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GHS Classification Results by the Japanese Government

GENERAL INFORMATION

Item	Information
CAS RN	624-18-0
Chemical Name	p-Phenylenediamine dihydrochloride
Substance ID	R01-B-007
Classification year (FY)	FY2019
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	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 (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)	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	*	- -	-	-	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	*	- -	-	-	Because it is classified in Division 6.1 (toxic substances), PG III in UNRTDG (UN1673), and it is considered to be not applicable to pyrophoric solids, hazards of the highest precedence, it was classified as "Not classified."
11	Self-heating substances and mixtures	*	- -	-	-	No data 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	*	- -	-	-	It is an organic compound which does not contain fluorine or oxygen but contains chlorine, which is ionically bonded to amine and does not contribute to oxidization of other substances. 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)	Category 3	Danger	H301	P301+P310 P264 P270 P321 P330 P405 P501	[Rationale for the Classification] Based on (1), it was classified in Category 3. [Evidence Data] (1) LD50 for rats: 147 mg/kg (NICNAS IMAP (Access on June 2019))
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] Based on (1) and (2), since p-phenylenediamine (CAS RN 106-50-3), the free base of this substance, was judged to be "Not classified," it was classified as "Not classified." [Evidence Data] (1) In a test in which 500 mg of p-phenylenediamine was administered to rabbits (24-hour application), it was reported to be non-irritant (BUA 97 (1992)). (2) No data on the local irritative effects of this substance is provided, but the irritative potential of this substance is expected to be weak or moderate, similarly to p-phenylenediamine, the free base (GESTIS (Access on May 2019)). [Reference Data, etc.] (3) It was reported that application of p-phenylenediamine in a 50% aqueous ointment to 6 volunteers resulted in only slight irritation (DFGOT vol.6 (1993)). (4) As for p-phenylenediamine, the free base of this substance, findings on the skin varied from none to moderately irritating depending on the concentration and duration of contact, and a test on rabbits' skin with 50% emulsion revealed distinct reactions, but irritation to human skin was minor. Based on these findings, this substance was assessed to be moderately irritating to the eyes and slightly irritating to the skin (GESTIS (Access on May 2019)).
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), since p-phenylenediamine (CAS RN 106-50-3), the free base of this substance, was judged to be Category 2B, it was classified in Category 2B. [Evidence Data] (1) It was reported to be slightly irritant in a Draize test in which the non-diluted substance was administered to rabbits (BUA 97 (1992)). (2) No data on the local irritative effects of this substance is provided, but the irritative potential of this substance is expected to be weak or moderate, similarly to p-phenylenediamine, the free base (GESTIS (Access on May 2019)). [Reference Data, etc.] (3) It was reported that in a test in which 30 mg was administered to rabbits, redness and edema of the conjunctiva and corneal clouding were observed, but these resolved within 7 days (BUA 97 (1992)). (4) It was classified in Eye Irrit. 2 (H319) in the EU-CLP classification (EU CLP classification (Access on July 2019)). (5) As for p-phenylenediamine, the free base of this substance, impact of the solid matter or saturated solutions on rabbits' eyes caused distinct irritation, whereas diluted solutions (2.5%) did not (GESTIS (Access on May 2019)).
4	Respiratory sensitization	Category 1	Danger	H334	P304+P340 P342+P311 P261 P284 P501	[Rationale for the Classification] Based on (1), since p-phenylenediamine (CAS RN 106-50-3) was judged to be Category 1, it was classified in Category 1. [Evidence Data] (1) There is a description that p-phenylenediamine is a potent sensitizer of the skin and respiratory tract and may cause asthma (PATTY (6th, 2012)).
