NITE - Chemical Management Field

GHS Classification Results by the Japanese Government

GENERAL INFORMATION

Item	Information
CAS RN	108-67-8
Chemical Name	1,3,5-Trimethylbenzene
Substance ID	R03-B-006-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	FY2014 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 3	Warning	H226	P303+P361+P353 P370+P378 P403+P235 P210 P233 P240 P241 P242 P243 P280 P501	It was classified in Category 3 based on a flash point of 44 deg C (closed cup) (GESTIS (Accessed July 2021)). Besides, it is classified in Class 3, PG III in UNRTDG (UN 2325).
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 550 deg C (GESTIS (Accessed July 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)	- -	-	-	Organic compounds containing no oxygen, fluorine or chlorine.
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) and (2), it was classified as "Not classified." [Evidence Data] (1) LD50 for rats: 5,000 mg/kg (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2013)) (2) LD50 for rats: in the range from 4,300 to 8,642 mg/kg (Initial Risk Assessment Report (NITE, CERI, NEDO, 2008))
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] 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)	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) and (2), it was classified as "Not classified." Besides, since the exposure concentration was higher than the saturated vapor pressure concentration (16.1 mg/L), it was judged as being in a mist state. [Evidence Data] (1) LC50 (4 hours) for rats: 4,800 ppm (24 mg/L) (Initial Risk Assessment Report (NITE, CERI, NEDO, 2008), Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2013), REACH registration dossier (Accessed July 2021)) (2) The vapor pressure of this substance was 2.48 mmHg (HSDB (Accessed July 2021)).
2	Skin corrosion/irritation	Category 2	Warning	H315	P302+P352 P332+P313 P362+P364 P264 P280 P321	[Rationale for the Classification] Based on (1) and (2), it was classified in Category 2. [Evidence Data] (1) In an acute dermal irritation/corrosion test with rabbits (n=6) (OECD TG 404, application for 4 hours, observation for 6 days), very slight redness appeared after one hour and it developed into moderate to severe redness after 144 hours. It was reported that slight edema appeared after an hour but it disappeared after 144 hours (Initial Risk Assessment Report (NITE, CERI, NEDO, 2008)). (2) This substance was irritating to the skin of the experimental animals (Initial Risk Assessment Report (NITE, CERI, NEDO, 2008)). [Reference Data, etc.] (3) It was reported that, in a skin irritation test with rabbits (application for 24 hours), moderate irritation of the skin was observed (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) and (2), it was classified in Category 2B. [Evidence Data] (1) It was reported that, in an eye irritation test with rabbits (application for 24 hours), slight irritation of the eyes was observed (Initial Risk Assessment Report (NITE, CERI, NEDO, 2008)). (2) This substance was irritating to the eyes of the experimental animals (Initial Risk Assessment Report (NITE, CERI, NEDO, 2008)).
4	Respiratory sensitization	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data. [Reference Data, etc.] (1) It was reported that, among 37 people exposed to vapor of the mixed solvent containing isomers of this substance (this substance: 30%, 1,2,4-trimethylbenzene: 50%, substances possibly present: 1,2,3- trimethylbenzene, 1-methyl-2-ethylbenzene, 1-methyl-4-ethylbenzene) for 7 years, 70% of the people exposed to the highest concentration developed asthmatic bronchitis but it could have been that the solvent had been contaminated with benzene (Initial Risk Assessment Report (NITE, CERI, NEDO, 2008), ACGIH (7th, 2001), DFG MAK (2012)).
4	Skin sensitization	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
5	Germ cell mutagenicity	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) to (3), it was classified as "Not classified." Although in vivo positive results were obtained in (1), the EPA judged in (3) that there was inadequate evidence to judge it as genotoxic. Therefore, it was classified as "Not classified." [Evidence Data] (1) As for in vivo, negative results were reported in a micronucleus test using the bone marrow cells of mice (single intraperitoneal administration) and a sister chromatid exchange assay using the bone marrow cells of mice (single intraperitoneal administration) (Initial Risk Assessment Report (NITE, CERI, NEDO, 2008)). In the subsequent evaluation, it was judged that the result of a micronucleus test with mice was negative but the result of a sister chromatid exchange assay was positive at high doses (730 mg/kg or higher) (US AEGL (2012), Patty (6th, 2012)). However, it was reported that the doses in intraperitoneal administration were 80% of the LD50 at most and the increased SCE frequency was only up to 1.5-fold higher than that of the control group (REACH registration dossier (Accessed July 2021)). (2) As for in vitro, a bacterial reverse mutation test showed negative results regardless of the presence or absence of metabolic activation (Initial Risk Assessment Report (NITE, CERI, NEDO, 2008), Patty (6th, 2012), US AEGL (2012), Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2013)). (3) The EPA expressed their opinion that there was inadequate evidence to conclude that any isomer of trimethylbenzene was genotoxic (EPA Tox Review (2016)).
