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GHS Classification Results by the Japanese Government

GENERAL INFORMATION

Item	Information
CAS RN	76-44-8
Chemical Name	1,4,5,6,7,8,8-Heptachloro-3a,4,7,7a-tetrahydro-4,7-methano-1H-indene; Heptachlor
Substance ID	R02-B-125-MHLW
Classification year (FY)	FY2020
Ministry who conducted the classification	Ministry of Health, Labour and Welfare (MHLW)
New/Revised	Revised
Classification result in other fiscal year	FY2006 FY2014
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	Not classified	- -	-	-	It was classified as "Not classified" from information that it is not combustible (ICSC (2003)).
8	Self-reactive substances and mixtures	Classification not possible	- -	-	-	There is a chemical group associated with self-reactive properties, a sulfonyl group, present in the molecule, but the classification is not possible due to no data.
9	Pyrophoric liquids	Not classified (Not applicable)	- -	-	-	Solid (GHS definition). It was classified as "Not classified."
10	Pyrophoric solids	Not classified	- -	-	-	It was classified as "Not classified" from information that it is not combustible (ICSC (2003)).
11	Self-heating substances and mixtures	Not classified	- -	-	-	It was classified as "Not classified" from information that it is not combustible (ICSC (2003)).
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)	Category 3	Danger	H301	P301+P310 P264 P270 P321 P330 P405 P501	[Rationale for the Classification] It was classified in Category 3 from (1) - (5). [Evidence Data] (1) LD50 for rats: males: 60 mg/kg, females: 230 mg/kg (ATSDR (2007)) (2) LD50 for rats: 60-142 mg/kg (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2013)) (3) LD50 for rats: males: 71 mg/kg (ATSDR (2007), Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2013)) (4) LD50 for rats: males: 100 mg/kg, females: 162 mg/kg (IARC 79 (2001), ATSDR (2007), Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2013)) (5) LD50 for rats: 105 mg/kg (ATSDR (2007))
1	Acute toxicity (Dermal)	Category 2	Danger	H310	P302+P352 P361+P364 P262 P264 P270 P280 P310 P321 P405 P501	[Rationale for the Classification] It was classified in Category 2 from (1) - (4). [Evidence Data] (1) LD50 for rats: 119 mg/kg (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2013)) (2) LD50 for rats: 119-250 mg/kg (CICAD 70 (2006)) (3) LD50 for rats: males: 195 mg/kg, females: 250 mg/kg (ATSDR (2007), Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2013)) (4) LD50 for rats: 195 mg/kg (Patty (6th, 2012))
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	Classification not possible	- -	-	-	[Rationale for the Classification] The classification was not possible due to lack of data because it was impossible to confirm the data (Patty 4th, 1994), which was the rationale for the previous classification.
3	Serious eye damage/eye irritation	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
4	Respiratory sensitization	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
4	Skin sensitization	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
5	Germ cell mutagenicity	Not classified	- -	-	-	[Rationale for the Classification] It was classified as "Not classified" from (1) - (3). [Evidence Data] (1) As for in vivo, it was reported to be negative in a gene mutation test by oral administration of this substance to transgenic mice and dominant lethal tests by intraperitoneal or oral administration to mice. And it was reported to be positive in a chromosomal aberration test with the bone marrow after intraperitoneal administration to mice (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2013), ATSDR (2007), CICAD 70 (2006), IARC 53 (1991), ACGIH (7th, 2001)). (2) As for in vitro, it was reported to be positive/negative in bacterial reverse mutation tests, and as for test systems using cultured mammalian cells, it was reported to be positive in a chromosomal aberration test, positive in a sister chromatid exchange test, positive /negative in unscheduled DNA synthesis tests, and positive/negative in gene mutation tests (same as the above). (3) It is described that it was considered that it did not have genotoxicity that could pose a problem in vivo (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2013)).
