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GHS Classification Results by the Japanese Government

GENERAL INFORMATION

Item	Information
CAS RN	121-82-4
Chemical Name	Hexahydro-1,3,5-trinitro-1,3,5-triazine (with 15% water, by mass)
Substance ID	R01-B-037
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	FY2018 FY2006
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)	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	Division 1.1	Danger	H201	P370+P372+P380+P373 P210 P230 P234 P240 P250 P280 P401 P501	It was classified in Division 1.1 because it is classified in Division 1.1D in UNRTDG (UN0072). Besides, one with a water content of less than 15% is deemed as unstable explosives, whose transportation is prohibited.
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	*	- -	-	-	Classification is not possible according to the GHS classification guidance for the Japanese government because it was classified as explosives.
8	Self-reactive substances and mixtures	*	- -	-	-	It was classified as "Not classified (Not applicable)" because it was classified as explosives.
9	Pyrophoric liquids	*	- -	-	-	Solid (GHS definition). It was classified as "Not classified (Not applicable)."
10	Pyrophoric solids	*	- -	-	-	Classification is not possible according to the GHS classification guidance for the Japanese government because it was classified as explosives.
11	Self-heating substances and mixtures	*	- -	-	-	Classification is not possible according to the GHS classification guidance for the Japanese government because it was classified as explosives.
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	*	- -	-	-	The substance is an organic compound containing oxygen (but not fluorine or chlorine) which is chemically bonded to an element (N) other than carbon or hydrogen. However, classification is not possible because it was classified as explosives.
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	*	- -	-	-	This substance is not applicable to desensitized explosives because it was classified as explosives.

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)-(4), it was classified in Category 3. Besides, this substance was classified based on the weight excluding that of the water content. [Evidence Data] (1) LD50 for rats: 100 mg/kg (Environmental Risk Assessment for Chemical Substances Vol.6 (Ministry of the Environment, 2008), HSDB (Access on July 2019)) (2) LD50 for rats: 119 mg/kg (ACGIH (7th, 2001)) (3) LD50 for rats: 71-300 mg/kg (ACGIH (7th, 2001), PATTY (6th, 2012)) (4) LD50 for rats: 71-118 mg/kg (ATSDR (2012))
1	Acute toxicity (Dermal)	*	- -	-	-	[Rationale for the Classification] Based on (1), it was classified as "Not classified." The category was changed from the previous classification by the use of the new information sources. Besides, this substance was classified based on the weight excluding that of the water content. [Evidence Data] (1) When rabbits were dermally exposed to this substance, toxicity was not observed at 2,000 mg/kg of this substance (ACGIH (7th, 2001)).
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), it was classified as "Not classified." Besides, the category was changed, since new data were obtained. [Evidence Data] (1) In a skin irritation test with rabbits equivalent or similar to OECD TG 404, the number of animals whose scores were 1 or above consecutively until 72 hours was only one out of six, and all of the scores for other animals were zero at 72 hours (REACH registration dossier (Access on August 2019)). [Reference Data, etc.] (2) There are a report that no irritation was observed in a human patch test (dose unknown) and a report that dermatitis was induced (ATSDR (2012)). (3) Slight erythema was induced in guinea pigs exposed to this substance (1,000 mg/kg) (ATSDR (2012)). (4) Dermatitis was induced in rabbits by exposure to this substance in acetone (27 mg/kg), in cyclohexane (37.5 mg/kg), or in DMSO (165 mg/kg) (ATSDR (2012)).
3	Serious eye damage/eye irritation	*	- -	-	-	[Rationale for the Classification] Despite the description in (1), it was classified as "Classification not possible" due to lack of data. [Reference Data, etc.] (1) It is reported that conjunctivitis was induced by the fumes of this substance (ATSDR (2012)).
4	Respiratory sensitization	*	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
4	Skin sensitization	*	- -	-	-	[Rationale for the Classification] Based on (1), it was classified as "Not classified." [Evidence Data] (1) In a skin sensitization test (maximization method, intradermal induction: 6.67%, induction (topical application): 60%, challenge: 60 or 30%) with guinea pigs, no skin reaction was observed, and it was reported as negative (REACH registration dossier (Access on August 2019)).
5	Germ cell mutagenicity	*	- -	-	-	[Rationale for the Classification]d Based on (1) and (2), since results of all standard combination tests, including in vivo and in vitro tests, were negative, it was classified as "Not classified." [Evidence Data] (1) As for in vivo, there were negative reports of a dominant lethal test and a mouse bone marrow micronucleus test (ACGIH (7th, 2001), ATSDR (2012)). (2) As for in vitro, there were negative reports of bacterial reverse mutation tests, and a DNA damage test and a mouse lymphoma assay with cultured mammalian cells (ACGIH (7th, 2001), ATSDR (2012)).
