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GHS Classification Results by the Japanese Government

GENERAL INFORMATION

Item	Information
CAS RN	89-32-7
Chemical Name	1, 2, 4, 5-Benzenetetracarboxylic acid anhydride
Substance ID	R03-B-001-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	FY2008
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)	- -	-	-	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. Besides, there is information that it is combustible (GESTIS (Accessed May 2021)).
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	Not classified	- -	-	-	It is estimated that it does not ignite at normal temperatures from an autoignition temperature of 630 deg C (GESTIS (Accessed May 2021)).
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 oxygen (but not fluorine or chlorine) which is chemically bonded only to carbon or hydrogen.
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	- -	-	-	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.

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 (females): > 2,000 mg/kg (OECD TG 420, GLP) (REACH registration dossier (Accessed May 2021)) (2) LD50 for rats: > 2,250 mg/kg (NIOSH in PubChem (Accessed May 2021))
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 (OECD TG 402, GLP) (REACH registration dossier (Accessed May 2021))
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	Category 2	Warning	H315	P302+P352 P332+P313 P362+P364 P264 P280 P321	[Rationale for the Classification] Based on (1), it was classified in Category 2. [Evidence Data] (1) This substance was irritating to the skin (Haz-Map, Information on Hazardous Chemicals and Occupational Diseases in PubChem (Accessed May 2021)). [Reference Data, etc.] (2) It was reported that, in an in vitro skin corrosion test (equivalent to OECD TG 431, GLP), the cell viability was 108.1% after 4-hour exposure and 96.7% after 24-hour exposure (REACH registration dossier (Accessed May 2021)).
3	Serious eye damage/eye irritation	Category 1	Danger	H318	P305+P351+P338 P280 P310	[Rationale for the Classification] Based on (1), it was classified in Category 1. [Evidence Data] (1) It was reported that, in an acute eye irritation/corrosion test (equivalent to OECD TG 405, 21-day observation) with rabbits, severe eye irritation effects were observed (REACH registration dossier (Accessed May 2021)). [Reference Data, etc.] (2) In the EU CLP, it was classified in Eye Dam. 1.
4	Respiratory sensitization	Category 1	Danger	H334	P304+P340 P342+P311 P261 P284 P501	[Rationale for the Classification] Based on (1) and (2), it was classified in Category 1. [Evidence Data] (1) In a cross-sectional study of 92 workers who had primary exposure to this substance as well as to phthalic anhydride, maleic anhydride, and trimellitic anhydride, of those with less than 1 year of exposure, 56 had work-related symptoms. Eighteen had dyspnea, and eight had bronchial obstruction. It was reported that specific IgE antibodies were found in 15 workers; 12 of those had symptoms (CICAD (2009)). (2) In a test (induction exposure: inhalation of 500 microg/m3, 6 hours/day, 5 days/week, challenge exposure: 500 microg/m3, 6 hours/day) with rats (n=10/sex/group), significant increases in relative lung weight, number of lung foci, and PMDA-specific serum IgG antibody were observed compared to the control group. Microscopic lung lesions (interstitial inflammation, and lymphoid infiltrates of the bronchiole) of minimal to mild severity were observed even in the control group, while the lung lesions observed in the test group included the same lesions cited above but in greater severity (i.e. mild to marked) than in the control group as well as mild to marked alveolar hemorrhage and perivascular acute and chronic inflammation. Significant increases in lung lesions and PMDA-specific serum IgG antibody levels which were observed in the test group suggested that this substance induced respiratory sensitization (REACH registration dossier (Accessed May 2021)). [Reference Data, etc.] (3) It was reported that, in a test (induction exposure: inhalation of 50 microg/m3, 6 hours/day, 5 days/week, challenge exposure: 50 microg/m3, 6 hours/day) with rats (n=10/sex/group), the rats were necropsied in 18 hours after the challenge exposure, and as a result of measurements of lung weight, number of lung foci, and serum IgG antibody, there was no significant change in either the lung weight or the number of lung foci, but 3 males which had the highest number of lung foci in an exposed group had the highest levels of serum IgG antibody (REACH registration dossier (Accessed May 2021)). (4) In EU CLP, it was classified in Resp. Sens. 1.
