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GHS Classification Results by the Japanese Government

GENERAL INFORMATION

Item	Information
CAS RN	127-19-5
Chemical Name	N,N-Dimethylacetamide
Substance ID	R03-B-012-METI, MOE
Classification year (FY)	FY2021
Ministry who conducted the classification	Ministry of Economy, Trade and Industry (METI)/Ministry of the Environment (MOE)
New/Revised	Revised
Classification result in other fiscal year	FY2018 FY2013 FY2008 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.
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	Category 4	- Warning	H227	P370+P378 P210 P280 P403 P501	It was classified in Category 4 based on a flash point of 66 deg C (closed cup) (GESTIS (Accessed June 2021)).
7	Flammable solids	Not classified (Not applicable)	- -	-	-	Liquid (GHS definition)
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	- -	-	-	It is estimated that it does not ignite at normal temperatures from an autoignition temperature of 400 deg C (GESTIS (Accessed June 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 (Not applicable)	- -	-	-	The substance is an organic compound containing oxygen (but not fluorine or chlorine) which is chemically bonded only to carbon or hydrogen.
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 (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)	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) to (6), it was classified as "Not classified." [Evidence Data] (1) LD50 for rats: 4,300 mg/kg (Risk Assessment Report (Ministry of Health, Labour and Welfare, 2013), Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2017)) (2) LD50 for rats (males): 5,809 mg/kg (ACGIH (2018)) (3) LD50 for rats (females): 4,930 mg/kg (ACGIH (2018)) (4) LD50 for rats: between 3,000 to 6,000 mg/kg (SIAR (2001)) (5) LD50 for rats: 5,000 mg/kg (OEL Documentations (Japan Society For Occupational Health (JSOH), 1990)) (6) LD50 for rats: between 4,800 to 5,830 mg/kg (AICIS IMAP (2013))
1	Acute toxicity (Dermal)	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) to (5), it was classified as "Not classified." [Evidence Data] (1) LD50 for rabbits: 2,240 mg/kg (Risk Assessment Report (Ministry of Health, Labour and Welfare, 2013), Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2017), OEL Documentations (Japan Society For Occupational Health (JSOH), 1990)) (2) LD50 for rabbits: between 2,100 to 3,600 mg/kg (SIAR (2001)) (3) LD50 for rabbits (males): 2,100 mg/kg (AICIS IMAP (2013)) (4) LD50 for rats: > 2,000 mg/kg (Risk Assessment Report (Ministry of Health, Labour and Welfare, 2013), Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2017)) (5) LD50 for rats: 7,500 mg/kg (SIAR (2001))
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)	Category 3	Danger	H331	P304+P340 P403+P233 P261 P271 P311 P321 P405 P501	[Rationale for the Classification] Based on (1), it was classified in Category 3. Also, since the exposure concentration was lower than 90% (1,776 ppm) of the saturated vapor pressure concentration, it was judged to be in a vapor state and classified based on the reference value in units of ppmV. [Evidence Data] (1) LC50 (1 hour) for rats: 2,475 ppm (converted 4-hour equivalent value: 1,237.5 ppm) (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2017), Risk Assessment Report (Ministry of Health, Labour and Welfare, 2013), SIAR (2001))
1	Acute toxicity (Inhalation: Dusts and mists)	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) and (2), it was classified as "Not classified." Also, since the exposure concentration was higher than the saturated vapor pressure concentration (6.32 mg/L), it was judged to be in a mist state. [Evidence Data] (1) LC50 (8 hours) for rats: between 10.7 to 32 mg/L (converted 4-hour equivalent value: 21.4 to 64 mg/L) (OECD TG 403) (REACH registration dossier (Accessed July 2021), AICIS IMAP (2013)) (2) LD50 (8 hours) for rats: > 12 mg/L (converted 4-hour equivalent value: 24 mg/L) (SIAR (2001))
2	Skin corrosion/irritation	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) and (2), it was classified as "Not classified." [Evidence Data] (1) It was reported that, in a skin irritation test with rabbits (n=2) (equivalent to OECD TG 404, occlusive, 20-hour application, 7-hour observation), slight erythema was observed in all animals after 24 and 72 hours, but it was reversible within 7 days (AICIS IMAP (2013), REACH registration dossier (Accessed Aug. 2021)). (2) It was reported that, in a skin irritation test with rabbits (n=2/group), after application of an undiluted solution of up to 500 mg/kg, no skin irritation was observed (SIAR (2001), AICIS IMAP (2013) REACH registration dossier (Accessed Aug. 2021)).
