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GHS Classification Results by the Japanese Government

GENERAL INFORMATION

Item	Information
CAS RN	3165-93-3
Chemical Name	4-chloro-o-toluidinium chloride
Substance ID	R02-B-073-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 (GESTIS (Access on May 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)	- -	-	-	The substance is an organic compound containing chlorine (but not fluorine or oxygen) which is chemically bonded only to carbon or hydrogen. 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), (2). [Evidence Data] (1) LD50 for rats: 860 mg/kg (MAK (DFG) vol.6 (1994), AICIS (formerly, NICNAS) IMAP (2014), GESTIS (Access on May 2020)) (2) LD50 for rats: 1,000 mg/kg (Risk Assessment Report (Ministry of Health, Labour and Welfare, 2009))
1	Acute toxicity (Dermal)	Not classified	- -	-	-	[Rationale for the Classification] It was classified as "Not classified" from (1), (2). [Evidence Data] (1) LD50 for rats: 2,150 mg/kg (Risk Assessment Report (Ministry of Health, Labour and Welfare, 2009)) (2) LD50 for rats: > 2,150 mg/kg (MAK (DFG) vol.6 (1994), AICIS (formerly, NICNAS) IMAP (2014))
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)	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
2	Skin corrosion/irritation	Classification not possible	- -	-	-	[Rationale for the Classification] There were descriptions of (1), (2), but because they were no sufficient data for classification, the classification was not possible. The rationale data for the previous classification were considered to be based on data on the free base of this substance (4-chloro-2-methylaniline, CAS RN 95-69-2), therefore, the classification result was changed. [Reference Data, etc.] (1) In an experiment by 24-hour occlusive application of this substance (500, 1,000, 2,000 mg/kg) to the rat skin, small red spots were seen at the application site (MAK (DFG) vol.6 (1994)). (2) This substance may cause skin irritation in humans (AICIS (formerly, NICNAS) IMAP (2014)).
3	Serious eye damage/eye irritation	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
4	Respiratory sensitization	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
4	Skin sensitization	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
5	Germ cell mutagenicity	Category 2	Warning	H341	P308+P313 P201 P202 P280 P405 P501	[Rationale for the Classification] It was classified in Category 2 from (1), (2). [Evidence Data] (1) As for in vivo, it was reported to be positive in a mouse spot test (Risk Assessment Report (Ministry of Health, Labour and Welfare, 2009), AICIS (formerly, NICNAS) IMAP (2014)), negative in a mutual translocation test with mice (Risk Assessment Report (Ministry of Health, Labour and Welfare, 2009)), and negative in a micronucleus test by oral administration to Chinese hamsters (MAK (DFG) vol.6 (1994)). (2) As for in vitro, it was reported to be positive and negative in bacterial reverse mutation tests (Risk Assessment Report (Ministry of Health, Labour and Welfare, 2009), MAK (DFG) vol.6 (1994), AICIS (formerly, NICNAS) IMAP (2014)). As for test systems using cultured mammalian cells, it was reported to be positive and negative in chromosomal aberration tests, positive and negative in sister chromatid exchange tests, weakly positive in a DNA strand break test, positive in a cell transformational test (Risk Assessment Report (Ministry of Health, Labour and Welfare, 2009), AICIS (formerly, NICNAS) IMAP (2014)), and positive in a mouse lymphoma test (CEBS (Access on May 2020)). [Reference Data, etc.] (3) It was classified in Muta.2 in EU CLP classification (EU CLP classification (Access on May 2020)).
6	Carcinogenicity	Category 1B	Danger	H350	P308+P313 P201 P202 P280 P405 P501	[Rationale for the Classification] It was classified in Category 1B from (1) - (4). [Evidence Data] (1) As for classification results by domestic and international organizations, IARC classified para-chloro-ortho-toluidine and its strong acid salts in Group 2A (IARC 48 (1990)), NTP classified them in R (NTP RoC (14th, 2016)), and this substance was classified in Carc.1B in EU CLP classification (EU CLP classification (Access on May 2020)). (2) In two carcinogenicity tests by 18-month or 24-month diet administration of this substance to male and female mice, a significant increase in the incidence of vascular tumors (hemangioma and hemangiosarcoma, combined) in the spleen and intraperitoneal adipose tissue was observed in both males and females in an 18-month administration test, and in a 24-month administration test, a significant increase in the incidence of hemangiosarcoma was found (IARC 99 (2010), Risk Assessment Report (Ministry of Health, Labour and Welfare, 2009)). (3) In two carcinogenicity tests by 18-month or 105-week diet administration of this substance to male rats, no treatment-related development of tumors was observed in either test (IARC 99 (2010), Risk Assessment Report (Ministry of Health, Labour and Welfare, 2009)). (4) In carcinogenicity tests by diet or gavage administration of the free base of this substance to male and female rats and mice for 80 weeks to 107 weeks, in mice, a significant increase in the incidence of hemangiosarcoma in the adipose tissue surrounding the reproductive organs and dose-dependent development of reticuloendothelial sarcoma were observed in both males and females. In rats, in one of two tests, no tumor incidence was observed, but in the other test, dose-dependent increases in liver carcinoma, benign liver tumors, and adrenal gland adenoma were observed (Risk Assessment Report (Ministry of Health, Labour and Welfare, 2009)). [Reference Data, etc.] (5) In humans, among three epidemiological studies in small cohorts occupationally exposed to the free base of this substance, a US study did not show an excessive risk of bladder cancer, but the study was small and had limited power to detect any excess. Two German studies showed high relative risks of bladder cancer. Co-exposure to o-toluidine could not be excluded as the cause of the excess risk in the production workers of the free base of this substance (IARC 99 (2010)).