6	Carcinogenicity	Category 2	Warning	H351	P308+P313 P201 P202 P280 P405 P501	[Rationale for the Classification] It was classified in A4 by ACGIH, however, based on the results for experimental animals in (2) and (3), and the fact that it was classified as S (Suggestive Evidence of Carcinogenic Potential) by EPA (IRIS (2018)), it was classified in Category 2, in accordance with the GHS Classification Guidance for the Japanese Government. Therefore, the category was changed from the previous classification. [Evidence Data] (1) As for classification results by domestic and international organizations, it was classified in A4 by ACGIH (ACGIH (7th, 2001)), and as S (Suggestive Evidence of Carcinogenic Potential) by EPA (IRIS (2018)). (2) In a test with mice dosed with this substance by feeding for 2 years, increases in the incidence of hepatocellular carcinoma or adenoma, and increases in the incidence of alveolar/bronchiolar adenoma or carcinoma in both sexes were observed (IRIS (2018)). (3) In a test with rats dosed with this substance by feeding for 2 years, an increase in the incidence of hepatocellular carcinoma in males was observed, but an increase in the incidence of tumors was not observed in females (IRIS (2018)).
7	Reproductive toxicity	*	- -	-	-	[Rationale for the Classification] Based on (1)-(4), it was classified as "Not classified." [Evidence Data] (1) In a two-generation reproduction toxicity study with rats dosed by feeding, a decreased number of pregnant animals and decreased survival rate of the pups were observed at the dose where maternal toxicity (significant increase in mortality, etc.) was observed, and a decrease in body weight of pups was observed at the dose where maternal toxicity was not observed (Environmental Risk Assessment for Chemical Substances Vol.6 (Ministry of the Environment, 2008), ACGIH (7th, 2001), ATSDR (2012)). (2) In a developmental toxicity test with rats dosed by gavage, fetotoxicity (early embryo absorption) was observed but no malformations were observed at the dose where maternal toxicity (increase in mortality (25%), convulsions, hyperactivity) was observed (Environmental Risk Assessment for Chemical Substances Vol.6 (Ministry of the Environment, 2008), ACGIH (7th, 2001)). (3) In a developmental toxicity test with rats dosed by gavage, a decrease in fetal weights and lengths was observed but no malformations were observed at the dose where maternal toxicity (increased mortality (31%), convulsions, prostration, hyperactivity) was observed (Environmental Risk Assessment for Chemical Substances Vol.6 (Ministry of the Environment, 2008), ACGIH (7th, 2001), ATSDR (2012)). (4) In a developmental toxicity test with rabbits dosed by gavage, no effects were observed (ACGIH (7th, 2001), ATSDR (2012)). [Reference Data, etc.] (5) In rats, transfer of this substance from the dam to the fetus during gestation and to pups via maternal milk was reported. Reproductive and developmental toxicity studies did not identify effects in offspring at the dose where maternal toxicity was not observed. Yet, based on the primary mode of action for nervous system effects (GABA receptor antagonism) induced by this substance, and the fact that GABAergic signaling plays a prominent role in nervous system development, a significant concern was raised regarding the potential for developmental neurotoxicity (IRIS Executive Summary (2018)).
8	Specific target organ toxicity - Single exposure	Category 1 (central nervous system, kidney)	Danger	H370	P308+P311 P260 P264 P270 P321 P405 P501	[Rationale for the Classification] Based on (1)-(5), it was classified in Category 1 (central nervous system, kidney). With regard to the effects on the liver seen in (5), since findings indicating hepatotoxicity were not observed but only micromorphological changes were, it was not adopted as evidence for the classification. Therefore, the classification result was changed from the previous classification. Besides, with regard to doses to experimental animals, the weight excluding that of the water content was used for classification. [Evidence Data] (1) When plastic explosive (C-4) containing 91% of this substance was used as cooking fuel on a battlefield, 3 soldiers who ingested 25-180 g in total, showed lethargy, semicoma, epileptic seizure, nausea, vomiting, headache, myalgia, and fever. Other than this, 18 men who accidentally ingested C-4 showed confusion, significant hyperirritability, involuntary myoclonic seizure of extremities, severe continuous epileptic seizure, nausea, vomiting, and long mental confusion after the seizure. Abnormal electroencephalograms in 9 men, effects on the kidney in 3 men, and an increase in the number of leukocytes in 13 men were observed. No mortality was observed, and all of them recovered (Environmental Risk Assessment for Chemical Substances Vol.6, Tentative Hazard Assessment Sheet (Ministry of the Environment, 2008), PATTY (6th, 2012), ATSDR (2012), ACGIH (7th, 2001)). (2) An increased incidence of spontaneous seizures and an increased incidence of audiogenic seizures in an oral acute toxicity test with rats and decreased startle-response amplitude, decreased motor activity, increased startle-response latency and decreased rates of schedule-controlled response in another test were observed within the dose range of Category 1 (10-12.5 mg/kg) (ACGIH (7th, 2001)). (3) This substance exhibited moderate to high acute toxicity with central nervous system effects in many species (ACGIH (7th, 2001)). (4) There is a description that this substance exhibits GABA receptor antagonism in the central nervous system (IRIS Executive Summary (2018)). (5) In an oral single dose test with rats at 100 mg/kg (corresponding to Category 1), micromorphological changes in hepatocytes (dilation of the rough endoplasmic reticulum, mitochondrial swelling), alterations to the distal renal tubules, and hematuria (presence of erythrocytes in the renal tubules) were observed (ACGIH (7th, 2001)).