3	Serious eye damage/eye irritation	Category 2	Warning	H319	P305+P351+P338 P337+P313 P264 P280	[Rationale for the Classification] Based on (1) to (4), it was classified in Category 2. Also, the findings in (1) suggested Category 2A, however, since the number of test animals was insufficient, the subcategorization was not conducted, and the classification result was changed. [Evidence Data] (1) It was reported that, in an eye irritation test with rabbits (n=2) (equivalent to OECD TG 405, 8-day observation), moderate corneal opacity and conjunctival redness were observed in all animals after 24 hours, and the effects in one animal disappeared within 8 days, but the effects in the other animal did not disappear within 8 days (cornea opacity score: 1.3/1.3, iritis score: 0.3/0, conjunctival redness score: 2/2, chemosis score: 0.7/1.3) (AICIS IMAP (2013), REACH registration dossier (Accessed Aug. 2021)). (2) In an eye irritation test with rabbits (n=2), one animal showed severe pain, and therefore, its eye was washed after 1 minute. In one animal for which the eye was washed, effects of cornea damage, iritis, chemosis, and conjunctival redness were observed. In the other animal, moderate cornea damage was observed. It was reported that the observed effects disappeared completely within 14 days (AICIS IMAP (2013), REACH registration dossier (Accessed Aug. 2021)). (3) When rabbits were instilled with undiluted N,N-dimethylacetamide, the score was assessed to be 3 by the assessment method of Smyth, et al. This suggested that cornea necrosis was caused within a narrow area. Also, this cornea damage was reversible (Risk Assessment Report (Ministry of Health, Labour and Welfare, 2013), ACGIH (7th, 2018)). (4) It was reported that, in an eye irritation test with rabbits, when an undiluted solution of 0.1 mL was applied, mild and reversible irritation was caused (SIAR (2001)).
4	Respiratory sensitization	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
4	Skin sensitization	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) and (2), it was classified as "Not classified." [Evidence Data] (1) This substance did not show sensitization in guinea pigs (ACGIH (7th, 2018), SIAR (2001)). (2) It was reported that, in a test with guinea pigs (n=7), irritation effects after challenge were observed in all animals out of which 4 animals were induced by intradermal administration of a 0.1% solution and 3 animals were induced by dermal administration of a 50% solution, but those effects disappeared within 48 hours (AICIS IMAP (2013), REACH registration dossier (Accessed Aug. 2021)).
5	Germ cell mutagenicity	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) and (2), it was classified as "Not classified." [Evidence Data] (1) As for in vivo, negative results were obtained in a chromosomal aberration test with the bone marrow cells of rats (inhalation exposure, up to 700 ppm, 5 consecutive days), and negative results were obtained in a dominant lethal assay with rats (inhalation exposure, up to 200 ppm, 5 consecutive days). As other dominant lethal assays, negative results were also observed in a test by dermal administration (up to 3,000 mg/kg) to rats and mice, a test by inhalation exposure (up to 2.53 mg/L) to mice, and a test by intraperitoneal injection (680 microL/kg) to mice (SIAR (2001), Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2017), ACGIH (7th, 2018)). (2) As for in vitro, negative results were reported in a bacterial reverse mutation test, positive or equivocal results were reported in a sister chromatid exchange assay with cultured mammalian cells (CHO), and negative results were reported in an unscheduled DNA synthesis assay with the human embryonic intestinal cells or human diploid fibroblasts (SIAR (2001), Risk Assessment Report (Ministry of Health, Labour and Welfare, 2013), Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2017), ACGIH (7th, 2018), IARC 123 (2020)). [Reference Data, etc.] (3) In a chromosomal aberration test using the human lymphocytes from 20 workers who were exposed to this substance (5 to 10 mg/m3), there was no increase in the incidence of chromosomal aberration, but there were few controls (16 unexposed workers), and the size of the group was small for a study report of occupational exposure (SIAR (2001)). AICIS IMAP (2013), REACH registration dossier (Accessed July 2021)).
