was used and the classification results were changed from the previous classification. [Evidence Data] (1) In a three-generation reproductive study with rats dosed by feeding, mild transient inhibition was observed in development and food consumption in the P generation of a group treated at 200 ppm, and a marked increase in mortality occurred during the lactation period of the F1 generation of the same group. Therefore, the study of a group treated at 200 ppm was terminated with the F1 generation. In a group treated at 50 ppm, no effect of the administration of the test substance was observed in number of litters and mean litter size, but a slight increase in mortality was observed in offspring of all generations, and although there was no significant difference, the litter size on day 21 of lactation was smaller than that in a control group (Risk Assessment Report (Pesticides and Veterinary Medicinal Products) (Food Safety Commission of Japan, 2007)). (2) In an extended one-generation reproductive toxicity study with rats dosed by feeding, toxicity in offspring (an increase in thyroid/parathyroid weight on postnatal day 21 (females)), and postweaning effects in the F1 generation (a decrease in T4 on postnatal day 90 (females)) were observed at a dose (1.5 mg/kg/day) at which no toxicity was observed in P parent animals. At a dose (7.5 mg/kg/day) at which toxicity (hypoactivity, an increase in alkaline phosphatase activity, vocalization at contact, increased response to handling, a decrease in body weight, etc.) was observed in P parent animals, toxicity in offspring (increased death on postnatal days 1 to 5 (including loss of 6 pups of the dam which had convulsions on day 1 of lactation), a decrease in viability, a decrease in body weight on postnatal day of 21, reduced body weight gain on postnatal days of 7 to 21, decreases in the thickness of the hippocampal gyrus and corpus callosum on postnatal day of 21 (males)) was observed, and postweaning effects in the F1 generation (a decrease in body weight, increased response to handling, a decrease in rearing, hypoactivity, an increase in alkaline phosphatase activity, increases in AST, ALT, and GGT, an increase in bilirubin, vacuolization of the hepatocytes, nerve degeneration of the amygdala (1 animal), etc.), and reproductive toxicity (a slight decrease in number of liveborn F1 pups, a decrease in absolute uterus weight, persistent diestrus, an increase in proestrus, and an increase in primordial follicles in F1 female animals, etc.) were observed (Canada Pesticides (2017)). (3) In a developmental toxicity study with pregnant rats dosed by gavage, at doses (at or above 15 mg/kg/day) at which maternal toxicity (reduced body weight gain and a decrease in food consumption) was observed, distended ureter and bilateral dilated renal pelvis were observed in fetuses (Risk Assessment Report (Pesticides and Veterinary Medicinal Products) (Food Safety Commission of Japan, 2007)). (4) In a developmental toxicity study with pregnant rats dosed by gavage, at a dose (12 mg/kg/day) at which maternal toxicity (reduced body weight gain) was observed, lower body weight was observed in fetuses (Risk Assessment Report (Pesticides and Veterinary Medicinal Products) (Food Safety Commission of Japan, 2007)). [Reference Data, etc.] (5) In a developmental toxicity study with pregnant rabbits dosed by gavage, no effect was observed in fetuses at a dose at which maternal toxicity (a decrease in body weight, abortion, worsening of infection) was observed (Risk Assessment Report (Pesticides and Veterinary Medicinal Products) (Food Safety Commission of Japan, 2007)).
8	Specific target organ toxicity - Single exposure	Category 1 (nervous system), Category 3 (narcotic effects)	Danger Warning	H370 H336	P308+P311 P260 P264 P270 P321 P405 P501 P304+P340 P403+P233 P261 P271 P312	[Rationale for the Classification] Based on (1) to (3), it was classified in Category 1 (nervous system), and Category 3 (narcotic effects). New information sources were used and the classification results were changed from the previous classification. [Evidence Data] (1) In a 17-year-old male farmworker who ingested this substance (stock solution of 50 cc), coma, hypopnea, arterial hypotension, and bradycardia were observed (Risk Assessment Report (Pesticides and Veterinary Medicinal Products) (Food Safety Commission of Japan, 2007)). (2) As a result of a single oral dose of this substance (0.25 mg/kg) to two volunteers, drowsiness, disorientation, slurred speech, and decreased pulse rate and blood pressure were observed (EPA Pesticides RED (1995), JMPR (1999), HSDB (Access on June 2020)). (3) In an acute oral neurotoxicity test with rats, a decrease in body weight and a decrease in motor activity were observed at or above the minimum dose (50 mg/kg, within the range for Category 1). Soiled perioculus, bradypnea, and a decrease in grip strength of the forelimbs at or above 200 mg/kg (within the range for Category 1), and irritability, abnormal grip strength of the hindlimbs, convulsions, inability to walk, etc. at or above 800 mg/kg (within the range for Category 2) were observed (Canada Pesticides (2017)).
9	Specific target organ toxicity - Repeated exposure	Category 1 (central nervous system, liver)	Danger	H372	P260 P264 P270 P314 P501	[Rationale for the Classification] There was no report on repeated exposure to this substance in humans. Based on (1) to (4), effects on the central nervous system and liver at doses of Category 1 were observed in experimental animals. Therefore, it was classified in Category 1 (central nervous system, liver). As a review of the information, the classification result was changed from the previous classification. [Evidence Data] (1) It was reported that, in a 90-day oral toxicity test with dogs dosed by capsules, central nervous system depression, ataxia, reduced recurrent rectal temperature and heart rate, and enlargement of hepatocytes were observed at or above 1.0 mg/kg/day (within the range for Category 1) (Risk Assessment Report (Pesticides and Veterinary Medicinal Products) (Food Safety Commission of Japan, 2007), JMPR (1988), EPA Pesticides RED (1995)). (2) It was reported that, in a two-year test with rats dosed by feeding, jittery nerve, hyperexcitability, and aggression at 50 ppm (converted guidance value: 2.5 mg/kg/day, within the range for Category 1) were observed (Risk Assessment Report (Pesticides and Veterinary Medicinal Products) (Food Safety Commission of Japan, 2007), EPA Pesticides RED (1995)). (3) It was reported that in a two-year test with mice dosed by feeding, hyperplastic nodules, basophilic hepatocellular degeneration, and mottled vasodilatation of the liver in females at or above 25 ppm (converted guidance value: 1.25 mg/kg/day, within the range for Category 1), aggressive behavior in males at or above 100 ppm (converted guidance value: 5 mg/kg/day, within the range for Category 1), and an increase in locomotor activity, increases in piloerection and hunchback position, and hepatic mass in males at 400 ppm (converted guidance value: 20 mg/kg/day, within the range for Category 2) were observed (Risk Assessment Report (Pesticides and Veterinary Medicinal Products) (Food Safety Commission of Japan, 2007), EPA Pesticides RED (1995)). (4) It was reported that, in a 21-day inhalation exposure test with rats, dyspnea, decreased sensitivity to sound, hypersensitivity to digital examination, and aggression were observed at or above 0.1 mg/L (dust, within the range for Category 2) (Risk Assessment Report (Pesticides and Veterinary Medicinal Products) (Food Safety Commission of Japan, 2007), EPA Pesticides RED (1995)).
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 48-hour EC50 = 0.035 mg/L for crustacea (Daphnia magna) (EPA RED, 1995).
11	Hazardous to the aquatic environment Long term (Chronic)	Category 1	Warning	H410	P273 P391 P501	It was classified in Category 1 because it is not rapidly degradable (BIOWIN) and due to 21-day NOEC = 0.0011 mg/L for crustacea (Daphnia magna) (ECOTOX, 2020, EPA OPP Pesticide Ecotoxicity Database, 2020).
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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