NITE - Chemical Management Field

GHS Classification Results by the Japanese Government

GENERAL INFORMATION

Item	Information
CAS RN	108-45-2
Chemical Name	m-Phenylenediamine
Substance ID	R01-B-009
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	FY2009 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 are no chemical groups associated with explosive properties present in the molecule. It was classified as "Not classified (Not applicable)."
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 no chemical groups associated with explosive or self-reactive properties present in the molecule. It was classified as "Not classified (Not applicable)."
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 an autoignition temperature of 560 deg C (ICSC (1999)).
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	*	- -	-	-	Organic compounds containing no oxygen, fluorine or chlorine. 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	*	- -	-	-	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 3	Danger	H301	P301+P310 P264 P270 P321 P330 P405 P501	[Rationale for the Classification] Based on (1)-(3), by giving priority to the values to be on the safe side, it was classified in Category 3. [Evidence Data] (1) LD50 for rats: 204-650 mg/kg (Initial Risk Assessment Report (NITE, CERI, NEDO, 2008)) (2) LD50 for rats: 280 mg/kg (Environmental Risk Assessment for Chemical Substances Vol.13 (Ministry of the Environment, 2015)) (3) LD50 for rats: 650 mg/kg (IARC 16 (1978), ACGIH (7th, 2001), DFGOT vol.6 (1994))
1	Acute toxicity (Dermal)	Category 4	Warning	H312	P302+P352 P362+P364 P280 P312 P321 P501	[Rationale for the Classification] Based on (1), it was classified in Category 4. [Evidence Data] (1) LD50 for rats: 1,100 mg/kg (Initial Risk Assessment Report (NITE, CERI, NEDO, 2008))
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] Classification not possible due to lack of data.
2	Skin corrosion/irritation	*	- -	-	-	[Rationale for the Classification] Based on (1), it was classified as "Not classified." [Evidence Data] (1) In a skin irritation test in which this substance was applied to rabbits for 4 hours according to EEC Directive 93/21, Annex VI, slight to mild erythema was observed in all animals 1 to 24 hours after removal of the test substance, slight erythema was observed in 2/6 animals after 48 hours, only slight edema was observed in 4 animals after 24 hours, and the mean scores at 1/24/48 hours was 1.39 (REACH registration dossier (Access on June 2019)). [Reference Data, etc.] (2) In a test in which 500 mg was applied occlusively to the auricles of rabbits for 24 hours, no irritation was noted (Initial Risk Assessment Report (NITE, CERI, NEDO, 2008)).
3	Serious eye damage/eye irritation	Category 2B	- Warning	H320	P305+P351+P338 P337+P313 P264	[Rationale for the Classification] Based on (1), it was classified in Category 2B. [Evidence Data] (1) In a rabbit eye irritation test according to OECD TG 405, severe conjunctival redness, moderate corneal opacity, moderate iritis, hemorrhage, chemosis, and damage to the cornea occurred. In addition, severe chemosis was observed in the eyes of unwashed rabbits, but all recovered by 7 days. The mean scores for corneal opacity, iris, conjunctival redness and chemosis at 24, 48, and 72 hours in the unwashed group were 0.67, 0, 2.7, and 2.0, respectively (REACH registration dossier (Access on June 2019)). [Reference Data, etc.] (2) It is reported that in a test in which 0.1 mL (equivalent to 20 mg) of a 20% aqueous solution was instilled into the eyes of rabbits, conjunctival redness and corneal opacity were observed which resolved within 7 days, and it is reported that in a test in which 50 mg was applied, corneal opacity was noted and this did not resolve within 7 days (Initial Risk Assessment Report (NITE, CERI, NEDO, 2008)). (3) It was classified as "Eye Irrit. 2 (H319)" in the EU-CLP classification (EU CLP classification (Access on May 2019)).
4	Respiratory sensitization	*	- -	-	-	[Rationale for the Classification] There is data in (1). However, since it was impossible to determine the classification of "respiratory sensitization," it was classified as "Classification not possible." [Reference Data, etc.] (1) A worker who had been repeatedly exposed to this substance due to the leakage accidents of this substance in the United States developed a wet cough, fatigue, shortness of breath in addition to skin symptoms by inhalation exposure, and decreased vital capacity, chest X-ray findings were observed and pulmonary fibrosis was observed at open lung biopsy, therefore, the person was diagnosed scleroderma. Since similar symptoms were observed in another worker in the same department, this substance was considered to be a causative agent (Environmental Risk Assessment for Chemical Substances Vol.13 (Ministry of the Environment, 2015)).