6	Carcinogenicity	Category 1B	Danger	H350	P308+P313 P201 P202 P280 P405 P501	[Rationale for the Classification] Based on (1) to (4), it was classified in Category 1B. Based on the new findings, the category was changed. [Evidence Data] (1) In a carcinogenicity study (OECD TG451, GLP) by 2-year inhalation exposure with rats (6 hours/day, 5 days/week), there were increases in the incidence of hepatocellular adenoma, and also liver tumors combining hepatocellular adenoma and hepatocellular carcinoma in males with an exposure to the highest concentration of 450 ppm. In females, there was no increase in the incidence of tumors (Results from Carcinogenicity Studies (Ministry of Health, Labour and Welfare, 2013), Risk Assessment Report (Ministry of Health, Labour and Welfare, 2013), Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2017), ACGIH (7th, 2018), IARC 123 (2020)). (2) In a carcinogenicity study (OECD TG451, GLP) by 2-year inhalation exposure with mice (6 hours/day, 5 days/week), there was an increase in the incidence of hepatocellular adenoma in males with an exposure to the highest concentration of 300 ppm. In females, there were increases in the incidence of hepatocellular carcinoma and hepatocellular adenoma (Results from Carcinogenicity Studies (Ministry of Health, Labour and Welfare, 2013), Risk Assessment Report (Ministry of Health, Labour and Welfare, 2013), Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2017), ACGIH (7th, 2018), IARC 123 (2020)). (3) As for carcinogenicity of this substance, the IARC concluded that there was inadequate evidence in humans and there was sufficient evidence in experimental animals, and classified it in Group 2B (IARC 123 (2020)). (4) This substance is a target substance of the guidelines in order to prevent the impairment of worker's health (Public announcement on guidelines in order to prevent the impairment of worker's health caused by the chemical substances decided by the Minister of Health, Labour and Welfare based on paragraph (3) of Article 28 of the Industrial Safety and Health Act) caused by the chemical substances decided by the Ministry of Health, Labour and Welfare (guidelines to prevent the impairment of health, announcement No. 23 on February 7, 2020). [Reference Data, etc.] (5) As for the classification results by domestic and international organizations, the IARC classified this substance in Group 2B (IARC 123 (2020)), the Japan Society For Occupational Health (JSOH) classified it in Group 2B (Recommendation of Occupational Exposure Limits (Japan Society For Occupational Health (JSOH), 2019)), the ACGIH classified it in A3 (ACGIH (7th, 2018)). (6) In a carcinogenicity study with rats dosed by drinking water for two years, no carcinogenicity related to the administration was observed (SIAR (2001), Government of Canada, Screening Assessment (2009), Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2017)). (7) In a study by inhalation exposure (6 hours/day, 5 days/week) of rats for two years and mice for 18 months, there was no increase in the incidence of tumors either in males or females at exposure concentrations up to 350 ppm (IARC 123 (2020), Risk Assessment Report (Ministry of Health, Labour and Welfare, 2013), Government of Canada, Screening Assessment (2009), AICIS IMAP (2013), Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2017), ACGIH (7th, 2018)). (8) In a study (1959 to 1990) of 671 male workers, who were exposed to acrylonitrile for one year or more in an acrylic-fiber manufacturing facility in Italy, 571 workers were also exposed to this substance. There was no increase in the total number of deaths of workers compared to the general group in the region (total number of deaths in cohort: 32 workers vs expected value: 31.2 workers), but the number of deaths from cancers of the small intestine and colon was significantly higher than the expected value (number of deaths due to cancer: 4 workers vs expected value: 0.38 workers). However, cancers of the small intestine and colon were significantly more common in the group exposed for 1 to 4 years and the group exposed for 1 to 9 years since the first exposure, with no increase in the incidence in the group with longer exposure period or incubation period. Therefore, the deaths from cancers were considered to be not related to the exposure (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2017), IARC 123 (2020)).
