NITE - Chemical Management Field

GHS Classification Results by the Japanese Government

GENERAL INFORMATION

Item	Information
CAS RN	129-73-7
Chemical Name	N,N,N',N'-tetramethyl-4,4'-benzylidenedianiline; Leucomalachite green
Substance ID	R01-A-004
Classification year (FY)	FY2019
Ministry who conducted the classification	Ministry of Health, Labour and Welfare (MHLW)/Ministry of the Environment (MOE)
New/Revised	New
Classification result in other fiscal year
Download of Excel format	Excel file

REFERENCE INFORMATION

Item	Information
Guidance used for the classification (External link)	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
UN GHS document (External link)	UN GHS document
Definitions/Abbreviations (Excel file)	Definitions/Abbreviations
Model Label by MHLW (External link)
Model SDS by MHLW (External link)
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	*	- -	-	-	There are no chemical groups associated with explosive properties present in the molecule. It was classified as "Not classified (Not applicable)."
2	Flammable gases	*	- -	-	-	Solid (GHS definition). It was classified as "Not classified (Not applicable)."
3	Aerosols	*	- -	-	-	Not aerosol products. It was classified as "Not classified (Not applicable)."
4	Oxidizing gases	*	- -	-	-	Solid (GHS definition). It was classified as "Not classified (Not applicable)."
5	Gases under pressure	*	- -	-	-	Solid (GHS definition). It was classified as "Not classified (Not applicable)."
6	Flammable liquids	*	- -	-	-	Solid (GHS definition). It was classified as "Not classified (Not applicable)."
7	Flammable solids	*	- -	-	-	No data available.
8	Self-reactive substances and mixtures	*	- -	-	-	There are no chemical groups associated with explosive or self-reactive properties present in the molecule. It was classified as "Not classified (Not applicable)."
9	Pyrophoric liquids	*	- -	-	-	Solid (GHS definition). It was classified as "Not classified (Not applicable)."
10	Pyrophoric solids	*	- -	-	-	No data available.
11	Self-heating substances and mixtures	*	- -	-	-	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	*	- -	-	-	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 (Not applicable)."
13	Oxidizing liquids	*	- -	-	-	Solid (GHS definition). It was classified as "Not classified (Not applicable)."
14	Oxidizing solids	*	- -	-	-	Organic compounds containing no oxygen, fluorine or chlorine. It was classified as "Not classified (Not applicable)."
15	Organic peroxides	*	- -	-	-	Organic compounds containing no bivalent -O-O- structure in the molecule. It was classified as "Not classified (Not applicable)."
16	Corrosive to metals	*	- -	-	-	Classification is not possible because test methods applicable to solid substances are not available.
17	Desensitized explosives	*	- -	-	-	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)	*	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
1	Acute toxicity (Dermal)	*	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
1	Acute toxicity (Inhalation: Gases)	*	- -	-	-	[Rationale for the Classification] Solid (GHS definition). It was classified as "Not classified (Not applicable)."
1	Acute toxicity (Inhalation: Vapours)	*	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
1	Acute toxicity (Inhalation: Dusts and mists)	*	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
2	Skin corrosion/irritation	*	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
3	Serious eye damage/eye irritation	*	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
4	Respiratory sensitization	*	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
4	Skin sensitization	*	- -	-	-	[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] Because there were positive results in some in vivo tests in (1), this substance was recognized as mutagenic in (3) and (4), and this substance is a metabolite of malachite green which was classified in Category 1B as in (5), it was classified in Category 2. [Evidence Data] (1) As for in vivo, it was almost negative in rodent micronucleus tests. It was, however, weakly positive in a micronucleus test with peripheral blood of mice exposed to the highest dosage. Also, in a cII gene mutation test on transgenic animals, it was negative in rats and positive in mice. Additionally, in a liver DNA adduct formation test, it was negative in mice and positive in rats. On the other hand, it was negative in spleen lymphocyte HPRT tests in transgenic animals (rats and mice) (NTP TR527 (2005), JECFA FAS61 (2009), JECFA TRS 954 (2009), EFSA (2016), NTP DB (Access on May 2019), Risk Assessment Report (Veterinary Medicinal Products) (Food Safety Commission of Japan, 2005)). (2) As for in vitro, it was negative in a mammalian cell HPRT test and a bacterial reverse mutation test (NTP TR527 (2005), JECFA FAS61 (2009), JECFA TRS 954 (2009), Risk Assessment Report (Veterinary Medicinal Products) (Food Safety Commission of Japan, 2005)). (3) It is concluded in the joint statement of UK COM (The Committee on Mutagenicity of Chemicals in Food, Consumer Products and the Environment) and UK COC (Committee on Carcinogenicity of Chemicals in Food, Consumer Products and the Environment) that this substance should be considered as an in vivo mutagenic substance (Risk Assessment Report (Veterinary Medicinal Products) (Food Safety Commission of Japan, 2005)). (4) It was classified in Carc. 2 in EU harmonized CLP classification. (5) This substance is a metabolite of malachite green (CAS RN 569-64-2) (Risk Assessment Report (Veterinary Medicinal Products) (Food Safety Commission of Japan, 2005)) which was positive in an in vivo chromosomal aberration test with mouse spermatocytes (EFSA (2016)). Therefore, it was classified in Category 1B in Japan (GHS classification in FY2017).
