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GHS Classification Results by the Japanese Government

GENERAL INFORMATION

Item	Information
CAS RN	91-23-6
Chemical Name	2-Nitroanisole
Substance ID	R03-B-014-MHLW
Classification year (FY)	FY2021
Ministry who conducted the classification	Ministry of Health, Labour and Welfare (MHLW)
New/Revised	Revised
Classification result in other fiscal year	FY2010 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	- -	-	-	There is a chemical group associated with explosive properties (N-O) present in the molecule, but because it is classified in Division 6.1, PG III in UNRTDG (UN 2730), it was considered to be not applicable to explosives, hazards of the highest precedence, therefore, it was classified as "Not classified." Besides, the calculated oxygen balance is -152.
2	Flammable gases	Not classified (Not applicable)	- -	-	-	Liquid (GHS definition)
3	Aerosols	Not classified (Not applicable)	- -	-	-	Not aerosol products.
4	Oxidizing gases	Not classified (Not applicable)	- -	-	-	Liquid (GHS definition)
5	Gases under pressure	Not classified (Not applicable)	- -	-	-	Liquid (GHS definition)
6	Flammable liquids	Not classified	- -	-	-	A flash point is 142 deg C (Closed cup) (HSDB in PubChem (Accessed Oct 2021)).
7	Flammable solids	Not classified (Not applicable)	- -	-	-	Liquid (GHS definition)
8	Self-reactive substances and mixtures	Type G	- -	-	-	There is a chemical group associated with explosive properties (N-O) present in the molecule, but because it is classified in Division 6.1, PG III in UNRTDG (UN 2730), it does not correspond to self-reactive substances and mixtures, hazards of the highest precedence, therefore, it was classified in Type G.
9	Pyrophoric liquids	Not classified	- -	-	-	It is estimated that it does not ignite at normal temperatures from an autoignition temperature of 464 deg C (ICSC (2004), HSDB in PubChem (Accessed Oct 2021)).
10	Pyrophoric solids	Not classified (Not applicable)	- -	-	-	Liquid (GHS definition)
11	Self-heating substances and mixtures	Classification not possible	- -	-	-	Test methods applicable to liquid 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).
13	Oxidizing liquids	Not classified	- -	-	-	The substance is an organic compound containing chlorine and oxygen (but not fluorine), and the oxygen is chemically bonded to the element other than carbon or hydrogen (N). But because it is classified in Division 6.1, PG III in UNRTDG (UN 2730), it does not correspond to oxidizing liquids, hazards of the highest precedence, therefore, it was classified as "Not classified."
14	Oxidizing solids	Not classified (Not applicable)	- -	-	-	Liquid (GHS definition)
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	- -	-	-	No data available.
17	Desensitized explosives	Not classified	- -	-	-	There is a chemical group associated with explosive properties (N-O) present in the molecule, but because it is classified in Division 6.1, PG III in UNRTDG (UN 2730), it was considered to be not applicable to explosives, hazards of the highest precedence, therefore, 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] Based on (1) to (8), it was classified in Category 4. [Evidence Data] (1) LD50 for rats: between 740 to 1,000 mg/kg (Risk Assessment Report (Ministry of Health, Labour and Welfare, 2011)) (2) LD50 for rats: 740 mg/kg (Patty (6th, 2012)) (3) LD50 for rats (males): 760 mg/kg (DFG MAK (1998)) (4) LD50 for rats (females): 740 mg/kg (DFG MAK (1998)) (5) LD50 for rats: 874 mg/kg (DFG MAK (1998)) (6) LD50 for rats (males): 1,000 mg/kg (DFG MAK (1998)) (7) LD50 for rats (females): 890 mg/kg (DFG MAK (1998)) (8) LD50 for rats: 1,980 mg/kg (DFG MAK (1998))
1	Acute toxicity (Dermal)	Not classified	- -	-	-	[Rationale for the Classification] Based on (1), it was classified as "Not classified." [Evidence Data] (1) LD50 for rats: > 2,000 mg/kg (Risk Assessment Report (Ministry of Health, Labour and Welfare, 2011), DFG MAK (1998))
1	Acute toxicity (Inhalation: Gases)	Not classified	- -	-	-	[Rationale for the Classification] Liquid (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	Not classified	- -	-	-	[Rationale for the Classification] Based on (1), it was classified as "Not classified." [Evidence Data] (1) It was reported that, in a skin irritation test (semiocclusive, 4-hour application) with rabbits (n=6), no irritation reactions were observed (Risk Assessment Report (Ministry of Health, Labour and Welfare, 2011), DFG MAK (1998)).
3	Serious eye damage/eye irritation	Not classified	- -	-	-	[Rationale for the Classification] Based on (1), it was classified as "Not classified." [Evidence Data] (1) It was reported that, in an eye irritation test with rabbits (n=6) (observation for 4 days), swelling and diffuse reddening of the conjunctiva and slight lacrimation were observed after one hour but all signs disappeared after 24 hours (Risk Assessment Report (Ministry of Health, Labour and Welfare, 2011), DFG MAK (1998)).