7	Reproductive toxicity	Category 1B	Danger	H360	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) It was reported that, in a test with rats dosed by gavage (days 6-19 of gestation), at 400 mg/kg/day, reduced body weight gain and increased postimplantation embryo loss were observed in parent animals, and developmental effects (lower body weight, an increase in malformations (malformations of the heart, major vessels, and oral cavity, 67% were cardiovascular malformations)) including malformations were observed in offspring (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2017), Risk Assessment Report (Ministry of Health, Labour and Welfare, 2013), ACGIH (7th, 2018), SIAR (2001), OEL Documentations (Reproductive toxicant classification) (Japan Society For Occupational Health (JSOH)), 2014)). (2) In a test by inhalation exposure with rats (days 6-19 of gestation, 6 hours/day), reduced body weight gain, increased relative liver weight, and centrilobular hepatocyte hypertrophy were observed in parent animals at 450 ppm and 600 ppm; lower body weight and an increase in the incidence of malformations (visceral system, skeletal system) were observed in fetuses at 450 ppm; and in addition to the effects observed at 450 ppm, an increase in the incidence of external malformations, and reduced survival (males) were observed at 600 ppm. It was reported that, as for malformations, the incidence of ventricular septal defect was the highest, and the incidence of common arterial trunk remnant was the second highest (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2017), Risk Assessment Report (Ministry of Health, Labour and Welfare, 2013), ACGIH (7th, 2018), OEL Documentations (Reproductive toxicant classification) (Japan Society For Occupational Health (JSOH)), 2014)). (3) In a test by inhalation exposure with rabbits (days 7-19 of gestation, 6 hours/day, 7 days/week), skeletal variations were observed in offspring at or above 199.5 ppm at which no general toxic effects were observed in parent animals, and decreases in body weight and placental weight, and an increasing tendency in the incidence of minor malformations (skeleton, major vessels: no significance) were observed at 570 ppm (ACGIH (7th, 2018), Government of Canada, Screening Assessment (2009), SIAR (2001)). (4) It was reported that, in a test with rabbits dosed by gavage (days 6-18 of gestation), developmental effects (lower body weight, fused ribs, cleft palate, microphthalmia) including malformations were observed in fetuses at doses (282, 472 mg/kg/day) at which general toxic effects (reduced body weight gain) were observed in parent animals (Government of Canada, Screening Assessment (2009), SIAR (2001)). (5) In a test by dermal administration with rabbits (days 6-18 of gestation), developmental effects (lower body weight, deviations of the sternum, cyclopy, umbilical hernia) including malformations were observed in fetuses at a dose (500 mg/kg/day) at which general toxic effects were observed in parent animals (Government of Canada, Screening Assessment (2009), SIAR (2001)). (6) Although there was no report on human cases and epidemiological studies, fetal toxicity and teratogenicity were obvious in animals, and therefore, the Japan Society For Occupational Health (JSOH) classified this substance in Group 2 of reproductive toxicants (OEL Documentations (Reproductive toxicant classification) (Japan Society For Occupational Health (JSOH)), 2014)). [Reference Data, etc.] (7) It was reported that, in a reproduction toxicity study by inhalation exposure with rats (from 10 weeks before mating to day 22 of lactation), at the highest concentration of 300 ppm, increased relative liver weight in dams, and lower body weight, and increased relative liver weight in liveborn pups at weaning were observed, but no adverse effects on fertility were observed (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2017), ACGIH (7th, 2018), SIAR (2001)). (8) It was reported that, as a result of inhalation exposure of rats (days 6 to 15 of gestation), at the highest dose of 282 ppm, reduced body weight gain in dams, and lower body weight in fetuses were observed, but there was no increase in the incidence of malformations (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2017), ACGIH (7th, 2018), Risk Assessment Report (Ministry of Health, Labour and Welfare, 2013), SIAR (2001)). (9) In the EU CLP, it was classified in Repr. 1B.