4	Skin sensitization	Category 1A	Warning	H317	P302+P352 P333+P313 P362+P364 P261 P272 P280 P321 P501	[Rationale for the Classification] Based on (1)-(4), since p-phenylenediamine (CAS RN 106-50-3), the free base of this substance, was judged to be Category 1A, it was classified in Category 1A. [Evidence Data] (1) Japan Society For Occupational Health (JSOH) classified p-phenylenediamine as occupational skin sensitizers Group 1 (OEL Documentations vol.52 (Japan Society For Occupational Health (JSOH), 2010)). (2) In various skin sensitization tests with guinea pigs, it was reported that the positive rate was 100% (DFGOT vol 6 (1994)). (3) In a sensitization test (repeated insult patch test) on p-phenylenediamine in humans, all persons were found to be sensitized (DFGOT vol.14 (2000)). (4) It was reported that in a mouse local lymph node assay (LLNA) on p-phenylenediamine, EC3 was less than 2 (0.06% and 0.20%) (SCCS (2006)).
5	Germ cell mutagenicity	*	- -	-	-	[Rationale for the Classification] Based on (1), according to expert judgements, it was classified as "Not classified." [Evidence Data] (1) As for in vivo, negative results were reported for micronucleus assays by intraperitoneal injection administration to rats or oral administration to mice (SCCS (2012)). (2) As for in vitro, positive results were reported for bacterial reverse mutation tests, mouse lymphoma assay (tk locus), and a micronucleus test with cultured mammalian cells, and a negative result was reported for an HPRT test with cultured mammalian cells (SCCS (2012), NTP DB (Access on May 2019)).
6	Carcinogenicity	*	- -	-	-	[Rationale for the Classification] Based on (1) and (2), it was classified as "Not classified." [Evidence Data] (1) As for classification results by domestic and international organizations for p-phenylenediamine (CAS RN 106-50-3), the free base of this substance, it was classified in Group 3 (IARC Suppl.7 (1987)) by IARC, in A4 (ACGIH (7th, 2001)) by ACGIH. (2) In a carcinogenicity test in which rats and mice were administered this substance in feed for 2 years, no statistically significant incidence of tumors was observed in both sexes of both species (NTP TR174 (1979)).
7	Reproductive toxicity	*	- -	-	-	[Rationale for the Classification] There are no data on this substance itself. In addition, p-phenylenediamine, the free base of this substance, was classified as "Classification not possible" due to the lack of data (please refer to classification results for p-phenylenediamine (CAS RN 106-50-3)). Therefore, it was classified as "Classification not possible" due to lack of data. [Evidence Data] (1) In a prenatal development toxicity test (OECD TG 414) in which p-phenylenediamine was administered by gavage to pregnant female rats on Day 6 through 19 of gestation, retardation in ossification was seen (SCCS (2012)). (2) In a test in which p-phenylenediamine was administered by gavage to pregnant female rats on Day 6 through 15 of gestation, although maternal toxicity (reduced body weight gain, decreased food consumption and death) was observed, no teratogenicity or embryotoxicity/fetotoxicity was observed (SCCS (2012), ACGIH 7th, (2001)). [Reference Data, etc.] (3) In a test in which p-phenylenediamine was administered subcutaneously to female mice on Days 5 to 7, 8 to 10 or 11 to 14 of gestation, no teratogenic effect was observed (SCCS (2012)).
8	Specific target organ toxicity - Single exposure	Category 1 (heart, kidney, muscle)	Danger	H370	P308+P311 P260 P264 P270 P321 P405 P501	[Rationale for the Classification] There are no reports on single exposure to this substance itself in humans or experimental animals. As for p-phenylenediamine (CAS RN 106-50-3), the free base of this substance, several cases of rhabdomyolysis and renal failure have been reported in humans following a single oral dose, as represented in (1) and (2). In addition, as shown in (3), there was a case of myocarditis in a person who accidentally or intentionally ingested a hair dye containing p-phenylenediamine as the main component. Since this substance has the potential to cause the same effects as p-phenylenediamine, as described in (4), this substance was classified in Category 1 (heart, kidney, muscle). [Evidence Data] (1) A 40-year-old man who orally ingested 5,000 mg (70 mg/kg) of p-phenylenediamine presented with dyspnea and edema of the face and tongue, followed by rhabdomyolysis, increased blood LDH, AST and ALT activities, acute kidney failure and red-brown urine (DFGOT vol.6 (1994)). (2) A 50-year-old man who accidentally swallowed 1 cup of an aqueous solution of p-phenylenediamine showed abdominal pain, facial edema and dyspnea, followed by rhabdomyolysis, increased blood LDH, AST, creatine phosphokinase (CPK), aldolase activities, acute kidney failure and dark brown urine (DFGOT vol.6 (1994)). (3) In humans, there are case reports on persons who developed angioneurotic edema, rhabdomyolysis and renal failure or persons who developed myocarditis after accidental and intentional ingestion of a hair dye in which p-phenylenediamine was the main component (SCCS (2012)). (4) Animal experiments have confirmed that this substance can also trigger effects that are similar to those of p-phenylenediamine (GESTIS (Access on June 2019)). [Reference Data, etc.] (5) In a test in which mice were administered p-phenylenediamine at 35 or 70 mg/kg by nasogastric tube, blood CPK activity significantly increased 24 hours after administration and necrosis of skeletal muscle microfibers was observed after 24 hours (DFGOT vol.6 (1994)).