9	Specific target organ toxicity - Repeated exposure	Category 1 (central nervous system, hematopoietic system, prostate), Category 2 (kidney, blood system, urinary bladder)	Danger Warning	H372 H373	P260 P264 P270 P314 P501	[Rationale for the Classification] Based on (1), effects on the central nervous system were observed by inhalation exposure of humans, and based on (2)-(6), effects on the central nervous system, hematopoietic system and prostate within the range of Category 1, and effects on the heart, kidney, blood system, urinary bladder and testis within the range of Category 2 were observed in experimental animals. Among these, it was judged that there was insufficient information to adopt the heart and testis as target organs. Therefore, it was classified as Category 1 (central nervous system, hematopoietic system, prostate), Category 2 (kidney, blood system, urinary bladder). Besides, with regard to the dose to experimental animals, the weight excluding that of water was used for classification. By reviewing the data in the information sources, the classification was changed from the previous classification. [Evidence Data] (1) Among workers in a manufacturing factory of this substance who potentially inhaled particles of this substance, tonic clonic convulsion that resembled seizures seen in epilepsy occurred without warning after 1 or 2 days of insomnia, restlessness and irritability. Temporary amnesia, malaise, fatigue, and asthenia were observed, but there was eventual recovery (Environmental Risk Assessment for Chemical Substances Vol.6, Tentative Hazard Assessment Sheet (Ministry of the Environment, 2008), PATTY (6th, 2012)). (2) As a result of administration to rats for 6 months by feeding, decreased hemoglobin and erythrocyte levels, etc. were observed at 40 mg/kg/day (within the range of Category 2) (ATSDR (2012)). (3) As a result of administration to rats for 13 weeks by feeding, slight increased leukocyte counts at or above 10 mg/kg/day (within the range of Category 1), a decrease in serum triglycerides at or above 30 mg/kg/day (within the range of Category 2), death, tremors, convulsions, and hepatomegaly at or above 100 mg/kg/day were observed (ATSDR (2012), PATTY (6th, 2012), ACGIH (7th, 2001)). (4) As a result of administration to rats for 13 weeks by feeding, hematological effects at or above 28 mg/kg/day (within the range of Category 2), lower heart weights, foci of myocardial degeneration, and hepatic portal inflammation at 40 mg/kg/day (within the range of Category 2) were observed (ACGIH (7th, 2001)). (5) As a result of administration to rats for 2 years by feeding, splenic hemosiderin-like pigment, and suppurative inflammation of the prostate at or above 1.5 mg/kg/day (within the range of Category 1), increases in relative weights of the liver and kidney, etc. at 8 mg/kg/day, anemia, bladder disorders like cystitis, pyelectasis, dark redness of the kidney with renal papillary necrosis, testicular atrophy, etc. at 40 mg/kg/day (within the range of Category 2) were observed (ACGIH (7th, 2001), Environmental Risk Assessment for Chemical Substances Vol.6, Tentative Hazard Assessment Sheet (Ministry of the Environment, 2008)). (6) As a result of administration to monkeys for 90 days, central nervous system disorders (tremors and convulsions), increases in necrotic/degenerate megakaryocytes and hemosiderin deposition in the bone marrow and spleen, hemosiderin deposition, histological change in the hepatic cell cord were observed at 10 mg/kg/day (within the range of Category 1) (ATSDR (2012), Environmental Risk Assessment for Chemical Substances Vol.6, Tentative Hazard Assessment Sheet (Ministry of the Environment, 2008), 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)	-	- -	-	-	-
11	Hazardous to the aquatic environment Long term (Chronic)	-	- -	-	-	-
12	Hazardous to the ozone layer	-	- -	-	-	-

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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