6	Carcinogenicity	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
7	Reproductive toxicity	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data. No developmental toxicity effects were observed in (1), but there were no data about effects on fertility. [Evidence Data] (1) It was reported that, in a developmental toxicity study by inhalation exposure with rats (days 6-20 of gestation), there was no developmental toxicity (US AEGL (2012), Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2013)). [Reference Data, etc.] (2) In a three-generation reproduction toxicity study with rats by inhalation exposure of aromatic hydrocarbon compound (C9, containing 8.37% of this substance) as a test substance, at a dose at which many parental animals and pups were reported to have died (7/30 cases (F0 females), 6/30 cases (F1 females), 36/40 (F2 males), 34/40 (F2 females)), prolonged mating interval in all generations of F0 to F2, a decrease in the fertility index and a decrease in the number of live litters at birth in F1 males; and in pups, lower body weight in all generations of F1 to F3, a decrease in birth index in F2, and a lower survival rate on day 4 after birth were observed (US AEGL (2012), Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2013)). (3) In a developmental toxicity study with mice (days 6 to 15 of gestation) by inhalation exposure of aromatic hydrocarbon compound (C9, containing 8.37% this substance) as a test substance, at 1,500 ppm, death, clinical signs (abnormal gait, labored breathing, etc.), a decrease in food consumption, a decrease in the number of live fetuses per litter, and an increase in post-implantation loss were observed in parental animals, and cleft palate and an increase in delayed ossification of the skull were observed in foetuses. In a dose-finding study, no malformations were observed at the exposure concentrations up to 1,500 ppm (US AEGL (2012), Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2013)).
8	Specific target organ toxicity - Single exposure	Category 3 (respiratory tract irritation, narcotic effects)	Warning	H335 H336	P304+P340 P403+P233 P261 P271 P312 P405 P501	[Rationale for the Classification] Based on (1) to (5), it was classified in Category 3 (respiratory tract irritation, narcotic effects). [Evidence Data] (1) It was reported that, in an acute inhalation exposure test (mist) with mice, central nervous system depression occurred at 5,000 to 9,000 ppm (25 to 45 mg/L, in the range corresponding to "Not classified") (ACGIH (2001)). (2) It was reported that, in an acute inhalation exposure test (vapor) with rats, the concentrations for 50% reduction (EC50s) in performance in a rotarod test and in pain sensitivity threshold in a hot-plate test were 963 ppm (4.82 mg/L, within the range for Category 1) and 1,212 ppm (6.06 mg/L, within the range for Category 1), respectively (US AEGL (2012), Initial Risk Assessment Report (NITE, CERI, NEDO, 2008)). (3) It was reported that, in an acute inhalation exposure test (vapor) with rats (24 hours), at 2,240 ppm (converted 4-hour equivalent value: 8,960 ppm (44.8 mg/L), in the range corresponding to "Not classified"), narcosis developed into respiratory failure and 4/16 rats died. It was also reported that pulmonary congestion was observed at necropsy (US AEGL (2012)). (4) It was reported that, in a respiratory function test with mice by single inhalation exposure (vapor), the RD50 (the concentration that reduces the respiratory rate by 50%) after 6-minutes of exposure was 519 ppm (2.59 mg/L, within the range for Category 1) (US AEGL (2012)). (5) This substance is irritating to the eyes, skin, and respiratory tract, and may have an effect on the central nervous system, and when the liquid is swallowed, it may be drawn in the lungs, causing chemical pneumonia. It was reported that, when it was inhaled or orally ingested, confusion, cough, vertigo, lethargy, headache, sore throat, and vomiting occurred; when it contacted the skin, redness or dry skin was caused; and when it entered the eyes, redness or pain was caused (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2013)). [Reference Data, etc.] (6) It was reported that, in an experiment in volunteers exposed by inhalation to this substance and isomers of this substance, no irritation nor central nervous system effects were observed at up to 25 ppm in 2-hour or 4-hour exposure and at up to 30 ppm in 8-hour exposure (US AEGL (2012)).