4	Skin sensitization	Category 1A	Warning	H317	P302+P352 P333+P313 P362+P364 P261 P272 P280 P321 P501	[Rational for the Classification] Based on (1), since new data that enabled sub-categorization were obtained, it was classified in Category 1A. [Evidence Data] (1) In a mouse local lymph node assay (LLNA) compliant with OECD TG 429, it was positive, and the EC3 was estimated to be 0.49 (REACH registration dossier (Access on June 2019), The MAK-Collection Part I, MAK Value Documentations 2015). [Reference Data, etc.] (2) It was classified as occupational skin sensitizers Group 3 (OEL Documentations (provisional) (Japan Society For Occupational Health (JSOH), 2010)). (3) In humans, a worker exposed three times in a month to spill accidents of this substance in the United States developed Raynaud's phenomenon and swelling of the hands about two years later. Three months later, they were exposed to this substance by inhalation and developed skin and respiratory symptoms such as swelling of the fingers and hands, skin thickening and hyperpigmentation. Since similar cases were observed in another worker in the same department, this substance was considered to be the causative agent (Environmental Risk Assessment for Chemical Substances Vol.13 (Ministry of the Environment, 2015)). (4) Reports on sensitization of this substance in humans were insufficient (The MAK-Collection Part I, MAK Value Documentations 2015). (5) Negative results were obtained in skin sensitization tests with guinea pigs (The MAK-Collection Part I, MAK Value Documentations 2015).
5	Germ cell mutagenicity	*	- -	-	-	[Rationale for the Classification] From (1) and (2), based on the weight of evidence by expert judgment, it was classified as "Not classified." In the previous classification, it was classified in Category 2 based on the data in IUCLID, but it became unreferenceable and the category was changed because the evidence data had changed. [Evidence Data] (1) As for in vivo, there were reports of negative results in a dominant lethal test with rats by intraperitoneal administration, an unscheduled DNA synthesis test with germ cells of male rats, and micronucleus tests with bone marrow cells of rats and mice (IARC 16 (1978), BUA 97 (1992), DFGOT vol.6 (1994), DFGOT vol.21 (2005), Cosmetic Ingredient Review Report (2012), OEL Documentations (Japan Society For Occupational Health (JSOH), 1999), ACGIH (7th, 2001), Initial Risk Assessment Report (NITE, CERI, NEDO, 2008), Environmental Risk Assessment for Chemical Substances Vol.13 (Ministry of the Environment, 2015)). (2) As for in vitro, there were reports of positive results in a bacterial reverse mutation test, a mouse lymphoma TK test, and a chromosomal aberration test with cultured mammalian cells (IARC 16 (1978), DFGOT vol.6 (1994), DFGOT vol.21 (2005), OEL Documentations (Japan Society For Occupational Health (JSOH), 1999), ACGIH (7th, 2001), Initial Risk Assessment Report (NITE, CERI, NEDO, 2008), Environmental Risk Assessment for Chemical Substances Vol.13 (Ministry of the Environment, (2015))).
6	Carcinogenicity	*	- -	-	-	[Rationale for the Classification] Based on classification results by other organizations in (1), it was classified as "Classification not possible" 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 in 3 by IARC (IARC Suppl.7 (1987)) and A4 by ACGIH (ACGIH (7th, 2001)). [Reference Data, etc.] (2) In a carcinogenicity study in which mice were given this substance in drinking water for 78 weeks, no increased incidence of tumors was observed in males and females (Initial Risk Assessment Report (NITE, CERI, NEDO, 2008), Environmental Risk Assessment for Chemical Substances Vol.13 (Ministry of the Environment, 2015), ACGIH (7th, 2001)). (3) In a test in which an acetone solution of this substance was applied dermally for 2 years, no increased incidence of tumors was observed in males and females (Initial Risk Assessment Report (NITE, CERI, NEDO, 2008), Environmental Risk Assessment for Chemical Substances Vol.13 (Ministry of the Environment, 2015), ACGIH (7th, 2001)). (4) In a carcinogenicity study in which the dihydrochloride of this substance (CAS RN 541-69-5) was administered by drinking water for 104 weeks, no carcinogenicity was noted in males and females (Results from Carcinogenicity Studies (Ministry of Health, Labour and Welfare) (Access on June 2019)).