8	Specific target organ toxicity - Single exposure	Category 1 (central nervous system, liver), Category 3 (narcotic effects)	Danger Warning	H370 H336	P308+P311 P260 P264 P270 P321 P405 P501 P304+P340 P403+P233 P261 P271 P312	[Rationale for the Classification] Based on (1) to (4), it was classified in Category 1 (central nervous system, liver) and Category 3 (narcotic effects). The classification result was changed by reviewing the classification using new information sources about effects on humans. [Evidence Data] (1) It was reported that, in a clinical study by oral administration of this substance to 17 patients with malignant tumors, expecting the anticancer effects of this substance, functional changes of the central nervous system was observed at 100 mg/kg/day (administration for 1 day or longer), and hepatotoxicity, mental abnormality, and obvious effects on the central nervous system (hallucination, delirium, mental confusion, drowsiness) were observed at 400 mg/kg/day (administration for 3 days or longer) (ACGIH (2018)). (2) In a clinical study by oral administration of this substance to 15 patients with cancer, expecting the anticancer effects of this substance, depression, lethargy, consciousness disorder, and hallucination were observed at 400 mg/kg. It was reported that hallucination disappeared completely after a few days (Risk Assessment Report (Ministry of Health, Labour and Welfare, 2013)). (3) In a case study of a male worker who was exposed accidentally to this substance and ethylenediamine orally and by inhalation for 90 minutes in a closed space at a chemical plant in the U.S., delirium, hallucination, skin burn, cellulitis, conjunctivitis of both eyes, inflammation of the liver, secondary coagulation disorder, rhabdomyolysis, and esophagus inflammation of Grade 2 were observed, and the urine concentration of NMAC (N-methylacetamide), which was a metabolite in urine of this substance, was 61 ppm (mg/L) after 6 days. Also, it was reported that the male worker completely recovered and was discharged after 13-day hospitalization, and returned to work after 30 days (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2017), Risk Assessment Report (Ministry of Health, Labour and Welfare, 2013), ACGIH (2018)). (4) In a case study of a male worker who was exposed to this substance, ethylenediamine, and diphenylmethane diisocyanate for 3 days (4 to 6 hours/day) in a synthetic fiber plant in Taiwan, on day 1 to 4 of hospitalization, hallucination, delusion, pulmonary edema with hypoxemia and resulting recurrent systemic tonic-clonic seizure, liver damage, and rhabdomyolysis were observed. The electroencephalogram showed a slow wave of 4 to 7 Hz and 20 to 80 microV, and moderate cortical function disorder was caused. The urine NMAC concentration decreased from 4,609 mg/g creatinine to 3,265 mg/g creatinine from the day of hospital admission to day 5, and then after 4-day hemoperfusion treatment, it decreased to 4 mg/g creatinine. It was reported that the urine NMAC concentration and the electroencephalogram were correlated with the clinical symptoms (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2017), Risk Assessment Report (Ministry of Health, Labour and Welfare, 2013)).