6	Carcinogenicity	Category 2	Warning	H351	P308+P313 P201 P202 P280 P405 P501	[Rationale for the Classification] It was classified in Category 2 from (1) - (3). [Evidence Data] (1) As for classification results by domestic and international organizations, it was classified in Group 2B by IARC (IARC 79 (2001)), Group 2B by the Japan Society for Occupational Health (JSOH) (Recommendation of Occupational Exposure Limits (Japan Society For Occupational Health (JSOH), proposed in 2001)), A3 by ACGIH (ACGIH (7th, 2001)), B2 (probable human carcinogen) by EPA (IRIS (1987)), and 4 in MAK (DFG) (DFG List of MAK and BAT Values 2019). (2) In a combined chronic toxicity/carcinogenicity test by 110-week diet administration of this substance to male and female rats, no neoplastic lesions with treatment-related increases in incidence were observed (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2013)). (3) In a carcinogenicity test by 24-month diet administration of this substance to male and female mice, a significant increase in the incidence of hepatocellular carcinoma in females and a significant increase in the incidence of hepatocellular carcinoma or nodular lesions (combined) in males and females were observed (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2013)). [Reference Data, etc.] (4) In a carcinogenicity test by 18-month diet administration of a mixture of this substance and its metabolite (25:75) to male and female mice, a significant increase in the incidence of hepatocellular carcinoma or nodular lesions (combined) was observed in males and females (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2013)).
7	Reproductive toxicity	Category 1B, Additional category for effects on or via lactation	Danger	H360	P308+P313 P201 P202 P280 P405 P501	[Rationale for the Classification] Based on (1) to (6), it was classified in Category 1B and the additional category for effects on or via lactation because possible effects via breast milk in humans and experimental animals were suggested, and because, in experimental animals, an increase in postnatal mortality, etc. were observed and effects on development in pups were observed at a dose at which no maternal toxicity was observed or described. [Evidence Data] (1) In a breast milk study in Victoria, Australia, a correlation was found between the levels of heptachlor epoxide in breast milk and the use of this substance as a termiticide (CICAD 70 (2006)). (2) The most significant source of exposure of infants to this substance and its metabolites appears to be breast milk, in which the concentrations can be much higher than those found in dairy milk. A large international survey performed in the 1970s found that the mean concentrations of this substance and heptachlor epoxide in human breast milk ranged from 2 to 720 ng/g of fat (CICAD 70 (2006)). (3) In female rats, the amount of this substance and heptachlor epoxide found in milk, blood, fat, and tissues was proportional to the dose of this substance administered (CICAD 70 (2006)). (4) In a three-generation reproduction study with rats dosed by feeding, in F1 generation group treated at 10 ppm, the mortality of pups on post-natal weeks 2 and 3 slightly increased. No effect on fertility was observed (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2013)). (5) In a developmental toxicity study with female rats dosed by gavage on days 6 to 15 of gestation, a marked increase in postnatal mortality was observed in pups at a dose at which no maternal toxicity was observed (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2013), CICAD 70 (2006)). The Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2013) indicated that the observation items in this study as a developmental toxicity study were insufficient and the data of this study was used as a reference material. (6) In a neurotoxicity study in which, after female rats were dosed by gavage from day 12 of gestation until day 7 postpartum, the rat pups were dosed directly by gavage until postnatal day 21 or 42, the outcomes at all dosages suggested developmental delays, alterations in GABAergic neurotransmission, and neurobehavioral changes including cognitive deficits. In female rats dosed with this substance until postnatal day 42, marked effects were observed, and in all dosage groups, slowed acquisition of the spatial task and impaired recall during probe trials of the Morris water maze were observed (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2013), CICAD 70 (2006)). [Reference Data, etc.] (7) In a developmental toxicity study in which female rats were dosed by gavage from day 8 of gestation until day 21 postpartum, and pups delivered spontaneously were examined for developmental effects on days 1, 3, 6 and 21 after birth, 2 of 7 to 8 dams in the group treated at 5.0 mg/kg/day died. In addition, in the same group, the body weights of pups on the postnatal day 0 were significantly lower than the group treated at 0.5 mg/kg/day and the control group, and all pups except one litter died within the first 4 postnatal days. Age at eye opening was delayed with increasing dose (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2013)). The data of this study was used as a reference data because the number of animals tested was small and many dams died. (8) Female rats were injected subcutaneously every other day with this substance at 5 or 20 mg/kg before mating. The result showed that animals treated at 20 mg/kg had longer mean gestational lengths and the proportion of pups that were alive until weaning time decreased (CICAD 70 (2006)). (9) In a three-generation reproduction study with rats dosed by feeding with a mixture of this substance/its metabolite I (3:1), the observed effect on fertility was a decrease in litter sizes (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2013)). (10) Heptachlor epoxide (CAS RN 1024-57-3) was classified in Category 1B and the additional category for effects on or via lactation (GHS Classification Results in FY2020).
