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GHS Classification Results by the Japanese Government

GENERAL INFORMATION

Item	Information
CAS RN	119446-68-3
Chemical Name	1-({2-[2-chloro-4-(4-chlorophenoxy)phenyl]-4-methyl-1,3-dioxolan-2-yl}methyl)-1H-1,2,4-triazole; Difenoconazole
Substance ID	R01-B-078
Classification year (FY)	FY2019
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 (FY2013 revised edition (Ver. 1.1))
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	*	- -	-	-	There is a chemical group associated with explosive properties (neighboring nitrogen atoms) present in the molecule, but the classification is not possible due to no data.
2	Flammable gases	*	- -	-	-	Solid (GHS definition). It was classified as "Not classified (Not applicable)."
3	Aerosols	*	- -	-	-	Not aerosol products. It was classified as "Not classified (Not applicable)."
4	Oxidizing gases	*	- -	-	-	Solid (GHS definition). It was classified as "Not classified (Not applicable)."
5	Gases under pressure	*	- -	-	-	Solid (GHS definition). It was classified as "Not classified (Not applicable)."
6	Flammable liquids	*	- -	-	-	Solid (GHS definition). It was classified as "Not classified (Not applicable)."
7	Flammable solids	*	- -	-	-	No data available.
8	Self-reactive substances and mixtures	*	- -	-	-	There are neighboring nitrogen atoms, a chemical group associated with explosive properties, present in the molecule, but the classification is not possible due to no data.
9	Pyrophoric liquids	*	- -	-	-	Solid (GHS definition). It was classified as "Not classified (Not applicable)."
10	Pyrophoric solids	*	- -	-	-	It was classified as "Not classified" because it is estimated that it does not ignite at normal temperatures from information that it is stable at up to 150 deg C (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2017)).
11	Self-heating substances and mixtures	*	- -	-	-	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	*	- -	-	-	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 (Not applicable)."
13	Oxidizing liquids	*	- -	-	-	Solid (GHS definition). It was classified as "Not classified (Not applicable)."
14	Oxidizing solids	*	- -	-	-	The substance is an organic compound containing chlorine and oxygen (but not fluorine) which are chemically bonded only to carbon or hydrogen. It was classified as "Not classified (Not applicable)."
15	Organic peroxides	*	- -	-	-	Organic compounds containing no bivalent -O-O- structure in the molecule. It was classified as "Not classified (Not applicable)."
16	Corrosive to metals	*	- -	-	-	Classification is not possible because test methods applicable to solid substances are not available.
17	Desensitized explosives	*	- -	-	-	It was classified as "Not classified" because it is not desensitized by wetting, dilution, etc.

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), it was classified in Category 4. [Evidence Data] (1) LD50 for rats: 1,453 mg/kg (JMPR (2007), Risk Assessment Report (Pesticides, Food additives) (Food Safety Commission, 2019), Food Sanitation Research, Vol.46, No.5 (1996) (Japan Crop Protection Association), A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2017), HSDB (Access on September 2019))
1	Acute toxicity (Dermal)	*	- -	-	-	[Rationale for the Classification] Based on (1) and (2), it was classified as "Not classified." [Evidence Data] (1) LD50 for rabbits: >2,010 mg/kg (JMPR (2007), Risk Assessment Report (Pesticides, Food additives) (Food Safety Commission, 2019), A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2017), HSDB (Access on September 2019)) (2) LD50 for rats: 2,010 mg/kg (HSDB (Access on September 2019))
1	Acute toxicity (Inhalation: Gases)	*	- -	-	-	[Rationale for the Classification] Solid (GHS definition). It was classified as "Not classified (Not applicable)."
1	Acute toxicity (Inhalation: Vapours)	*	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
1	Acute toxicity (Inhalation: Dusts and mists)	*	- -	-	-	[Rationale for the Classification] The category could not be specified based on (1). Therefore, it was classified as "Classification not possible." [Evidence Data] (1) LC50 (dust, 4 hours) for rats: > 3,300 mg/m3 (3.3 mg/L) (JMPR (2007), Risk Assessment Report (Pesticides, Food additives) (Food Safety Commission, 2019), A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2017), HSDB (Access on September 2019))
2	Skin corrosion/irritation	*	- -	-	-	[Rationale for the Classification] Based on (1)-(4), it was classified as "Not classified." [Evidence Data] (1) In a skin irritation test in which the substance (0.5 g) was applied to rabbits for 4 hours, 1/6 of the animals showed very slight erythema 30 minutes after the application, but this disappeared after 24 hours. No skin reactions were observed in the other 5 animals (JMPR (2007), A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2017)). (2) In a skin irritation test in which the substance (0.5 g) was applied to rabbits for 4 hours, 1/6 of the animals showed very slight erythema 30 minutes and 24 hours after removal, but it disappeared 48 hours after removal, and the other 5 animals showed no skin reaction (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2017)). (3) No irritation was observed in a skin irritation test with rabbits (Risk Assessment Report (Pesticides, Food additives) (Food Safety Commission, 2019)). (4) This substance was very slightly irritating to the skin of rabbits (HSDB (Access on September 2019)).