4	Skin sensitization	Category 1	Warning	H317	P302+P352 P333+P313 P362+P364 P261 P272 P280 P321 P501	[Rationale for the Classification] Based on (1), it was classified in Category 1. [Evidence Data] (1) It was reported that, in a Local Lymph Node Assay (LLNA) (OECD TG 429, GLP) with mice (n=4), the Stimulation Index (SI values) were 9.12 (5%), 8.62 (10%), and 9 (25%) (REACH registration dossier (Accessed May 2021)). [Reference Data, etc.] (2) In the EU CLP, it was classified in Skin Sens. 1.
5	Germ cell mutagenicity	Not classified	- -	-	-	[Rationale for the Classification] There were no data on an in vivo test, but based on (1) to (4), results were negative for all three different indices, and therefore, it was classified as "Not classified." [Evidence Data] (1) In a bacterial reverse mutation test (OECD TG471, GLP), negative results were reported (Toxicity Testing Results for Existing Chemical Substances under the Chemical Substances Control Law (2016)). (2) In a chromosomal aberration test (OECD TG473, GLP) using the human lymphocytes, negative results were obtained (REACH registration dossier (Accessed May 2021)). (3) In a chromosomal aberration test (OECD TG473, GLP) using the cultured mammalian cells (CHL), negative results were obtained (Toxicity Testing Results for Existing Chemical Substances under the Chemical Substances Control Law (2016)). (4) In a gene mutation test (OECD TG476, GLP) using the cultured mammalian cells (CHL), negative results were obtained (REACH registration dossier (Accessed May 2021)). [Reference Data, etc.] (5) It was reported that, in a chromosomal aberration test with peripheral blood lymphocytes obtained from 42 workers engaged in the production of this substance and 35 donors, the group exposed to this substance demonstrated increased occurrence of aberrant metaphases (4.47%) in comparison with the value in the control group (2.29%) (HSDB (Accessed May 2021)).
6	Carcinogenicity	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) and (2), in a carcinogenicity study, results were negative in 2 species of animals, and therefore, it was classified as "Not classified." [Evidence Data] (1) In a 2-year (105-week) combined chronic toxicity/carcinogenicity study with rats dosed by feeding, there was no increase in the incidence of tumors related to the administration both in males and females at doses up to 15,000 ppm (1,000 mg/kg/day) (REACH registration dossier (Accessed May 2021)). (2) In a 2-year (104-week) carcinogenicity study with mice dosed by feeding, there was no increase in the incidence of tumors related to the administration in males at doses up to 16,346 ppm (approx. 2,340 mg/kg/day) and in females at doses up to 12,019 ppm (approx. 1,717 mg/kg/day) (REACH registration dossier (Accessed May 2021)).
7	Reproductive toxicity	Category 1B	Danger	H360	P308+P313 P201 P202 P280 P405 P501	[Rationale for the Classification] Based on (1), it was classified in Category 1B. At a dose at which no severe general toxic effects were observed in parent animals, effects on fertility (lower numbers of corpora lutea and implantation sites, an increase in preimplantation death rate, and lower numbers of births and liveborn pups) were observed. [Evidence Data] (1) It was reported that, in a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test with rats dosed by gavage (OECD TG 422, GLP, 42 days in total (males) from 14 days before mating through the mating period, 41 to 46 days in total (females) from 14 days before mating through the mating and gestation periods until day 4 of lactation), general toxic effects (hyperplasia of the limiting ridge squamous epithelium, and cellular infiltration of the glandular stomach submucosa (males and females), etc.), lower numbers of corpora lutea and implantation sites, an increase in preimplantation death rate, and lower numbers of births and liveborn pups were observed in parent animals at 1,000 mg/kg/day (Toxicity Testing Results for Existing Chemical Substances under the Chemical Substances Control Law (2017)). [Reference Data, etc.] (2) It was reported that in a reproduction/developmental toxicity screening test (OECD TG 421, GLP, 42 days in total (males) from prior to mating, until day 4 of lactation (females)) with rats dosed by gavage, no reproductive toxicity was observed (REACH registration dossier (Accessed May 2021)).
