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GHS Classification Results by the Japanese Government

GENERAL INFORMATION

Item	Information
CAS RN	1596-84-5
Chemical Name	3-(2,2-dimethylhydrazinecarbonyl)propanoic acid (synonym: Daminozide)
Substance ID	R03-A-002-MHLW, MOE
Classification year (FY)	FY2021
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 (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)
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	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 Sep. 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	Classification not possible	- -	-	-	No data available.
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	- -	-	-	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: > 5,000 mg/kg (EPA Pesticides RED (1993)) (2) LD50 for rats: 8,400 mg/kg (HSDB in PubChem (Accessed Sep. 2021))
1	Acute toxicity (Dermal)	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) and (2), it was classified as "Not classified." [Evidence Data] (1) LD50 for rabbits: > 5,000 mg/kg (HSDB in PubChem (Accessed Sep. 2021)) (2) LD50 for rabbits: > 16,000 mg/kg (EPA Pesticides RED (1993))
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)	Not classified	- -	-	-	[Rationale for the Classification] Based on (1), it was classified as "Not classified." [Evidence Data] (1) LC50 (1 hour) for rats: > 20 mg/L (converted 4-hour equivalent value: > 5 mg/L) (HSDB in PubChem (Accessed Sep. 2021)) (2) LC50 (4 hours) for rats: > 2.1 mg/L (CLH Report (2018))
2	Skin corrosion/irritation	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data. [Reference Data, etc.] (1) It was reported that, in an acute dermal irritation/corrosion test (OECD TG 404, 4-hour application, observation for 72 hours) with rabbits (n=6) using an 85% formulation of this substance, no skin irritation reactions were observed (erythema and eschar score: 0/0/0/0/0/0, edema score: 0/0/0/0/0/0) (ECHA RAC Opinion (2020), CLH Report (2018)).
3	Serious eye damage/eye irritation	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data. [Reference Data, etc.] (1) It was reported that, in an acute eye irritation/corrosion test (OECD TG 405, observation for 7 days) with rabbits (n=6) using an 85% formulation of this substance, the mean scores of conjunctival redness and chemosis at 24/48/72 hours after application were 2 or above in 2/6 animals, and the observed symptoms were reversible within 7 days (corneal opacity score: 0/0/0/0/0/0, iritis score: 0/0/0/0/0/0, conjunctival redness score: 1/2/2/1.3/1.7/1.3, conjunctival chemosis score: 1.7/2/2/1/1.7/1.3) (ECHA RAC Opinion (2020), CLH Report (2018)).
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] Based on (1), it was classified as "Not classified." [Evidence Data] (1) It was reported that, in a Local Lymph Node Assay (LLNA) (OECD TG 429) with mice (n=5/group), the Stimulation Index (SI) values were 0.58 (5%), 0.80 (10%), and 1.28 (25%) (ECHA RAC Opinion (2020), CLH Report (2018)). [Reference Data, etc.] (2) It was reported that, in a Buehler test (OECD TG 406, dermal administration: 100% test substance) with guinea pigs (n=20) using an 85% formulation of this substance, no skin reactions were observed (ECHA RAC Opinion (2020), CLH Report (2018)).
5	Germ cell mutagenicity	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) to (3), it was classified as "Not classified." [Evidence Data] (1) In a mammalian erythrocyte micronucleus test using the bone marrow cells of mice (OECD TG 474), negative results were reported (CLH Report (2018), ECHA RAC (Background Doc.) (2020), ECHA RAC Opinion (2020)). (2) In a mammalian bone marrow chromosomal aberration test (OECD TG 475) and a rodent dominant lethal test (OECD TG 478) using the bone marrow cells of mice, negative results were reported (CLH Report (2018), ECHA RAC (Background Doc.) (2020), ECHA RAC Opinion (2020)). (3) In multiple bacterial reverse mutation tests (OECD TG 471), a cell gene mutation test (OECD TG 476) with the cultured mammalian cells (mouse lymphoma cells), and a vitro mammalian chromosomal aberration test (OECD TG 473) using CHO cells, negative results were reported in all of the above tests (CLH Report (2018), ECHA RAC (Background Doc.) (2020), ECHA RAC Opinion (2020)).