3	Serious eye damage/eye irritation	Category 2B	- Warning	H320	P305+P351+P338 P337+P313 P264	[Rationale for the Classification] Based on (1)-(4), it was classified in Category 2B. [Evidence Data] (1) In an eye irritation test in which this substance (0.1 g) was applied to the eyes of rabbits, the average scores for the cornea, iris, conjunctival redness and conjunctival edema at 24/48/72 hours were 0.44, 0.44, 2.0, 0.83, and all reactions had cleared by Day 4 after treatment (JMPR (2007)). (2) In an eye irritation test with this substance (0.1 g) applied to the eyes of rabbits, the mean scores for the cornea, iris, conjunctival redness and chemosis at 24/48/72 hours were 0.66, 0.1, 1.16 and 1.16 and all symptoms resolved within 7 days (A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2017)). (3) Moderate irritation was observed in an eye irritation test with rabbits (Risk Assessment Report (Pesticides, Food additives) (Pesticides, Food additives) (Food Safety Commission, 2019)). (4) This substance was moderately irritating to the eyes of rabbits (HSDB (Access on September 2019)).
4	Respiratory sensitization	*	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
4	Skin sensitization	*	- -	-	-	[Rationale for the Classification] Based on (1) and (2), it was classified as "Not classified." [Evidence Data] (1) In a skin sensitization test with guinea pigs (a modified Buehler method), no positive reactions were observed and it was concluded that this substance was not sensitizing (JMPR (2007), HSDB (Access on September 2019), A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2017)). (2) In a skin sensitization test with guinea pigs (guinea pig maximization test), the substance was judged as negative for sensitization (Risk Assessment Report (Pesticides, Food additives) (Food Safety Commission, 2019), Agricultural Chemicals Times supplement "Agricultural chemicals technology information" Vol.16 (1996) (Japan Crop Protection Association)).
5	Germ cell mutagenicity	*	- -	-	-	[Rationale for the Classification] Based on (1) and (2), it was classified as "Not classified." [Evidence Data] (1) As for in vivo, a negative result was reported in a micronucleus test with mice (JMPR (2007), Risk Assessment Report (Pesticides, Food additives) (Food Safety Commission, 2019), A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2017)). (2) As for in vitro, negative results were reported in a bacterial reverse mutation test, chromosomal aberration tests with human lymphocytes, and unscheduled DNA synthesis tests and a gene mutation test with cultured mammalian cells, and a positive (S9+) result was reported in a chromosomal aberration test (same as above). [Reference Data, etc.] (3) As for in vivo, a negative result was reported in a nuclear abnormality induction test (Risk Assessment Report (Pesticides, Food additives) (Food Safety Commission, 2019), A pesticide abstract and evaluation report (Food and Agricultural Materials Inspection Center, 2017)).
6	Carcinogenicity	Category 2	Warning	H351	P308+P313 P201 P202 P280 P405 P501	[Rationale for the Classification] Based on the classification results by other organizations described in (1), it was classified in Category 2 in accordance with the GHS Classification Guidance for the Japanese Government. [Evidence Data] (1) As for classification results by domestic and international organizations, it was classified as S by EPA (Suggestive Evidence of Carcinogenicity) (EPA Annual Cancer Report (2018): classified in 2007). [Reference Data, etc.] (2) In a combined chronic toxicity/carcinogenicity study in which this substance was administered by feeding to rats for 2 years, no neoplastic lesions with increased incidence were observed after administration (Risk Assessment Report (Pesticides, Food additives) (Food Safety Commission, 2019)). (3) In a carcinogenicity test with mice in which this substance was administered by feeding for 18 months, increased incidences of hepatocellular adenomas in males and females and hepatocellular carcinomas in males were observed (Risk Assessment Report (Pesticides, Food additives) (Food Safety Commission, 2019)).
7	Reproductive toxicity	*	- -	-	-	[Rationale for the Classification] Based on (1)-(3), as no clear reproductive and developmental effects were observed, this substance was classified as "Not classified." [Evidence Data] (1) In a 2-generation reproductive toxicity test with rats dosed by feeding, low body weight (F1 and F2 generations) and decreased viability index on postnatal Day 4 (observed only in F1 males, slight and no significant difference) were observed in pups at the dose at which reduced body weight gain and decreased food consumption were observed in parental animals (Risk Assessment Report (Pesticides, Food additives) (Food Safety Commission, 2019), JMPR (2007)). Besides, decreased viability index on postnatal Day 4 observed in males was found to be significantly different in a trend test (JMPR (2007)). (2) In a developmental toxicity test in which female rats were administered by gavage on Days 6-15 of gestation, a reduced trend in body weight, delayed ossification such as bifid and unilaterally ossified thoracic vertebral centres, an increase in the number of ribs accompanied by changes in the number of vertebrae (an increase in the number of thoracic vertebrae and a decrease in the number of lumbar vertebrae) were observed in fetuses at the dose at which maternal toxicity (salivation, decreased body weight gain, decreased food consumption) was observed (Risk Assessment Report (Pesticides, Food additives) (Food Safety Commission, 2019), JMPR (2007)) (3) In a developmental toxicity test with female rabbits dosed by gavage on Days 7-19 of gestation, no effects on fetuses or teratogenicity were observed at the dose at which maternal toxicity (death (1/19 animal), miscarriages (2 animals), decreased body weight gain, decreased food consumption) was observed (Risk Assessment Report (Pesticides, Food additives) (Food Safety Commission, 2019), JMPR (2007)).