9	Specific target organ toxicity - Repeated exposure	Category 1 (central nervous system, respiratory organs)	Danger	H372	P260 P264 P270 P314 P501	[Rationale for the Classification] Based on (1), it was classified in Category 1 (respiratory organs) since bronchitis with asthma observed in human cases was considered to be an effect on the respiratory organs. In addition, based on (1) and (2), it was classified in Category 1 (central nervous system) since effects on the central nervous system were observed within the range for Category 1. Therefore, it was classified in Category 1 (central nervous system, respiratory organs). [Evidence Data] (1) In a survey of 27 painters and their 10 assistants exposed to paint thinner (Fleet-X-DV-99) containing more than 30% of this substance and more than 50% of isomers of this substance for several years, the concentration of high-boiling hydrocarbon in the air sample collected during paint work and after work were in the range of 10 to 60 ppm. These workers complained frequently of headaches, tiredness, dizziness, and numbness, and asthmatiform bronchitis was generally observed, and gastric symptoms were also observed in many workers. In addition, it was reported that hematological effects (decreases in red blood cell count and blood platelet count, lengthened clotting times) were observed but it was pointed out that they might have been caused by contamination of the solvent with benzene (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2013), Initial Risk Assessment Report (NITE, CERI, NEDO, 2008), ACGIH (2001), DFG MAK (2012)). (2) It was reported that, in a 4-week inhalation exposure test (vapor) with rats (males) (6 hours/day, 6 days/week), a decreased duration of passive avoidance behavior and an increased frequency of active avoidance behaviors were observed at or above 25 ppm (converted guidance value: 0.033 mg/L/6 hours, within the range for Category 1) (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2013), Initial Risk Assessment Report (NITE, CERI, NEDO, 2008)). [Reference Data, etc.] (3) It was reported that, in a repeated dose 90-day oral toxicity study with rats, increases in liver and kidney weight were observed at 600 mg/kg/day (in the range corresponding to "Not classified") (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2013), Initial Risk Assessment Report (NITE, CERI, NEDO, 2008)). (4) It was reported that, in a 5-week inhalation exposure test (vapor) with rats (males) (6 hours/day, 6 days/week), an increase in serum AST activity was observed at 600 ppm (converted guidance value: 0.98 mg/L/6 hours, within the range for Category 2) (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2013), Initial Risk Assessment Report (NITE, CERI, NEDO, 2008)).
10	Aspiration hazard	Category 1	Danger	H304	P301+P310 P331 P405 P501	[Rationale for the Classification] Based on (1) - (4), it was classified in Category 1. [Evidence Data] (1) This substance is a hydrocarbon compound. (2) It was reported that the kinematic viscosity was 0.843 and 0.630 mm2/s at 20 deg C and 50 deg C, respectively (REACH registration dossier (Accessed July 2021)). (3) There is a warning that if this liquid is swallowed, aspiration into the lungs may result in chemical pneumonitis (HSDB (Accessed July 2021), ICSC (2002)). (4) It was reported that if this substance remains in the lungs may result in chemical pneumonitis (OEL Documentations (Japan Society For Occupational Health (JSOH), 1984)).

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 = 6 mg/L for crustacea (Daphnia magna) (Initial Risk Assessment (NITE, CERI, NEDO, 2008), Hazard Assessment Report (CERI, NITE, 2006)).
11	Hazardous to the aquatic environment Long term (Chronic)	Category 2	-	H411	P273 P391 P501	If chronic toxicity data are used, then it is classified in Category 2 because it was not rapidly degradable (a 14-day degradation rate by BOD: 0% (Biodegradation and Bioconcentration Results of Existing Chemical Substances under the Chemical Substances Control Law, METI, 1980)), and due to 21-day NOEC = 0.4 mg/L for crustacea (Daphnia magna) (SIAP, 2012). If acute toxicity data are used for a trophic level for which chronic toxicity data are not obtained (algae, fish), then it is classified in Category 3 because it was not rapidly degradable and due to 96-hour LC50 = 12.5 mg/L for fish (Carassius auratus) (Initial Risk Assessment (NITE, CERI, NEDO, 2008)). By drawing a comparison between the above results, it was classified in Category 2.
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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