NITE - Chemical Management Field

GHS Classification Results by the Japanese Government

GENERAL INFORMATION

Item	Information
CAS RN	101-14-4
Chemical Name	3,3'-Dichloro-4,4'-diaminodiphenylmethane
Substance ID	R02-B-031-MHLW, MOE
Classification year (FY)	FY2020
Ministry who conducted the classification	Ministry of Health, Labour and Welfare (MHLW)/Ministry of the Environment (MOE)
New/Revised	Revised
Classification result in other fiscal year	FY2006 FY2011
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. It was classified as "Not classified."
2	Flammable gases	Not classified (Not applicable)	- -	-	-	Solid (GHS definition). It was classified as "Not classified."
3	Aerosols	Not classified (Not applicable)	- -	-	-	Not aerosol products. It was classified as "Not classified."
4	Oxidizing gases	Not classified (Not applicable)	- -	-	-	Solid (GHS definition). It was classified as "Not classified."
5	Gases under pressure	Not classified (Not applicable)	- -	-	-	Solid (GHS definition). It was classified as "Not classified."
6	Flammable liquids	Not classified (Not applicable)	- -	-	-	Solid (GHS definition). It was classified as "Not classified."
7	Flammable solids	Classification not possible	- -	-	-	No data available. Besides, there is information that it is combustible (ICSC (2013)).
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. It was classified as "Not classified."
9	Pyrophoric liquids	Not classified (Not applicable)	- -	-	-	Solid (GHS definition). It was classified as "Not classified."
10	Pyrophoric solids	Classification not possible	- -	-	-	No data available.
11	Self-heating substances and mixtures	Classification not possible	- -	-	-	Classification is not possible because test methods applicable to solid (melting point <= 140 deg C) 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). It was classified as "Not classified."
13	Oxidizing liquids	Not classified (Not applicable)	- -	-	-	Solid (GHS definition). It was classified as "Not classified."
14	Oxidizing solids	Not classified (Not applicable)	- -	-	-	The substance is an organic compound containing chlorine (but not fluorine or oxygen) which is chemically bonded only to carbon or hydrogen. It was classified as "Not classified."
15	Organic peroxides	Not classified (Not applicable)	- -	-	-	Organic compounds containing no bivalent -O-O- structure in the molecule. It was classified as "Not classified."
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. 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)	Not classified	- -	-	-	[Rationale for the Classification] It was classified as "Not classified" from (1). [Evidence Data] (1) LD50 for rats (OECD TG 423, GLP test): > 2,000 mg/kg (SIAR (2014), JECDB (Access on May 2020)) [Reference Data, etc.] (2) LD50 for rats: 2,100 mg/kg (ACGIH (7th, 2019)) (3) LD50 for rats: 750 mg/kg (ACGIH (7th, 2019)) (4) LD50 for rats: 1,140 mg/kg (HSDB (Access on April 2020))
1	Acute toxicity (Dermal)	Not classified	- -	-	-	[Rationale for the Classification] It was classified as "Not classified" from (1) - (3). [Evidence Data] (1) LD50 for rats: > 2,000 mg/kg (SIAR (2014), AICIS IMAP (2014)) (2) LD50 for rabbits: > 5,000 mg/kg (ACGIH (7th, 2019)) (3) LD50 for rabbits: > 5,000 mg/kg (HSDB (Access on April 2020))
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	Not classified	- -	-	-	[Rationale for the Classification] It was classified as "Not classified" from (1), (2). [Evidence Data] (1) This substance irritated the skin of guinea pigs very mildly (ACGIH (7th, 2019), Hazard Assessment Report (CERI, NITE, 2005), AICIS IMAP (2014), GESTIS (Access on May 2020), HSDB (Access on May 2020)). (2) In an in-vitro skin irritation test using reconstructed human epidermis model according to OECD Draft TG, the cell viability was 135% at 15 minutes after application, and it was judged as non-irritant (SIDS Dossier (2014), REACH registration dossier (Access on June 2020)).
3	Serious eye damage/eye irritation	Not classified	- -	-	-	[Rationale for the Classification] It was classified as "Not classified" from (1) - (3). The classification result was changed due to new data obtained. [Evidence Data] (1) This substance produced mild conjunctival irritation with no corneal or iritic effect in the eyes of rabbits (ACGIH (7th, 2019), Hazard Assessment Report (CERI, NITE, 2005), AICIS IMAP (2014), GESTIS (Access on May 2020), HSDB (Access on May 2020)). (2) In an in-vitro eye damage test using bovine cornea (BCOP) according to OECD TG 437, the mean In vitro irritancy score (IVIS) was 8.1, and Category 1 was denied (SIDS Dossier (2014), REACH registration dossier (Access on June 2020)). (3) In an eye irritation test with rabbits according to Federal Register, August 16, 1961, it was judged as not irritating (SIDS Dossier (2014)).