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) and (2), it was classified in Category 2. It was classified based on the new information source. [Evidence Data] (1) As for in vivo, negative results were obtained in a micronucleus test using the bone marrow cells of rats, but in an adduct formation test for multiple target organs of rats (intraperitoneal injection, for 5 days, 0.15 mg/kg/day), positive results were observed for the liver, kidney, spleen, and urinary bladder, and negative results were obtained for the lung, heart, and brain. In a comet assay for the kidney, urinary bladder, and liver cells of rats (DNA strand breaks: gavage administration, for 2 days (2 times), up to 750 mg/kg/day), positive results were observed for the kidney (at or above 250 mg/kg/day) and negative results were observed for the others, and in another comet assay (and a modified comet assay with hOGG1) for urinary bladder cells (gavage administration, for 3 days (3 times)), negative or positive results were obtained (IARC 127 (2021)). (2) As for in vitro, positive results were obtained in multiple bacterial reverse mutation tests, positive results were observed in a mouse lymphoma test, negative results were obtained in a gene mutation test using the Chinese hamster lung (V79) cells, and positive results (mainly, +S9) were obtained in a chromosomal aberration test using the Chinese hamster ovary (CHO) cells, Chinese hamster lung (CHL) cells, and V79 cells (IARC 127 (2021), DFG MAK (1998), Risk Assessment Report (Ministry of Health, Labour and Welfare, 2011), Mutagenicity Test Data of Existing Chemical Substances based on the toxicity investigation system of the Industrial Safety and Health Law (Accessed Nov. 2021)).
6	Carcinogenicity	Category 1B	Danger	H350	P308+P313 P201 P202 P280 P405 P501	[Rationale for the Classification] Based on (1) and (2), it was classified in Category 1B, since an increased incidence of malignant tumors was observed in two species of animals and there was sufficient evidence for carcinogenicity in the animal tests. Based on the new information source, the classification result was changed. [Evidence Data] (1) In a 2-year (103-week) carcinogenicity study with rats and mice dosed by feeding (GLP, rats: 222 to 2,000 ppm, mice: 666 to 6,000 ppm), an increasing trend in the incidence of mononuclear cell leukemia and a significant increase compared to the control group were observed in both male and female rats; and increased incidences of hepatocellular adenoma, hepatocellular carcinoma, and hepatoblastoma in male mice, and hepatocellular adenoma in female mice were observed (IARC 127 (2021), Risk Assessment Report (Ministry of Health, Labour and Welfare, 2011), DFG MAK (1998), NTP TR416 (1993)). (2) In a carcinogenicity study (stop-exposure study) in which rats were dosed by feeding for 27 weeks (6,000, 18,000 ppm), then given basal diet, and sacrificed for necropsy at experimental weeks 28, 40, 65, and 103, increases in benign and malignant neoplasms of the urinary bladder, transitional cell neoplasms of the kidney, and benign and malignant neoplasms of the large intestine were observed in males and females (IARC 127 (2021), NTP TR416 (1993)). (3) As for the classification results by domestic and international organizations, the IARC classified this substance in Group 2A (IARC 127 (2021)), the NTP classified it in R (NTP RoC 14th. (2016)), the Japan Society For Occupational Health (JSOH) classified it in Group 2B (Recommendation of Occupational Exposure Limits (Japan Society For Occupational Health (JSOH), 2021)), the EU classified it in Carc. 1B (EU CLP Classification Results (Accessed November 2021)), the DFG classified it in Category 2 (List of MAK and BAT values 2020 (Accessed November 2021)). [Reference Data, etc.] (4) There is strong mechanistic evidence that, in view of the metabolism of this substance to the aromatic amine ortho-anisidine (CAS RN 90-04-0), this substance belongs within a mechanistic class of aromatic amines, several member compounds of which have been classified as carcinogenic to humans. This substance exhibits concordance with aromatic amines with respect to the formation of common DNA-reactive moieties, genotoxicity and target organs of carcinogenicity in chronic animal bioassays (IARC 127 (2021)).
7	Reproductive toxicity	Category 2	Warning	H361	P308+P313 P201 P202 P280 P405 P501	[Rationale for the Classification] Based on (1) and (2), since there was a report that suggested developmental effects, it was classified in Category 2. [Evidence Data] (1) In a developmental toxicity study with female rats dosed by gavage (20 to 320 mg/kg/day, days 6 to 15 of gestation), at the high dose at which effects on dams (symptoms, decreased food consumption) were observed, a slight increase in resorbed embryos (8.5%, controls: 5.0%) and slight increases in visceral variations and fusions in fetuses were observed (DFG MAK (1989), Risk Assessment Report (Ministry of Health, Labour and Welfare, 2011)). (2) Based on the effects in (1), the Ministry of Health, Labour and Welfare concluded as "Reproductive and developmental toxicity: Positive" (Risk Assessment Report (Ministry of Health, Labour and Welfare, 2011)). [Reference Data, etc.] (3) In a 13-week study with rats dosed by feeding (200 to 18,000 ppm), at the highest dose (18,000 ppm: approx. 900 mg/kg/day), degeneration of the seminiferous tubule epithelium accompanied by loss of spermatogenic cells and decreased numbers of spermatozoa in the testes were observed, while uterine atrophy was observed in female rats (NTP TR416 (1993), DFG MAK (1998), Risk Assessment Report (Ministry of Health, Labour and Welfare, 2011)).