7	Reproductive toxicity	*	- -	-	-	[Rationale for the Classification] Since there was not enough information to contribute to the evaluation and classification of the reproductive and developmental toxicity of this substance, classification was not possible. Besides, the category was changed by reviewing the evidence data for the classification. [Reference Data, etc.] (1) In a developmental toxicity test in which female rats were dosed by gavage on gestational Days 6-15, an increase in resorptions, a decrease in the number of viable fetuses, lower fetal body weight and delayed ossification of the sternum were observed at the dose where reduced body weight gain or death (6/25 animals) was observed in maternal animals (Environmental Risk Assessment for Chemical Substances Vol.13 (Ministry of the Environment, 2015), ACGIH (7th, 2001), DFGOT vol.6 (1994)). This data was not adopted as evidence for classification because effects on embryos/fetuses were observed only at the dose where maternal toxicity (deaths in 6/25 animals, 24% mortality) was observed. (2) In a developmental toxicity test in which female rats were dosed by gavage on gestational Days 6-15, reduced body weight gain was observed in maternal animals, but no effects on fetal development were observed (Environmental Risk Assessment for Chemical Substances Vol.13 (Ministry of the Environment, 2015), Initial Risk Assessment Report (NITE, CERI, NEDO, 2008), ACGIH (7th, 2001), DFGOT vol.6 (1994)). The number of maternal animals is as small as 7-9 animals/group on this data and is insufficient to evaluate the effects.
8	Specific target organ toxicity - Single exposure	Category 1 (central nervous system, blood system)	Danger	H370	P308+P311 P260 P264 P270 P321 P405 P501	[Rationale for the Classification] There are no reports on single exposure to this substance in humans. In experimental animals, effects on the central nervous system and blood system were seen at doses corresponding to Category 1 as in (1) and (2). Therefore, it was classified in Category 1 (central nervous system, blood system) [Evidence Data] (1) In a single oral dose test with cats, cyanosis, loss of appetite, respiratory disturbance, sedation, convulsions, and production of methemoglobin were observed at 10 and 25 mg/kg (corresponding to Category 1) (Initial Risk Assessment Report (NITE, CERI, NEDO, 2008), BUA 97 (1992)). (2) In a single oral dose test with rats, convulsions and inflammation of the gastrointestinal tract were observed at 200 mg/kg (corresponding to Category 1) (Initial Risk Assessment Report (NITE, CERI, NEDO, 2008), BUA 97 (1992)).
9	Specific target organ toxicity - Repeated exposure	Category 1 (urinary bladder), Category 2 (heart, kidney, muscle, blood system)	Danger Warning	H372 H373	P260 P264 P270 P314 P501	[Rationale for the Classification] Based on (1), effects on the urinary bladder were observed due to exposure in humans, and based on (2)-(4), effects on the kidney and blood system were observed within the range of Category 2 by oral administration of the dihydrochloride salt of this substance (CAS RN 541-69-5) to rats and mice. Therefore, it was classified in Category 1 (urinary bladder), Category 2 (heart, kidney, muscle, blood system). Besides, the classification result was changed from the previous classification by adding new information sources and reviewing. [Evidence Data] (1) One hundred and twelve workers in their 30s to 50s in a Russian factory producing phenylenediamine were exposed to 1-2 mg/m3 of this substance for 5-10 years, 15 of them complained of dysuria. In a scratch test with this substance, 9 out of the 112 persons showed an allergy-positive reaction, and edema of the mucous membranes and polypous swellings were observed in the triangle and cervix of the urinary bladder in cystoscopy of the persons who showed a positive reaction, and all of the 9 persons were diagnosed eosinophilia. In addition, 0.003-0.40 mg/L of this substance was detected in the urine (DFGOT vol.6 (1994), ACGIH (7th, 2001), Initial Risk Assessment Report (NITE, CERI, NEDO, 2008), Environmental Risk Assessment for Chemical Substances Vol.13 (Ministry of the Environment,2015)). (2) When rats were given 62.5-1,000 ppm of the dihydrochloride salt of this substance by drinking water for 13 weeks, increased kidney weight and