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] It was classified as "Not classified" from (1), (2). The classification result was changed due to new data (1) obtained. [Evidence Data] (1) In a mouse local lymph node assay (LLNA) according to TG 429, it was judged as negative (AICIS IMAP (2014), REACH registration dossier (Access on June 2020)). (2) This substance was not sensitizing to guinea pigs (ACGIH (7th, 2019), Hazard Assessment Report (CERI, NITE, 2005), AICIS IMAP (2014), GESTIS (Access on May 2020), HSDB (Access on May 2020)).
5	Germ cell mutagenicity	Category 2	Warning	H341	P308+P313 P201 P202 P280 P405 P501	[Rationale for the Classification] It was classified in Category 2 from (1), (2). [Evidence Data] (1) As for in vivo, it is reported that it was positive in a micronucleus test in mice (bone marrow) (Hazard Assessment Report (CERI, NITE, 2005), ATSDR (2017)), negative in a micronucleus test mice (erythrocytes), negative in micronucleus tests in rats (bone marrow, peripheral blood lymphocytes) (ATSDR (2017)), positive in sister chromatid exchange tests in rats (peripheral blood lymphocytes) (Hazard Assessment Report (CERI, NITE, 2005), ATSDR (2017)). positive in DNA adduct formation tests (liver, kidney, lung, urinary bladder, lymphocytes) in rats, and in DNA single-strand break tests (comet assay) in rats, it was positive in the lung and liver and negative in the kidney (ATSDR (2017)). (2) As for in vitro, it is reported that it was positive in a bacterial reverse mutation test and a gene mutation test in cultured mammalian cells (Hazard Assessment Report (CERI, NITE, 2005), ATSDR (2017)). And it is reported in test systems in cultured mammalian cells that it was negative in a chromosomal aberration test, positive in an unscheduled DNA synthesis test, positive in a cell transformational test, and positive and negative in sister chromatid exchange tests (Hazard Assessment Report (CERI, NITE, 2005), ATSDR (2017)). It was reported to be positive in a DNA damage test in cultured mammalian cells (ATSDR (2017)).
6	Carcinogenicity	Category 1B	Danger	H350	P308+P313 P201 P202 P280 P405 P501	[Rationale for the Classification] In classification results by other organizations in (1), IARC classified it in Group 1 based on strong evidence of genotoxicity due to occupational exposure in (2) and the results in experimental animals in (3), despite inadequate evidence in epidemiology in humans. However, the IARC's assessment as Group 1 was not supported in classification results by other organizations after the IARC's classification in 2012. At this time, even limited evidence of carcinogenicity was not obtained in humans, therefore, it was considered to be appropriate to classify it in Category 1B based on the classification results by other organizations. The classification result was changed due to the addition of new information such as classification results (ACGIH, NTP, MAK (DFG) in (1)). [Evidence Data] (1) As for classification results by domestic and international organizations, it was classified in Group 1 by IARC (IARC 100F (2012)), Group 2A by the Japan Society for Occupational Health (JSOH) (OEL Documentations (Carcinogenicity classification) (Japan Society For Occupational Health (JSOH) 2012)), A2 by ACGIH (ACGIH (7th, 2019)), R (Reasonably anticipated to be human carcinogens) by NTP (NTP RoC (14th, 2016)), Carc.1B in EU CLP (EU CLP classification (Access on April 2020)), and 2 in MAK (DFG) (DFG List of MAK and BAT Values 2019). (2) This substance has many properties typical of aromatic amines and has genotoxicity, including metabolic activation to DNA-reactive intermediates, formation of DNA adducts, and induction of mutagenic and clastogenic effects, in humans. This substance was shown to interact with DNA to form adducts in the urothelium of the workers exposed to this substance and interact with hemoglobin to form adducts in the blood of workers exposed to this compound. And it was also shown to increase the incidences of sister chromatid exchange (SCE) and micronuclei in urothelial cells and lymphocytes of exposed workers (IARC 100F (2012)). (3) In a test by 2-year diet administration of this substance to male and female rats, in addition to significant increases in the incidences of lung adenomatosis and adenocarcinoma, formation of pleural mesothelioma and hepatocellular adenoma and carcinoma was observed. In a test by 18-month diet administration of the hydrochloride of this substance to male rats, significant increases in the incidences of lung tumors, mammary gland adenocarcinoma, Zymbal's gland carcinoma, and hepatocellular carcinoma were seen (IARC 100F (2012)). Also, in a test by 18-month diet administration of the hydrochloride of this substance to male and female mice, a significant increase in the incidence of hepatoma was found in females (IARC 100F (2012)).
7	Reproductive toxicity	Classification not possible	- -	-	-	[Rationale for the Classification] Based on (1), no effect on fertility was observed, but since there was insufficient data on the effects on the development of offspring, including teratogenicity, it was determined that classification was not possible. [Evidence Data] (1) In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test with rats dosed by gavage (OECD TG 422), no effects on fertility and development of offspring were observed even at a dose of toxicity in parent animals (effects on the blood and liver) (JECDB (Accessed May, 2020)).
