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GHS Classification Results by the Japanese Government

GENERAL INFORMATION

Item	Information
CAS RN	298-81-7
Chemical Name	9-Methoxy-7H-furo[3,2-g][1]benzopyran-7-one; Methoxsalen
Substance ID	R02-B-075-MHLW, MOE
Classification year (FY)	FY2020
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	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 (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	Classification not possible	- -	-	-	No data available. Besides, there is information that it is combustible (HSDB (Access on May 2020)).
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. It was classified as "Not classified."
9	Pyrophoric liquids	Not classified (Not applicable)	- -	-	-	Solid (GHS definition). It was classified as "Not classified."
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). 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 oxygen (but not fluorine or chlorine) 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 4	Warning	H302	P301+P312 P264 P270 P330 P501	[Rationale for the Classification] It was classified in Category 4 from (1), (2). [Evidence Data] (1) LD50 for rats: males: 791 mg/kg (NTP TR359 (1989), HSDB (Access on May 2020)) (2) LD50 for rats: females: 930 mg/kg, males: 1,170 mg/kg (IF (OXORALEN tab. 10 mg) (April 2019 (Rev. No. 13)))
1	Acute toxicity (Dermal)	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.
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] There were descriptions of (1), (2), but there were no sufficient data for classification, and the classification was not possible due to lack of data. [Reference Data, etc.] (1) In products containing this substance, skin disorders such as erythema, blisters, swelling, and crusts by excessive ultraviolet irradiation after application were reported (IF (OXORALEN tab. 10 mg) (April 2019 (Rev. No. 13))). (2) It is reported that it was phototoxic in an experiment with rats (HSDB (Access on May 2020)).
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	Not classified	- -	-	-	[Rationale for the Classification] It was classified as "Not classified" from (1). The classification result was changed due to new data obtained. [Evidence Data] (1) In a mouse local lymph node assay according to OECD TG 429 (LLNA), the SI value did not exceed 3, and it was judged as negative (Maeda Y et al., J Applied Toxicol 38:1316-1322 (2018)).
5	Germ cell mutagenicity	Category 2	Warning	H341	P308+P313 P201 P202 P280 P405 P501	[Rationale for the Classification] It was classified in Category 2 from (1), (2). [Evidence Data] (1) As for in vivo, there are reports on a positive result in a chromosomal aberration test and an equivocal result in a micronucleus test after intraperitoneal administration to mice (CEBS (Access on May 2020)). (2) As for in vitro, it was reported to be positive in a bacterial reverse mutation test, and it was reported in test systems in cultured mammalian cells that it was positive in a chromosomal aberration test and positive in a sister chromatid exchange test (NTP TR359 (1989), CEBS (Access on May 2020)).
6	Carcinogenicity	Category 1A	Danger	H350	P308+P313 P201 P202 P280 P405 P501	[Rationale for the Classification] It was classified in Category 1A based on classification results by other organizations in (1). [Evidence Data] (1) As for classification results by domestic and international organizations, IARC classified methoxsalen (this substance) plus UVA radiation in Group 1 (IARC 100A (2012)), and NTP classified methoxsalen (this substance) with ultraviolet A therapy in K (NTP RoC (14th, 2016)). (2) There was sufficient evidence in humans for the carcinogenicity of this substance plus UVA radiation. This substance in combination with UVA radiation caused cancer of the skin (squamous cell carcinoma) (IARC 100A (2012)). (3) In many carcinogenicity tests in which mice were given oral or dermal administration of this substance and UVA radiation at the same time, increased incidences of skin carcinoma were observed. There was sufficient evidence in experimental animals for the carcinogenicity of this substance plus UVA radiation (IARC 100A (2012)). (4) Also, diet administration of this substance alone to rats was reported to be carcinogenic. There was limited evidence in experimental animals for the carcinogenicity of this substance alone (IARC 100A (2012)).
7	Reproductive toxicity	Category 1B	Danger	H360	P308+P313 P201 P202 P280 P405 P501	[Rationale for the Classification] Based on (1), although maternal toxicity was observed, the severity of fetal toxicity was considered and it was classified in Category 1B. Since the new information was obtained, the classification results were changed from the previous classification. [Evidence Data] (1) In a developmental toxicity study with female rats dosed by gavage on days 6 to 15 of gestation, an increase in resorption, reduced number of live fetuses, lower fetal weight, and increases in the incidence of skeletal variations and malformations (mainly enlargement of the lateral ventricle) were observed in fetuses at a dose at which maternal toxicity (reduced body weight gain, a decrease in food consumption, and an increase in relative liver weight) was observed (NTP Abstract for TER91017 (Access on July 2020)). [Reference Data, etc.] (2) In a developmental toxicity study with female rabbits dosed by gavage on days 6 to 19 of gestation, no effect in fetuses was observed even at doses at which maternal toxicity (transient reduced body weight gain and a decrease in food consumption) was observed (NTP Abstract for TER91016 (Access on July 2020)). (3) As a result of a repeated dose of this substance to pregnant rats and mice on days 7 to 13 of gestation, no teratogenicity was observed in either of the species (IF (OXSORALEN tab. 10 mg) (April 2019 (Rev. No. 13))).