pigmentation in the kidneys in females at or above 250 ppm (a converted value equivalent to this substance: 14 mg/kg/day, within the range of Category 2), slight degeneration of the renal papilla, etc. in males and females at or above 500 ppm (a converted value equivalent to this substance: male: 18 mg/kg/day, female: 19 mg/kg/day, within the range of Category 2), and decreased platelet count, etc. in males and females at 1,000 ppm (a converted value equivalent to this substance: male: 32 mg/kg/day, female: 34 mg/kg/day, within the range of Category 2) were observed (Results from Carcinogenicity Studies (Ministry of Health, Labour and Welfare) (Access on June 2019)). (3) When mice were given 24.4-2,000 ppm of the dihydrochloride salt of this substance in drinking water for 13 weeks, increases in AST, ALP and total cholesterol, pigment granules in Kupffer cells in the liver and in the spleen at 222 ppm (a converted value equivalent to this substance: male: 17 mg/kg/day, female: 31 mg/kg/day, within the range of Category 2), decreased red blood cell counts, hemoglobin and hematocrit, etc. at or above 667 ppm (a converted value equivalent to this substance: male: 29 mg/kg/day, female: 40 mg/kg/day, within the range of Category 2), and deaths at 2,000 ppm (male: 108 mg/kg/day, female: 132 mg/kg/day, exceeding Category 2) were observed. Heart dilation and muscle necrosis, etc. were also observed in the dead or moribund animals (Results from Carcinogenicity Studies (Ministry of Health, Labour and Welfare) (Access on June 2019)). (4) When this substance was administered by drinking water to rats for 90 days, increased liver weight, pyknosis of hepatocyte, and increased kidney weight were observed at 18 mg/kg/day (within the range of Category 2) (IRIS (1987), DFGOT vol.6 (1994), ACGIH (7th, 2001), Initial Risk Assessment Report (NITE, CERI, NEDO, 2008), Environmental Risk Assessment for Chemical Substances Vol.13 (Ministry of the Environment, 2015)). [Reference Data, etc.] (5) There was a report that two male chemical factory workers who were exposed to amines containing this substance as the main component suffered from systemic sclerosis (Initial Risk Assessment Report (NITE, CERI, NEDO, 2008), Environmental Risk Assessment for Chemical Substances Vol.13 (Ministry of the Environment, 2015)). (6) When mice were given 0.02 and 0.04% (within the range of Category 2) of this substance by drinking water for 78 weeks, increased organ weights and pigmentation, etc., but no toxicological effects on tissues were observed (Initial Risk Assessment Report (NITE, CERI, NEDO, 2008), Environmental Risk Assessment for Chemical Substances Vol.13 (Ministry of the Environment, 2015)).
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 2	- -	H401	P273 P501	It was classified in Category 2 from 48-hour EC50 = 2 mg/L for crustacea (Daphnia magna) (Results of Aquatic Toxicity Tests of Chemicals conducted by Ministry of the Environment in Japan (Ministry of the Environment, 2001), Environmental Risk Assessment for Chemical Substances Vol. 13 (Ministry of the Environment, 2015)).
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 (not readily degradable, a degradation rate by BOD: 2% (Biodegradation and Bioconcentration Results of Existing Chemical Substances under the Chemical Substances Control Law, 2002)), and 21-day NOEC = 0.05 mg/L for crustacea (Daphnia magna) (Environmental Risk Assessment for Chemical Substances Vol. 13 (Ministry of the Environment, 2015)). If acute toxicity data are used for a trophic level for which chronic toxicity data are not obtained, then it is classified as "Not classified" due to being not rapidly degradable (not readily degradable, a degradation rate by BOD: 2% (Biodegradation and Bioconcentration Results of Existing Chemical Substances under the Chemical Substances Control Law, 2002)), and 96-hour LC50 > 100 mg/L for fish (Oryzias latipes) (Results of Aquatic Toxicity Tests of Chemicals conducted by Ministry of the Environment in Japan (Ministry of the Environment, 2001), Environmental Risk Assessment for Chemical Substances Vol. 13 (Ministry of the Environment, 2015)). By drawing a comparison between the above results, it was classified in Category 1.
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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