NITE - Chemical Management Field

GHS Classification Results by the Japanese Government

GENERAL INFORMATION

Item	Information
CAS RN	134-29-2
Chemical Name	o-Anisidine Hydrochloride
Substance ID	R03-A-005-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.
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	- -	-	-	No data 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 chlorine (but not fluorine or oxygen), but the chlorine is ionically bonded and does not contribute to oxidization.
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)	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
1	Acute toxicity (Dermal)	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
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] Classification not possible due to lack of data.
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] Based on (1) to (5), it was classified in Category 2. [Evidence Data] (1) In a DNA strand break test using the bladder tissues of rats (alkaline comet assay, oral administration, 17 mg/kg, 3 times/week, 4 weeks), positive results were reported (IARC 127 (2021)). (2) In a DNA adduct formation test using the bladder tissues of rats (32P-post-labelling assay, oral administration, 17 mg/kg, 3 times/week, 4 weeks), positive results were reported (IARC 127 (2021)). (3) In multiple bacterial reverse mutation tests, positive and negative results were reported (IARC 127 (2021)). (4) o-Anisidine (CAS RN 90-04-0) is a basic compound and will undergo acid-base reactions. o-Anisidine and its hydrochloride salt (this substance) will achieve a pH-dependent acid-base equilibrium in the body. Therefore, both substances were considered to exhibit similar biological reactions in the body (IARC 127 (2021)). (5) O-Anisidine was classified in Category 2 for this hazard class (GHS Classification Results in FY2009) [Reference Data] (6) In the EU CLP classification, it was classified as Muta. 2 (EU-CLP Classification Results (Accessed Sep. 2021)).
6	Carcinogenicity	Category 1B	Danger	H350	P308+P313 P201 P202 P280 P405 P501	[Rationale for the Classification] Based on (1) to (6), it was classified in Category 1B. [Evidence Data] (1) As for the classification results by domestic and international evaluation organizations, the IARC classified this substance and o-Anisidine (CAS RN 90-04-0) in Group 2A (IARC 127 (2021)) and the NTP classified them in R (NTP RoC (14th, 2016)). (2) It was reported that, in a 2-year carcinogenicity study with rats dosed by feeding, tumors were observed in the urinary bladder (transitional cell carcinoma, transitional cell papilloma or carcinoma (combined)) in males and females, in the renal pelvis of the kidney (transitional cell carcinoma) and the thyroid (follicular cell adenoma + cystadenoma + papillary cystadenoma + follicular cell carcinoma + papillary cystadenocarcinoma) in males (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2021), Risk Assessment Report (Ministry of Health, Labour and Welfare, 2009), IARC 127 (2021), EU RAR (2002), ACGIH (2002), Recommendation of Occupational Exposure Limits (Japan Society For Occupational Health (JSOH), 1996), NTP TR89 (1978)). (3) It was reported that, in a 2-year carcinogenicity study with mice dosed by feeding, tumors were observed in the urinary bladder (transitional cell carcinoma, transitional epithelial papillomas + carcinomas) in males and females (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2021), Risk Assessment Report (Ministry of Health, Labour and Welfare, 2009), IARC 127 (2021), EU RAR (2002), ACGIH (2002), Recommendation of Occupational Exposure Limits (Japan Society For Occupational Health (JSOH), 1996), NTP TR89 (1978)). (4) It was reported that, since o-Anisidine, the parent compound of this substance, is a basic compound and will undergo acid-base reactions, o-Anisidine and its hydrochloride salt (this substance) will achieve a pH-dependent acid-base equilibrium in the body, and accordingly, both substances were considered to exhibit similar biological reactions in the body and the classification for carcinogenicity was applicable to both substances (IARC 127 (2021)). (5) Considering the mechanism of action of o-Anisidine, there was strong evidence that several member compounds share a common mechanism of action with a class of aromatic amines classified as known human carcinogens. o-Anisidine had structural similarities to other member compounds of this class, and was fairly consistent with respect to the mechanism of bioactivation to DNA-reactive moieties, genotoxicity, and the target organs of carcinogenicity in chronic animal bioassays (IARC 127 (2021)). (6) There was inadequate evidence in humans regarding the carcinogenicity, but based on (2) to (5), both o-Anisidine and this substance were classified in Group 2A for carcinogenicity (IARC 127 (2021)). [Reference Data, etc.] (7) In humans, bladder cancer