6	Carcinogenicity	Category 2	Warning	H351	P308+P313 P201 P202 P280 P405 P501	[Rationale for the Classification] In addition to the classification results by domestic and international organizations based on (1), a comprehensive judgment was made according to the opinions of the Committee for Risk Assessment of the European Chemical Agency (ECHA RAC) in (5) based on the test results, etc. in (2) to (4), and the carcinogenicity classification results of the major metabolite of this substance in (6), and this substance was classified in Category 2. [Evidence Data] (1) As for the classification results by domestic and international organizations, the EPA has classified this substance in Group B (Probable Human Carcinogen: Category 1B) since 1991 (EPA OPP Annual Cancer Report 2020 (Accessed Sep. 2021)). Besides, this substance was classified in B2 in the assessment by the EPA in 1993 (EPA Pesticides (1993)). (2) In combined chronic toxicity/carcinogenicity studies (OECD TG453, GLP) with rats dosed by feeding for two years, no clear evidence for carcinogenicity was observed in either males or females (CLH Report (2018), ECHA RAC (Background Doc.) (2020)). (3) It was reported that, in carcinogenicity studies (OECD TG451, GLP) with mice dosed by feeding for two years, significant increases in the combined incidences of bronchiolar/alveolar adenoma and carcinoma were observed in the group of males treated at 6,000 ppm and of females treated at 6,000 and 10,000 ppm (CLH Report (2018), ECHA RAC (Background Doc.) (2020), ECHA RAC Opinion (2020)). (4) In a carcinogenicity study with rats and mice dosed by feeding for two years in the past NTP carcinogenicity study, adenocarcinomas of the endometrium and leiomyosarcomas of the uterus were observed in female rats in low-dose and high-dose (5,000 and 10,000 ppm) groups. In male mice, even though a statistically significant increase in hepatocellular carcinoma was observed in a high-dose (10,000 ppm) group, given the frequency of occurrence in the historical-control data, it was concluded that the association with administration was not clear (NTP TR83 (1978)). It is currently concluded that the NTP carcinogenicity study results were negative in male rats, positive in female rats, equivocal in male mice, and negative in female mice (CEBS (Accessed Sep. 2021)). (5) It was reported that, as an overall assessment from the three study results in (2) to (4), the RAC of ECHA concluded that the classification of this substance in Category 2 was appropriate based on the facts that neoplastic lesions, which were relevant for the carcinogenicity classification of this substance, were limited to lung tumors in male and female mice and uterus tumors in female rats, that this substance lacked genotoxicity, that carcinogenicity of UDMH was sufficiently covered by the carcinogenicity study results for this substance since 1,1-dimethylhydrazine (UDMH, CAS RN 57-14-7), which was a major metabolite, was known as a carcinogenic substance, and that the evidence obtained for carcinogenicity was strong (ECHA RAC Opinion (2020)). (6) 1,1-dimethylhydrazine (UDMH, CAS RN 57-14-7), which is a major metabolite of this substance, is classified in Group 2B by the IARC (IARC 71 (1999)), in Category 2 in the GHS Classification Results in FY2010, and in Carc. 1B in the EU (CLP Classification Results (Accessed Sep. 2021)). [Reference Data, etc.] (7) It was reported that, according to the assessment by the EFSA, the impurity UDMH of up to 30 ppm (up to 0.3%) was contained in the administered test substance, but no neoplastic lesions were observed (EFSA (2004)).
7	Reproductive toxicity	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) to (6), it was classified as "Not classified." [Evidence Data] (1) It was reported that, in a two-generation reproduction toxicity study (OECD TG 416) with rats dosed by gavage and feeding, loose feces, perianal fur staining, and salivation were observed in F0 and F1 parental animals at the highest dose of 1,200 mg/kg/day, but no adverse effects on fertility and sexual function of parental animals or development of F1 and F2 offspring were observed (CLH Report (2018), ECHA RAC (Background Doc.) (2020), ECHA RAC Opinion (2020)). (2) It was reported that, in a two-generation reproduction toxicity study (OECD TG 416) with rats dosed by gavage and feeding, lower weaning weight was observed in F1 male parental animals at the highest dose of 10,000 ppm (equivalent to 500 mg/kg/day), but no adverse effects on fertility and sexual function of parental animals or development of F1 and F2 offspring were observed (CLH Report (2018), ECHA RAC (Background Doc.) (2020), ECHA RAC Opinion (2020)). (3) It was reported that, in a prenatal development toxicity study with female rats dosed by gavage (OECD TG 414, days 6 to 15 of gestation), no developmental toxicity was observed in fetuses at doses up to 1,500 mg/kg/day at which reduced body weight gain was observed in dams (CLH Report (2018), ECHA RAC (Background Doc.) (2020), ECHA RAC Opinion (2020)). (4) It was reported that, in a prenatal development toxicity study with female rabbits dosed by gavage (OECD TG 414, days 6 through 28 of gestation), a high death rate of 7 deaths and 2 animals sacrificed in extremis (9/24 animals in total: 37.5%) in dams at an intermediate dose of 500 mg/kg/day, and 8 deaths and 6 animals sacrificed in extremis (14/24 animals in total: 58.3%) at a high dose of 1,000 mg/kg/day was observed, and in these two groups, clear symptoms (soft/liquid feces, hyperpnea, hyperactivity, convulsions) were also observed, but as developmental effects on fetuses, only lower body weight and delayed ossification were observed in viable fetuses at a high-dose group (CLH Report (2018), ECHA RAC (Background Doc.) (2020), ECHA RAC Opinion (2020)). (5) It was reported that, in a prenatal development toxicity study with rabbits dosed by gavage (OECD TG 414, days 7 to 19 of gestation), no effects were observed in dams or fetuses at doses up to the highest dose of 300 mg/kg/day at which no death was observed in dams (CLH Report (2018), ECHA RAC (Background Doc.) (2020), ECHA RAC Opinion (2020)). (6) This substance causes some maternal toxicity in rats and rabbits, but does not cause developmental toxicity. It was reported that, in a reproduction study with rats, this substance caused systemic toxicity at the highest-dose level, but did not cause reproductive toxicity (EPA Pesticides (1993)).