8	Specific target organ toxicity - Single exposure	Category 1 (nervous system, respiratory organs, liver, kidney)	Danger	H370	P308+P311 P260 P264 P270 P321 P405 P501	[Rationale for the Classification] Based on (1) to (5), it was classified in Category 1 (nervous system, respiratory organs, liver, kidney). New information sources were used and the classification results were changed from the previous classification. [Evidence Data] (1) Acute poisoning by this substance causes vomiting, headache, tremor, convulsions, kidney disorder, weakened respiratory organ, etc. In humans having liver damage, treatment with 1 to 3 g may cause serious symptoms, resulting in death (Environmental Risk Assessment for Chemical Substances Vol. 1 (Ministry of the Environment, 2003)). (2) The clinical symptoms of acute poisoning were hypoactivity, tremor, convulsions, ataxia, and change in the brain-wave pattern. In a histopathological examination, a serious liver damage was observed (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2013)). (3) In an acute oral neurotoxicity test with rats (dosed by gavage, 7, 23, 69 and 129 mg/kg), acute toxicity effects on activity and excitability became greatest 4 hours after dosing, and excitability changes were also observed 24 hours after dosing (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2013)). (4) In an acute oral toxicity test with rats, at 60 mg/kg (within the range for Category 1), increases in serum ALT and aldolase, decreases in liver ALT and aldolase, vacuolated hepatocytes, and pyknotic nuclei were observed (ATSDR (2007)). (5) In an acute oral toxicity test with rats, excitability was observed at 7 mg/kg (within the range for Category 1) (ATSDR (2007)). [Reference Data, etc.] (6) Heptachlor epoxide (CAS RN 1024-57-3) which is a metabolite of this substance was classified as "Classification not possible" for specific target organ toxicity (single exposure) (GHS Classification Results in FY2020).
9	Specific target organ toxicity - Repeated exposure	Category 1 (nervous system, liver)	Danger	H372	P260 P264 P270 P314 P501	[Rationale for the Classification] Based on (1) to (3), it was classified in Category 1 (nervous system, liver). As a result of a review based on the new information, the classification results were changed from the previous classification. [Evidence Data] (1) It was reported that in a 14-day acute neurotoxicity test with rats dosed by feeding at 7 to 69 mg/kg/day, one rat died immediately after the last dosing at 7 mg/kg/day (converted guidance value: 0.006 mg/kg/day, within the range for Category 1) and all rats died during dosing at 23 and 69 mg/kg/day (converted guidance value: 0.02 and 0.05 mg/kg/day, within the range for Category 1), and behavioral changes, hyperexcitability, and effects on the autonomic nervous system due to the administration of the test substance were observed (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2013)). (2) In a 10-week feeding test of this substance with mice, body weight loss as well as hepatitis, necrosis, granuloma, and congestion in the liver were observed at 9.3 mg/kg/day (converted guidance value: 7.2 mg/kg/day, within the range for Category 1); difficulties in standing, walking, and righting were observed at 19 mg/kg/day (converted guidance value: 15 mg/kg/day, within the range for Category 2); and granuloma in the kidney was observed at 37 mg/kg/day (converted guidance value: 29 mg/kg/day, within the range for Category 2) (ATSDR (2007)). (3) In a 110-week combined chronic toxicity/carcinogenicity study of this substance with rats dosed by feeding, mild hepatocellular lesions such as hypertrophy of centrilobular hepatocytes, homogenization of cytoplasm, and uneven peripheral distribution of cytoplasmic granules were observed in males and females at or above 7.0 ppm (0.35 mg/kg/day, within the range for Category 1) (Risk Assessment Report (Pesticides) (Food Safety Commission of Japan, 2013)). [Reference Data, etc.] (4) In the National Health and Nutrition Examination Survey (NHANES) in the United States, in humans exposed for an unspecified period of time to contaminated raw milk products from cattle which was given feed contaminated with this substance, a significant increase in serum levels of metabolites of this substance was observed. No changes in serum liver enzyme activity levels were found, and no hepatomegaly was detected by clinical examination. It was considered that this information was insufficient to draw any meaningful conclusion regarding liver effects of this substance in humans (ATSDR (2007)). (5) Heptachlor epoxide (CAS RN 1024-57-3) which is a metabolite of this substance was classified in Category 1 (liver) (GHS Classification Results in FY2020).
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)	-	- -	-	-	-
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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