8	Specific target organ toxicity - Single exposure	Category 2 (central nervous system)	Warning	H371	P308+P311 P260 P264 P270 P405 P501	[Rationale for the Classification] There are no reports of a single human exposure to this substance. As for experimental animals, based on the information in (1)-(3), it was classified in Category 2 (central nervous system). The classification result was changed from the previous classification by using the new information sources. [Evidence Data] (1) In a single oral dose test with rats, hypoactivity, ataxia, hypothermia, prostration and spasms were observed at or above 1000 mg/kg (equivalent to Category 2) (JMPR (2007), Risk Assessment Report (Pesticides, Food additives) (Food Safety Commission, 2019)). (2) In a single oral dose test with mice, hypolocomotion, staggering gait and crawling gait were observed at or above 400 mg/kg (equivalent to Category 2) (Evaluation of effect for the food safety (Food Safety Commission, 2019)). In addition, in another single oral dose test with mice, reduced locomotor activity and ataxia were observed at or above 1,000 mg/kg and tonic spasms were observed at 2,000 mg/kg (upper limit of Category 2) (JMPR (2007), Risk Assessment Report (Pesticides, Food additives) (Food Safety Commission, 2019)). (3) In a 4-hour single inhalation exposure test with rats, piloerection, dyspnea, hunched posture and reduced locomotion were observed at 3.29 mg/L of the aerosol of this substance (equivalent to Category 2) (JMPR (2007), Risk Assessment Report (Pesticides, Food additives) (Food Safety Commission, 2019)).
9	Specific target organ toxicity - Repeated exposure	Category 2 (visual organs, liver)	Warning	H373	P260 P314 P501	[Rationale for the Classification] Based on (1)-(5), it was classified in Category 2 (visual organs, liver). The classification result was changed from the previous classification by examination using the new information sources. [Evidence Data] (1) In a 90-day repeated dose toxicity test with rats by dietary administration, increased liver weight in males and females, and decreased erythrocyte count, decrease in hemoglobin and hematocrit, etc. in males were observed at or above 750 ppm (males/females: 50.7/65.7 mg/kg/day, within the range of Category 2) (Evaluation of effect for the food safety (Food Safety Commission, 2019)). (2) In a 90-day repeated dose toxicity test with mice by administration in the diet, centrilobular hypertrophy of hepatocytes in males and females and increased AST (only at 250 ppm), etc. in males were observed at or above 250 ppm (male/female: 34.8/37.2 mg/kg/day, within the range of Category 2) (Evaluation of effect for the food safety (Food Safety Commission, 2019)). (3) In a 28-week repeated dose toxicity test with dogs by dietary administration, lens opacity (cataract) in males and females and increased ALP, irregular pupillary margin, miosis and increased absolute liver weight (only at 3,000 ppm), etc. in females were observed at or above 3,000 ppm (male/female: 96.6/111, male: within the range of Category 2, females: exceeding Category 2) (Evaluation of effect for the food safety (Food Safety Commission, 2019)). (4) In a combined chronic toxicity/carcinogenicity study with rats by administration in the diet for 2 years, hepatocellular hypertrophy in males and females and decreased platelets, etc. in males were observed at or above 500 ppm (male/female: 24.1/32.8 mg/kg/day, within the range of Category 2) (Evaluation of effect for the food safety (Food Safety Commission, 2019)). (5) In an 18-month repeated dose toxicity test with mice by administration in the diet, an increase of SDH, hepatic single cell necrosis and hepatocellular hypertrophy in males and increased liver weight, etc. in females were observed at or above 300 ppm (males/females: 46.3/57.8 mg/kg/day, within the range of Category 2) (Evaluation of effect for the food safety (Food Safety Commission, 2019)).
10	Aspiration hazard	*	- -	-	-	[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 = 0.001329 mg/L for fish (Danio rerio) (HSDB, 2019, AQUIRE, 2020, Dong, 2013).
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 268-day NOEC = 0.0019 mg/L for fish (Pimephales promelas) (U.S.EPA: OPP Pesticide Ecotoxicity Database, 2020).
12	Hazardous to the ozone layer	Classification not possible	- -	-	-	Classification not possible due to lack of data.

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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