9	Specific target organ toxicity - Repeated exposure	Category 1 (liver, respiratory organs)	Danger	H372	P260 P264 P270 P314 P501	[Rationale for the Classification] Based on (1) to (4), it was classified in Category 1 (liver, respiratory organs). Also, as for chronic nephropathy observed in (4), the possibility of extrapolation to humans was low, and therefore, the kidney was not adopted as the target organ. With the additional new information sources, the classification result was changed. [Evidence Data] (1) In a study of 440 workers who were exposed to this substance in a polyurethane fiber production plant in Korea, 28 workers developed liver damage of a hepatocyte damage type due to this substance, and the incidence in a high exposure group (group with a high urine concentration of NMAC (N-methylacetamide) which was a metabolite in urine of this substance) was 7 to 10 times higher than that in a low exposure group. It was reported that the incidence of liver damage was smaller in workers employed for a long time, and liver damage was not observed when the exposure period was more than 7 months (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2017)). (2) In a study which monitored 1,045 workers in a polyurethane fiber production plant in Korea, liver damage of a hepatocyte damage type due to this substance was observed in 38 workers (22 male workers, 16 female workers). Also, 29 workers developed the symptom within 2 months after the first exposure, and the incubation period did not exceed 6 months. In a recurrent case, the incubation period of liver damage was shorter at the time of the recurrence than at the first time. It was reported that, in 21 out of 38 workers, the urine NMAC concentration was higher than that in workers who did not develop the symptom (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2017)). (3) In a study of 41 workers who had been working for 2 to 10 years in a spinning department, the absorption routes of this substance were considered to be via skin and by inhalation. The symptoms most frequently complained of or observed as clinical signs were indicated of liver involvement. Moreover, in numerous cases, troubles of bronchi and of the upper respiratory tract, gastric and nervous troubles, and joint paints were also present. The BSP was the most sensitive method for the detection of liver impairment, and this test method demonstrated liver impairment in 63% of the cases (19/30) and a clear relationship between the liver impairment and the duration of exposure to this substance (Risk Assessment Report (Ministry of Health, Labour and Welfare, 2013), SIAR (2001), ACGIH (2018)). (4) It was reported that, in a 2-year inhalation (vapor) exposure test with rats (6 hours/day, 5 days/week), effects on the liver (increased absolute and relative weight, an increase in gamma-GTP, brown pigmentation of the Kupffer cells (females)), effects on the kidney (increased relative weight, chronic nephropathy (males), increases in urea nitrogen and creatinine, brown pigmentation of the proximal tubules (females)), increases in total cholesterol and phospholipid, an increase in triglyceride, an increase in calcium, a decrease in mean corpuscular hemoglobin (females), and significant decreases in albumin and A/G ratio (females) were observed at 90 ppm (0.32 mg/L, within the range for Category 2); and a decrease in mean corpuscular volume, a decrease in mean corpuscular hemoglobin (males), effects on the liver (brown pigmentation of the Kupffer cells (males), granulation, an increase in the incidence of clear foci), effects on the kidney (brown pigmentation of the proximal tubules, an increase in the incidence of urothelium hyperplasia of the cyst and renal pelvis) (males), increases in platelet, reticulocyte ratio, and white blood cell count (females), and an increase in calcium (females) were observed at 450 ppm (1.6 mg/L, in the range corresponding to "Not classified") (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2017), ACGIH (2018)). [Reference Data, etc.] (5) It was reported that, in a 2-year inhalation (vapor) exposure test with mice (6 hours/day, 5 days/week), decreases in red blood cell count, hematocrit level, lymphocyte ratio, and eosinophil ratio (males), and increases in urea nitrogen and sodium (males) were observed at 60 ppm (0.21 mg/L, within the range for Category 2), and effects on the liver (increased absolute and relative weight, increases in AST, ALT, and ALP, eosinophilic foci), effects on the kidney (papillary necrosis, an increase in the incidence of scar), increases in platelet and reticulocyte ratio, and increased absolute and relative weight of the spleen and lung (males) were observed at 300 ppm (1.07 mg/L, in the range corresponding to "Not classified") (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2017), ACGIH (2018)).
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)	Not classified	- -	-	-	It was classified as "Not classified" from 72-hour ErC50 > 500 mg/L for algae (Desmodesmus subspicatus) (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2017)), 48-hour EC50 > 500 mg/L for crustacea (Daphnia magna), and 96-hour LC50 > 500 mg/L for fish (Leuciscus idus) (both, SIAR (2001), Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2017)).
11	Hazardous to the aquatic environment Long term (Chronic)	Not classified	- -	-	-	If chronic toxicity data are used, then it is classified as "Not classified" due to being rapidly degradable (a degradation rate by BOD (NO2): 80%, (NH3): 107% (Biodegradation and Bioconcentration Results of Existing Chemical Substances under the Chemical Substances Control Law, METI, 1988)), and 72-hour NOEC = 500 mg/L for algae (Desmodesmus subspicatus) (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2017)). If acute toxicity data are used for a trophic level for which chronic toxicity data are not obtained (fish), then it is classified as "Not classified" due to being rapidly degradable and 96-hour LC50 > 500 mg/L for fish (Leuciscus idus) (SIAR (2001), Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2017)). by drawing a comparison between the above results, it was classified as "Not classified."
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.
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