7	Reproductive toxicity	Classification not possible	- -	-	-	[Rationale for the Classification] Since only data of (1) was available, classification was not possible due to lack of data. [Evidence Data] (1) It was reported that in male mice which were given this substance by a single-dose oral administration and then mated with untreated female mice, there were no effects on male germinal cells, no change in the number of implantations or of embryonic deaths (MAK (DFG) vol.6 (1994), Risk Assessment Report (Ministry of Health, Labour and Welfare, 2009)). [Reference Data, etc.] (2) In a study in which male mice were given 4-chloro-2-methylaniline (CAS RN 95-69-2) by oral administration for 7 weeks and then mated with untreated females to investigate their fertility, no changes was observed in the litter size, sterility trends, and developmental abnormalities (MAK (DFG) vol.6 (1994)、Risk Assessment Report (Ministry of Health, Labour and Welfare, 2009)).
8	Specific target organ toxicity - Single exposure	Category 1 (blood system, urinary bladder), Category 2 (central nervous system), Category 3 (narcotic effects, respiratory tract irritation)	Danger Warning	H370 H371 H336 H335	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 (blood system, urinary bladder), Category 2 (central nervous system) and Category 3 (narcotic effects, respiratory tract irritation). A new information source was used and the classification results were changed from the previous classification. [Evidence Data] (1) The following symptoms of acute poisoning in humans were observed: (1) this substance caused irritation to the urinary bladder, and gross hematuria, dysuria, frequent urination, miction pain, etc. due to hemorrhagic cystitis were observed; (2) blood disorders (methemoglobinemia, cyanosis of the lips, nails and skin) occurred; and (3) neurologic symptoms (headache, dizziness, nausea, lethargy) appeared (Risk Assessment Report (Ministry of Health, Labour and Welfare, 2009)). (2) In an inhalation exposure study with cats dosed with this substance at 0.1 to 5 mg/L (exposure time unknown), irritation of the nasal mucosa, conjunctivitis, corneal opacity, increased secretion in the respiratory tract, bronchitis, etc. were observed, and necropsy showed pulmonary edema (Risk Assessment Report (Ministry of Health, Labour and Welfare, 2009), AICIS (previous NICNAS) IMAP (2014)). (3) In an oral administration test of this substance with rats (1,000 mg/kg body weight, within the range for Category 2), dose-dependent cyanosis, exophthalmos, increased secretion from the lacrimal gland, dyspnea, consciousness disorder, collapse, tonic-colonic convulsions, etc. were observed 1 to 3 hours after administration, and some animals died. Necropsy findings showed dilation of the digestive tract, degeneration of hepatocytes, renal ischemia, and splenomegaly in both dead and survived animals (Risk Assessment Report (Ministry of Health, Labour and Welfare, 2009), AICIS (previous NICNAS) IMAP (2014), MAK (DFG) vol.6 (1994)).
9	Specific target organ toxicity - Repeated exposure	Category 1 (urinary bladder), Category 2 (blood system, liver)	Danger Warning	H372 H373	P260 P264 P270 P314 P501	[Rationale for the Classification] Based on (1), it was reported that effects on the urinary bladder were observed in humans. Based on (2), it was reported that effects on the blood system and liver at doses within the range for Category 2 were observed in experimental animals. Therefore, it was classified in Category 1 (urinary bladder) and Category 2 (blood system, liver). As a result of reviewing the information, the classification results were changed from the previous classification. [Evidence Data] (1) It was reported that chloroaniline derivatives caused hematuria and affected the bladder mucosa in humans (IARC 48 (1990)). (2) In a 60-day feeding study with rats, at the concentration of 750 mg/kg diet (converted guidance value: 37.5 to 75 mg/kg/day, within the range for Category 2), hemolytic anemia with increased reticulocytes, occurrence of polychromatophilia, Heinz bodies, methemoglobinemia and reduced hemoglobin levels, hematocrit and erythrocyte count was observed. It was also reported that dose-dependent enlargement of the liver and spleen, vacuolation of hepatocytes, congestion of the urinary bladder mucosa, and proliferation of the transitional epithelium of the urinary bladder mucosa were observed (Risk Assessment Report (Ministry of Health, Labour and Welfare, 2009), MAK (DFG) vol.6 (1994), AICIS (previous NICNAS) IMAP (2014)).
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)	Classification not possible	- -	-	-	No data available.
11	Hazardous to the aquatic environment Long term (Chronic)	Classification not possible	- -	-	-	No data available.
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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