8	Specific target organ toxicity - Single exposure	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) to (4), it was classified as "Not classified." [Evidence Data] (1) It was reported that, in an acute neurotoxicity study by oral administration to rats (OECD TG 424), at 2,000 mg/kg (within the range for Category 2), decreased locomotor activity was observed, but no abnormalities were observed in other clinical symptoms or FOB observation items (CLH Report (2018)). (2) It was reported that, in an acute oral toxicity test with rats (OECD TG 401), no effects were observed at 5,000 mg/kg (in the range corresponding to "Not classified") (CLH Report (2018)). (3) It was reported that, in an acute dermal toxicity test with rabbits (OECD TG 402), diarrhea, perianal staining, prostration, and decreased excretion were observed at 5,000 mg/kg (in the range corresponding to "Not classified") (CLH Report (2018)). (4) It was reported that, in an acute inhalation toxicity test (OECD TG 403, 4 hours) with rats, a few scattered signs of nasal discharge were observed at 2.1 mg/L (within the range for Category 2) (CLH Report (2018)).
9	Specific target organ toxicity - Repeated exposure	Classification not possible	- -	-	-	[Rationale for the Classification] Based on (1) to (5), it was classified as "Not classified" in the oral route and dermal route. However, classification was not possible due to lack of data since there was no information on toxicity in the inhalation route. Besides, based on (6), bile duct hyperplasia was judged to be not a serious change, and therefore, the liver was not adopted as the target organ. [Evidence Data] (1) It was reported that, in a repeated dose 90-day oral toxicity study in rodents (OECD TG 408) with rats dosed by gavage, no abnormalities were observed at 1,000 mg/kg/day (in the range corresponding to "Not classified") (CLH Report (2018)). (2) It was reported that, in a 1-year chronic toxicity study with dogs dosed by feeding, emesis and soft stool were observed at 7,500 ppm (199 mg/kg/day, in the range corresponding to "Not classified") (CLH Report (2018), EPA Pesticides RED (1993)). (3) It was reported that, in a 2-year combined chronic toxicity/carcinogenicity study (OECD TG 453) with rats dosed by feeding, bile duct hyperplasia (females) was observed at 100 ppm (5 mg/kg/day, within the range for Category 1), and bile duct hyperplasia (males) was observed at 10,000 ppm (500 mg/kg/day, in the range corresponding to "Not classified") (CLH Report (2018), EPA Pesticides RED (1993)). (4) It was reported that, in a 2-year carcinogenicity study (OECD TG 451) with mice dosed by feeding, decreased platelet count (females) was observed at 3,000 ppm (450 mg/kg/day, in the range corresponding to "Not classified"), and inflammation and brown pigmentation of the liver (males), and decreased erythrocyte count (females) were observed at 10,000 ppm (1,500 mg/kg/day, in the range corresponding to "Not classified") (CLH Report (2018), EPA Pesticides RED (1993)). (5) It was reported that, in a repeated dose dermal toxicity: 28-day study (OECD TG410) with rats, no effects were observed at 2,000 mg/kg/day (converted guidance value: 622 mg/kg/day, in the range corresponding to "Not classified") (CLH Report (2018)). (6) It was reported that bile duct hyperplasia was a lesion which occurs commonly with age in rats (CLH Report (2018)).
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 3	- -	H402	P273 P501	It was classified in Category 3 from 96-hour EC50 = 71 mg/L for crustacea (Daphnia magna) (EPA Pesticides RED, 1993, OPP Pesticide Ecotoxicity Database).
11	Hazardous to the aquatic environment Long term (Chronic)	Category 3	- -	H412	P273 P501	If chronic toxicity data are used, then it is classified as "Not classified" due to being not rapidly degradable (BIOWIN) and 21-day NOEC = 1.7 mg/L for fish (Pimephales promelas) (EU CLP CLH, 2019). If acute toxicity data are used for a trophic level for which chronic toxicity data are not obtained (crustacea), then it is classified in Category 3 due to being not rapidly degradable and 96-hour EC50 = 71 mg/L for crustacea (Daphnia magna) (EPA Pesticides RED, 1993, OPP Pesticide Ecotoxicity Database). By drawing a comparison between the above results, it was classified in Category 3.
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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