9	Specific target organ toxicity - Repeated exposure	Category 2 (heart, muscle)	Warning	H373	P260 P314 P501	[Rationale for the Classification] Based on (1) to (3), when p-phenylenediamine (CAS RN 106-50-3), the free base of this substance, was administered to experimental animals, effects on the heart and muscles were observed within the range of Category 2 of the converted value equivalent to this substance. Therefore, it was classified in Category 2 (heart, muscle). As a result of dose conversion, the classification was different from that of p-phenylenediamine. Besides, the classification result was changed from the previous classification by excluding the case where the causal substance was unclear (a mixture) from the classification basis of the previous classification and by adding and examining information from the new information sources. [Evidence Data] (1) As a result of oral administration of 5 to 40 mg/kg/day of p-phenylenediamine to rats for 14 days, increased LDH level was observed at or above 5 mg/kg/day (converted guidance value: 0.8 mg/kg/day (a converted value equivalent to this substance: 1.3 mg/kg/day), within the range of Category 1), increased ALT, AST and creatinine phosphokinase levels and increased relative thyroid weights were observed at or above 10 mg/kg/day (converted guidance value: 1.6 mg/kg/day (a converted value equivalent to this substance: 2.6 mg/kg/day), within the range of Category 1), and an increase of liver weights and minimal myodegeneration in the skeletal muscle were observed at 40 mg/kg/day (converted guidance value: 6.2 mg/kg/day (a converted value equivalent to this substance: 10.4 mg/kg/day), within the range of Category 2) (SCCS (2012)). (2) As a result of oral administration of 2 to 16 mg/kg/day of p-phenylenediamine to rats for 13 weeks, increases in liver and kidney weights were observed at or above 8 mg/kg/day (a converted value equivalent to this substance: 13 mg/kg/day, within the range of Category 2), and slight skeletal muscle degeneration was observed at 16 mg/kg/day (a converted value equivalent to this substance: 27 mg/kg/day, within the range of Category 2) (Environmental Risk Assessment for Chemical Substances Vol.3 (Ministry of the Environment, 2004), SCCS (2012)). (3) As a result of oral administration of this substance to rabbits at 10 mg/kg/day (a converted value equivalent to this substance: 17 mg/kg/day, within the range of Category 2) for 90 days, alterations of the myocardial parenchyma (edema, swelling of muscular fibers, cytoplasmic homogenization and disappearance of cross-striation) were observed (ACGIH (7th, 2001)). [Reference Data, etc.] (4) It is well known that p-phenylenediamine and its derivatives can induce myotoxicity (SCCS (2012)). (5) As for information in humans, there was a report that a 51-year-old woman who had regularly been dying her hair with a commercial preparation consisting of p-phenylenediamine and that hepatomegaly and spleen enlargement were observed and the patient developed progressive neurological symptoms prior to her death 11 weeks after admission to hospital (IARC 16 (1978), ACGIH (7th, 2001)). There was a report that gastrointestinal and nervous symptoms were observed in the person who had used a p-phenylenediamine hair-dye preparation (ACGIH (7th, 2001)). There is a report on one worker who died of jaundice and subacute atrophy of the liver after occupational exposure to p-phenylenediamine hair dyes over a period of 5 years (ACGIH (7th, 2001)).
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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