8	Specific target organ toxicity - Single exposure	Category 3 (Respiratory tract irritation)	Warning	H335	P304+P340 P403+P233 P261 P271 P312 P405 P501	[Rationale for the Classification] Based on (1), it was classified in Category 3 (respiratory tract irritation). [Evidence Data] (1) It was reported that, based on multiple human exposure cases, this substance caused eye irritation, skin irritation, and respiratory tract irritation (EU REGULATION (EC) No 1272/2008 in PubChem (Accessed May 2021)). [Reference Data, etc.] (2) A 17-year-old man was exposed to this substance during the production of epoxy resin, and was clinically diagnosed as having acute hemorrhagic alveolitis associated with anemia. It was reported that, by the serologic analysis, immunoblotting of the patient's serum indicated autoantibodies of normal serum proteins (HSDB in PubChem (Accessed May 2021). (3) Based on multiple human exposure cases, noncardiac pulmonary edema, immune sensitization, and irritation of mucous membranes and skin were generally observed after the exposure to this substance. However, it was reported that some of the reports of pulmonary edema, pulmonary hemorrhage, and chemical pneumonitis might represent immune sensitization (HSDB in PubChem (Accessed May 2021)). (4) It was reported that, in an acute oral toxicity test (OECD TG 420, GLP) with rats, no effect was observed at 2,000 mg/kg (within the range for Category 2) (REACH registration dossier (Accessed May 2021)). (5) It was reported that, in an acute dermal toxicity test (OECD TG 402, GLP) with rats, no effect was observed at 2,000 mg/kg (within the range for Category 2) (REACH registration dossier (Accessed May 2021)).
9	Specific target organ toxicity - Repeated exposure	Category 1 (respiratory organs)	Danger	H372	P260 P264 P270 P314 P501	[Rationale for the Classification] Based on (1), it was classified in Category 1 (respiratory organs). [Evidence Data] (1) It was reported that, in an inhalation toxicity study (dust, 14 days (10-day administration)) with rats, reduced body weight gain, slight breathing difficulties and nasal irritation, and slight pulmonary lesions (focal/multifocal interstitial pneumonia, aggregates of foamy macrophages in bronchiolar lumens, hypertrophy and hyperplasia of type 2 alveolar cells with formation of alveolar giant cells (foreign body type)) were observed at 0.021 mg/L (converted guidance value: 0.015 mg/L, within the range for Category 1); labored breathing was observed at 0.035 mg/L (converted guidance value: 0.004 mg/L, within the range for Category 2); and red nasal discharge, breathing difficulties and gasping, and an increase in neutrophils were observed at 0.091 mg/L (converted guidance value: 0.01 mg/L, within the range for Category 2) (REACH registration dossier (Accessed May 2021)). (2) It was reported that, in an oral toxicity test with rats dosed by gavage (OECD TG422, GLP, males: 42 days, females: 41 to 46 days), at 100 mg/kg/day (converted guidance value: 46.7 mg/kg/day (males), 45.6 to 51.1 mg/kg/day (females), within the range for Category 2), hyperplasia of the limiting ridge squamous epithelium and cellular infiltration of the glandular stomach submucosa were observed in males and females; and at 1,000 mg/kg/day (converted guidance value: 467 mg/kg/day (males), 456 to 511 mg/kg/day (females), in the range corresponding to "Not classified"), a tendency of lower body weight or lower body weight, higher food consumption, lower excretion per day of urine sodium and potassium, and lower inorganic phosphorus were observed in males, and higher fibrinogen, lower inorganic phosphorus, higher ALT, and a tendency of lower locomotor activity or lower locomotor activity were observed in females (Toxicity Testing Results for Existing Chemical Substances under the Chemical Substances Control Law (2017)). (3) It was reported that, in a 105-week oral toxicity test with rats dosed by feeding, no effect was observed at 7,500 ppm (500 mg/kg/day, in the range corresponding to "Not classified"), and lower body weight was observed at 15,000 ppm (1,000 mg/kg/day, in the range corresponding to "Not classified") (REACH registration dossier (Accessed May 2021)).
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)	Category 2	- -	H401	P273 P501	Since this substance is anhydrate and is rapidly hydrolyzed in water to produce pyromellitic acid (CAS RN 89-05-4), the data on pyromellitic acid was adopted as the evidence for classification. It was classified in Category 2 from 72-hour ErC50 = 8.1 mg/L for algae (Desmodesmus subspicatus) (REACH registration dossier, 2021). The classification result was changed from the previous classification by using new information.
11	Hazardous to the aquatic environment Long term (Chronic)	Not classified	- -	-	-	Chronic toxicity data available for classification were not obtained. It was classified as "Not classified" because it was rapidly degradable, and due to a low bioaccumulation estimate (log Kow = 2.14 (KOWWIN v1.68 (EPI Suite)), although it was classified in Category 2 in acute toxicity. The classification result was changed from the previous classification by using new information.
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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