8	Specific target organ toxicity - Single exposure	Category 3 (Narcotic effects)	Warning	H336	P304+P340 P403+P233 P261 P271 P312 P405 P501	[Rationale for the Classification] There was no report on hazards by a single exposure to this substance alone in humans. Based on (2), central nervous system depression was suspected, but since the dose level was unknown, it was classified in Category 3 (narcotic effects) based on (1) and (2). A new information was used and the classification results were changed from the previous classification. [Evidence Data] (1) It was reported that, in a general pharmacological test with mice, after an oral administration, reduced locomotor activity at or above 100 mg/kg (within the range for Category 1), and reduced maximal electroshock seizure at 400 mg/kg (within the range for Category 2) were observed (IF (OXSORALEN tab. 10 mg) (April 2019 (Rev. No. 13))). (2) It was reported that in an acute toxicity test with mice and rats, reduced locomotor activity, reduced respiration, respiratory distress, salivation, clonic convulsions, tremor, lethargy, and lacrimation were observed as toxic symptoms due to an oral or subcutaneous administration although the dose level was unknown (IF (OXSORALEN tab. 10 mg) (April 2019 (Rev. No. 13))). [Reference Data, etc.] (3) This substance was used with UVA irradiation for the treatment of cutaneous diseases, and although impairment of the immune system in humans due to treatment with this substance and UVA irradiation was reported, no adverse effects were reported with this substance alone (NTP TR359 (1989)). (4) As information on the adverse effects of this substance in patients with leukoderma vulgaris, in the case of tablets, blush, abdominal pain, nausea, dizziness, insomnia, facial edema, chest distress, depression, headache, and liver dysfunction were reported (JAPIC Ethical Pharmaceuticals 2017 (2016)). (5) The most common adverse effect of this substance by an oral administration was nausea, which occurred in about 10% of patients. GI disturbances might also occur with UVA irradiation treatment utilizing this substance (HSDB (Access on May 2020)).
9	Specific target organ toxicity - Repeated exposure	Category 1 (thyroid, kidney)	Danger	H372	P260 P264 P270 P314 P501	[Rationale for the Classification] There was no report on repeated exposure to this substance alone in humans. Based on (1) to (3), effects on the thyroid and kidney at doses of Category 1 or above were observed in experimental animals. Therefore, it was classified in Category 1 (thyroid, kidney). With the addition of new information, the classification results were changed from the previous classification. [Evidence Data] (1) It was reported that in a 3-month oral toxicity test with rats, at or above 25 mg/kg (within the range for Category 2), enlargement and hypertrophy of the hepatocytes, hypertrophy of the renal cortical tubular epithelial cells, gland cell hypertrophy of the pituitary gland, decreased follicle size, epithelial cell enlargement of the thyroid, enlargement of zona fasciculata cells of the adrenal gland, and enlargement of the spleen lymph follicles were observed (IF (OXSORALEN tab. 10 mg) (April 2019 (Rev. No. 13))). (2) It was reported that in a 103-week oral toxicity test with rats, in males, focal hyperplasia of the renal tubular epithelium, chronic nephropathy (degeneration and regeneration of the tubular epithelium with dilatation and atrophy of tubules, hyaline casts, granular casts, thickening of basement membranes, interstitial fibrosis, glomerulosclerosis), and diffuse hypertrophy of the thyroid were observed at or above 37.5 mg/kg (within the range for Category 2), and mineralization in the medulla and papilla of the kidney were observed at 75 mg/kg (within the range for Category 2) (NTP TR359 (1989)). (3) It was reported that in a 3-month dermal exposure test with rats, at or above 5 mg/kg (within the range for Category 1), enlargement and hypertrophy of the hepatocytes, hypertrophy of the renal cortical tubular epithelial cells, anterior lobe hyperemia and gland cell hypertrophy of the pituitary gland, decreased follicle size, epithelial cell enlargement and a decrease in colloids of the thyroid, enlargement of zona fasciculata cells of the adrenal gland, prickle cell and basal cell enlargement of the treated local skin, follicular enlargement, sinus catarrh and nerve cell enlargement of the regional axillary lymph node, etc. were observed (IF (OXSORALEN tab. 10 mg) (April 2019 (Rev. No. 13))). [Reference Data, etc.] (4) This substance was used with UVA irradiation for the treatment of cutaneous diseases, and no adverse effects of this substance alone were reported in humans (NTP TR359 (1989)).
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)	Classification not possible	- -	-	-	No data available.
11	Hazardous to the aquatic environment Long term (Chronic)	Classification not possible	- -	-	-	No data available.
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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