occurred in 3 workers exposed to o-Anisidine while working in the plants producing organic dye and pigment intermediates. Since all 3 cases were co-exposed to other known bladder carcinogens (o-toluidine, tobacco smoking), no conclusion could be drawn about the presence of a causal association between the exposure to o-Anisidine and urinary bladder cancer (IARC 127 (2021)). (8) As for the classification results of o-Anisidine besides (1), the EU classified it in Carc. 1B (EU-CLP Classification Results (Accessed Sep. 2021), the ACGIH classified it in A3 (ACGIH (2002)), the Japan Society For Occupational Health (JSOH) classified it in Group 2B (Recommendation of Occupational Exposure Limits (Japan Society For Occupational Health (JSOH), 1996)), and the DFG classified it in Category 2 (DFG MAK (2020)).
7	Reproductive toxicity	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
8	Specific target organ toxicity - Single exposure	Category 2 (blood system)	Warning	H371	P308+P311 P260 P264 P270 P405 P501	[Rationale for the Classification] As for this hazard class, since there is no data of this substance itself, the classification was based on the data of o-Anisidine (CAS RN 90-04-0). Based on (1) and (2), it was classified in Category 2 (blood system). [Evidence Data] (1) It was reported that, in an acute oral toxicity test with rats (males) and mice (males), blood was taken with a sampling time ranging from 3 to 48 hours after administration at 690 mg/kg (within the range for Category 2) in mice and at 1,380 mg/kg (within the range for Category 2) in rats, and as a result, significantly elevated methemoglobin values (up to 4.8% in mice and up to 15.4% in rats compared to pre-administration values) were observed (EU RAR (2002), Risk Assessment Report (Ministry of Health, Labour and Welfare, 2009)). (2) It was reported that, in an acute oral toxicity test with rats, effects on the blood (elevated methemoglobin values, Heinz bodies) were observed (DFG MAK (2005)).
9	Specific target organ toxicity - Repeated exposure	Category 2 (blood system)	Warning	H373	P260 P314 P501	[Rationale for the Classification] Based on (4), it was classified in Category 2 (blood system) since blood system effects were observed within the range for Category 2 in the study for o-Anisidine used as a test substance in (4). [Evidence Data] (1) It was reported that, in a repeated dose 7-week oral toxicity study with rats and mice dosed by feeding, darkening and enlargement of the spleen (with granular appearance of the spleen in rats) were observed at or above 1% (10,000 ppm, converted guidance value: 544 mg/kg/day, in the range corresponding to "Not classified") in rats and at or above 1% (10,000 ppm, converted guidance value: 817 mg/kg/day, in the range corresponding to "Not classified") in mice (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2021), Risk Assessment Report (Ministry of Health, Labour and Welfare, 2009), EU RAR (2002), NTP TR89 (1978)). (2) It was reported that, in a 103-week combined chronic toxicity/carcinogenicity study with rats dosed by feeding, all animals died at or above 1% (10,000 ppm, 1,000 mg/kg/day, in the range corresponding to "Not classified"), but no clear increase in nonneoplastic lesions was observed (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2021), Risk Assessment Report (Ministry of Health, Labour and Welfare, 2009), EU RAR (2002), NTP TR89 (1978)). (3) It was reported that, in a 103-week combined chronic toxicity/carcinogenicity study with mice dosed by feeding, an increase in the incidence of transitional-cell hyperplasia of the urinary bladder was observed at or above 0.5% (5,000 ppm, 750 mg/kg/day, in the range corresponding to "Not classified") (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2021), Risk Assessment Report (Ministry of Health, Labour and Welfare, 2009), EU RAR (2002), NTP TR89 (1978)). (4) It was reported that, in a repeated dose 28-day oral toxicity study using o-Anisidine (CAS RN 90-04-0) as a test substance with rats dosed by gavage, at or above 80 mg/kg/day (converted guidance value: 24.9 mg/kg/day, within the range for Category 2), yellow urine, effects on the spleen (swelling, darkening, hemosiderin deposit, hyperemia, increased extramedullary hematopoiesis), and increased myelopoiesis were observed, and decreased red blood cell count and increased relative liver weight were observed in females; and at 400 mg/kg/day (converted guidance value: 124 mg/kg/day, in the range corresponding to "Not classified"), salivation, crouching posture, abnormal gait, distended abdomen, and decreases in hemoglobin and hematocrit were observed, and increases in relative liver and kidney weight were observed in males (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2021), EU RAR (2002)).
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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