8	Specific target organ toxicity - Single exposure	Category 1 (blood)	Danger	H370	P308+P311 P260 P264 P270 P321 P405 P501	[Rationale for the Classification] Based on (1) and (2), effects on the blood system were suggested within the dose range for guidance value Category 1. Therefore, it was classified in Category 1 (blood system). [Evidence Data] (1) It was stated that, in repeated dose oral toxicity studies with dogs, on day 1 from the start of the study, the methemoglobin concentration in the blood was elevated in a group at or above 10 mg/kg/day; weakness, vomiting, pallor, and cyanosis appeared in groups at 40 and 80 mg/kg/day; and methemoglobinemia and macrocytic anemia developed by daily administration in smaller amounts (ACGIH (7th, 2019)). (2) In an acute oral toxicity test with rats dosed by gavage (OECD TG 423), at 300 mg/kg (within the range for Category 1), dark discoloration of the ear auricles and limbs was observed in one animal; and at 2,000 mg/kg (within the range for Category 2), dark discoloration of the ear auricles and limbs, an increase in water intake activity, a decrease in spontaneous movement, bradypnea, and abnormal gait (ataxic gait) were observed, and one animal died after 2 days with deep breathing and unkempt fur. Necropsy of the dead animal revealed white foci in the liver, dark red adrenal gland, dark red foci in the stomach, and dark red contents in the intestine from the jejunum to ileum (JECDB (Accessed May, 2020)), SIAR (2014)).
9	Specific target organ toxicity - Repeated exposure	Category 2 (blood system, liver)	Warning	H373	P260 P314 P501	[Rationale for the Classification] Based on (1), effects on the kidney, blood system, and liver were observed. Effects on the kidney were considered to be minor effects. Therefore, it was classified in Category 2 (blood system, liver). [Evidence Data] (1) In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test with rats dosed by gavage (OECD TG 422) (males: 42-day administration; females: 42 to 55-day administration), at or above 10 mg/kg/day (converted guidance value: 4.7 mg/kg/day, within the range for Category 1), renal tubular basophilia of the kidney and an increasing tendency of hemosiderin deposit of the spleen in males, and decreased levels of total protein and albumin in serum, and an increase in relative kidney weight in females were observed; and at 50 mg/kg/day (converted guidance value: 23.3 mg/kg/day, within the range for Category 2), salivation, an increase in the methemoglobin concentration, a decrease in erythrocyte counts, and centrilobular swelling and mid-zonal fatty degeneration of hepatocytes in males and females were observed; decreases in hemoglobin and hematocrit, increases in the reticulocyte and platelet counts, decreased levels of total protein and albumin, increases in total cholesterol, triglycerides, and inorganic phosphorus, increases in absolute and relative liver weight, an increase in relative spleen weight, and centrilobular single cell necrosis of hepatocytes in males were observed; and lower body weight during the last half of gestation, an increase in erythrocytes with Heinz bodies, increases in LDH and gamma-GTP, a decrease in A/G ratio, increases in absolute and relative spleen weight, increases in relative weight of the liver and thyroid, an increasing tendency in hemosiderin deposit of the spleen, and an increase in extramedullary hematopoiesis of the spleen in females were observed (JECDB (Accessed May, 2020)), SIAR (2014)).
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 1	Warning	H400	P273 P391 P501	It was classified in Category 1 from 48-hour EC50 = 0.250 mg/L for crustacea (Daphnia magna) (Initial Risk Assessment (NITE, CERI, NEDO, 2005), SIAR, 2013).
11	Hazardous to the aquatic environment Long term (Chronic)	Category 1	Warning	H410	P273 P391 P501	If chronic toxicity data are used, then it is classified in Category 1 because it was not rapidly degradable (a 4-week degradation rate by BOD: 0% (Biodegradation and Bioconcentration Results of Existing Chemical Substances under the Chemical Substances Control Law, METI, 1983)) and due to 21-day NOEC = 0.0095 mg/L for crustacea (Daphnia magna) (Results of Aquatic Toxicity Tests of Chemicals conducted by Ministry of the Environment in Japan (Ministry of the Environment, 2001), Environmental Risk Assessment for Chemical Substances Vol. 7 (Ministry of the Environment, 2009), SIAR, 2013). If acute toxicity data are used for a trophic level for which chronic toxicity data are not obtained, then it is classified in Category 1 because it was not rapidly degradable (not readily degradable, a 4-week degradation rate by BOD: 0% (Biodegradation and Bioconcentration Results of Existing Chemical Substances under the Chemical Substances Control Law, METI, 1983)) and due to 96-hour LC50 = 0.61 mg/L for fish (Oryzias latipes) (Results of Aquatic Toxicity Tests of Chemicals conducted by Ministry of the Environment in Japan (Ministry of the Environment, 2001), Environmental Risk Assessment for Chemical Substances Vol. 7 (Ministry of the Environment, 2009), SIAR, 2013). From the above results, it was classified in Category 1.
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.

To GHS Information