6	Carcinogenicity	Category 2	Warning	H351	P308+P313 P201 P202 P280 P405 P501	[Rationale for the Classification] Based on EU CLP classification (1) corresponding to Category 2, and the fact that carcinogenicity was confirmed in (2) to (4), it was classified in Category 2. [Evidence Data] (1) As for classification results by domestic and international organizations, it was classified in Carc.2 in EU CLP (EU CLP classification (Access on May 2019)). (2) In a carcinogenicity test with male and female rats dosed with this substance by feeding for 2 years, slight increases in the incidence of thyroid gland follicular cell adenomas or carcinomas (combined) in both sexes, increases in bilateral testicular interstitial cell adenoma in males, and slight increases in hepatocellular adenoma in females were observed (equivocal evidence) (NTP TR527 (2005), Risk Assessment Report (Veterinary Medicinal Products) (Food Safety Commission of Japan, 2005), EFSA (2016), JECFA FAS61 (2009)). (3) In a carcinogenicity test with female mice dosed with this substance by feeding for 2 years, an increased incidence of hepatocellular adenoma or carcinoma (combined) was observed (some evidence) (NTP TR527 (2005), Risk Assessment Report (Veterinary Medicinal Products) (Food Safety Commission of Japan, 2005), EFSA (2016), JECFA FAS61 (2009)). (4) Food Safety Commission of Japan expressed its opinions that the carcinogenic risk of this substance for humans was unclear, however, animal test results suggested its carcinogenicity, and genetic toxicity was undeniable (Risk Assessment Report (Veterinary Medicinal Products) (Food Safety Commission of Japan, 2005)). On the other hand, the EFSA Panel concluded that this substance may be considered as carcinogenic (EFSA (2016)) based on the observations that an increase in hepatocellular adenomas and a small increase in hepatocellular carcinomas in mice and increases in the incidence of mammary gland carcinomas and of thyroid gland follicular cell adenomas or carcinomas (combined) in rats were observed.
7	Reproductive toxicity	Category 2	Warning	H361	P308+P313 P201 P202 P280 P405 P501	[Rationale for the Classification] Based on (1), since an increase in post-implantation losses was observed at a dosage of maternal toxicity, it was classified in Category 2. [Evidence Data] (1) In a developmental toxicity test with female rats orally administered (by gavage) on gestational Days 6-15, an increased incidence of fetuses with skeletal abnormalities (predominant abnormalities were bipartite ossification of the thoracic centrum), increases in post-implantation losses, decreases in fetal body weight and placental weight, and an increased incidence of fetuses with visceral abnormalities (hydronephrosis) were observed at a dosage of maternal toxicity (a severe reduction in maternal weight and feed consumption) (EFSA (2016), HSDB (Access on May 2019)).
8	Specific target organ toxicity - Single exposure	*	- -	-	-	Classification not possible due to lack of data.
9	Specific target organ toxicity - Repeated exposure	Category 1 (thyroid, liver), Category 2 (urinary bladder, blood system)	Danger Warning	H372 H373	P260 P264 P270 P314 P501	[Rationale for the Classification] Based on (1) to (4), in oral dose toxicity tests with rats and mice, effects on the thyroid and liver at doses within the range for Category 1, and effects on the urinary bladder and blood system at doses within the range for Category 2 were observed. Therefore, it was classified in Category 1 (thyroid, liver) and Category 2 (urinary bladder, blood system). [Evidence Data] (1) In a 28-day feeding toxicity test with male rats, increases in liver weight at or above 290 ppm (converted guidance value: 9 mg/kg/day, within the range for Category 1), decreased body weight gain and hepatocellular vacuolization at or above 580 ppm (converted guidance value: 19 mg/kg/day, within the range for Category 2), and less body weight, anemic tendency (decreased hemoglobin, hematocrit value, and erythrocyte counts, etc.) and an increase in gamma-GT activity at 1,160 ppm (converted guidance value: 36 mg/kg/day, within the range for Category 2) were observed (NTP TR527 (2005), Risk Assessment Report (Veterinary Medicinal Products) (Food Safety Commission of Japan, 2005), EFSA (2016)). (2) In a 28-day feeding toxicity test with female mice, increases in liver weight at or above 290 ppm (converted guidance value: 19 mg/kg/day, within the range for Category 2), decreased body weight gain at or above 580 ppm (converted guidance value: 34 mg/kg/day, within the range for Category 2), and less body weight and apoptosis in the transitional epithelium cells of the urinary bladder at 1,160 ppm (converted guidance value: 68 mg/kg/day, within the range for Category 2) were observed (the same as in the above data). (3) In a 2-year feeding toxicity test with rats, acidophilic foci and cystic degeneration in the liver and follicular cysts in the thyroid at 91 ppm (male: 5 mg/kg/day, female: 6 mg/kg/day, within the range for Category 1), and hepatocellular vacuolization at or above 272 ppm (17 mg/kg/day, within the range of Category 2) were observed as non-neoplastic lesions (the same as in the above data). (4) In a 2-year feeding toxicity test with female mice, an increased incidence of intracytoplasmic inclusions in the transitional epithelium of the urinary bladder was observed at 91 ppm (13 mg/kg/day, within the range for Category 2) as non-neoplastic lesions (the same as in the above data). [Reference Data, etc.] (5) Malachite green (CAS RN 569-64-2) which is a precursor of this substance was classified in Category 1 (thyroid) and Category 2 (blood system, liver) in GHS classifications in FY2017.
10	Aspiration hazard	*	- -	-	-	[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)	Classification not possible	- -	-	-	Classification not possible due to lack of data.
11	Hazardous to the aquatic environment Long term (Chronic)	Classification not possible	- -	-	-	Classification not possible due to lack of data.
12	Hazardous to the ozone layer	Classification not possible	- -	-	-	Classification not possible due to lack of data.

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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