8	Specific target organ toxicity - Single exposure	Category 2 (systemic)	Warning	H371	P308+P311 P260 P264 P270 P405 P501	[Rationale for the Classification] Based on (1), since the signs of toxicity in which no target organ could be identified were observed and deaths occurred within the range for Category 2, it was classified in Category 2 (systemic toxicity). [Evidence Data] (1) It was reported that, in an acute oral toxicity test with rats, non-specific symptoms of intoxication (such as crouching, prostration, unsteady gait, irregular breathing, ruffled fur, partially closed eye-lids, reduced spontaneous activity, dazed behavior, reduced reflexes and lacrimation) were seen after treatment and the LD50 was 874 mg/kg (within the range for Category 2). In addition, it was reported that necropsy of the animals which died revealed slight reddening of the mucous membranes of the stomach or of the whole gastrointestinal tract, and in some cases, pale kidneys, dark coloration of the adrenal glands, and reddish brown discoloration of the lungs (DFG MAK (1998)). [Reference Data, etc.] (2) It was reported that, after an accident involving spillage of 2-nitroanisole at an industrial plant, methemoglobin levels were determined in 50 workers involved in cleaning up the contaminated area and all values were within the normal range (Risk Assessment Report (Ministry of Health, Labour and Welfare, 2011), DFG MAK (1998)).
9	Specific target organ toxicity - Repeated exposure	Category 2 (kidney)	Warning	H373	P260 P314 P501	[Rationale for the Classification] Based on (1) and (2), it was classified in Category 2 (kidney). Besides, the blood system effects observed in (3) and (4) were regarded as effects at doses exceeding the range for Category 2 based on the long-term test results and were not adopted for classification. [Evidence Data] (1) It was reported that, in a repeated dose 13-week oral toxicity study with rats dosed by feeding, increased absolute liver weight (females), increased absolute kidney weight (males), and kidney effects (multifocal degeneration and necrosis of the renal tubule epithelium with infiltration of mononuclear inflammatory cells (males)) were observed at 200 to 2,000 ppm (10 to 100 mg/kg/day, within the range for Category 2); effects on the urinary bladder (benign/malignant neoplasms, transitional epithelium hyperplasia) were observed at 6,000 ppm (300 mg/kg/day, in the range corresponding to "Not classified"); and effects on the blood (increased methemoglobin), the spleen (congestion, hemosiderin deposits), and the reproductive organs (degeneration of the seminiferous tubule epithelium associated by loss of spermatogenic cells and decreased numbers of spermatozoa in the testes, uterine atrophy) were observed at 18,000 ppm (900 mg/kg/day, in the range corresponding to "Not classified") (DFG MAK (1998), Risk Assessment Report (Ministry of Health, Labour and Welfare, 2011), NTP TR416 (1993)). (2) It was reported that, in a 2-year combined chronic toxicity/carcinogenicity study with rats dosed by feeding, hyperplasia of the forestomach, hyperplasia of the renal tubule (males), and increased severity of nephropathy (males) were observed at 222 to 2,000 ppm (10 to 80 mg/kg/day (males), 10 to 90 mg/kg/day (females), within the range for Category 2) (NTP TR416 (1993)). [Reference Data, etc.] (3) It was reported that, in a repeated dose 28-day oral toxicity study with rats dosed by gavage, hematological changes indicating slight hemolytic anemia and increased spleen weight were observed at 200 mg/kg/day (converted guidance value: 62.2 mg/kg/day, within the range for Category 2) (DFG MAK (1998), Risk Assessment Report (Ministry of Health, Labour and Welfare, 2011)). (4) It was reported that, in a study in which only one dose (150 mg/kg) was orally administed 30 times to rats (males), slight hemolytic anemia and increased relative liver, kidney, and spleen weight were observed (DFG MAK (1998), Risk Assessment Report (Ministry of Health, Labour and Welfare, 2011)). (5) It was reported that, in a repeated dose 13-week oral toxicity study with mice dosed by feeding, an increase in the number of animals with hepatocellular hypertrophy (males) and increases in absolute and relative liver weight (females) were observed at 60 to 2,000 ppm (9 to 90 mg/kg/day, within the range for Category 2), and effects on the blood (reduced hemoglobin and hematocrit) were observed at 2,000 and 6,000 ppm (300 and 900 mg/kg/day in the range corresponding to "Not classified") (DFG MAK (1998), Risk Assessment Report (Ministry of Health, Labour and Welfare, 2011)). (6) It was reported that, in a 2-year combined chronic toxicity/carcinogenicity study with mice dosed by feeding, no nonneoplastic lesions were observed at 6,000 ppm (830 mg/kg/day (males), 1,200 mg/kg/day (females), in the range corresponding to "Not classified") (NTP TR416 (1993)).
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)	-	- -	-	-	-
11	Hazardous to the aquatic environment Long term (Chronic)	-	- -	-	-	-
12	Hazardous to the ozone layer	-	- -	-	-	-

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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