GHS Classification Results by the Japanese Government

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GENERAL INFORMATION
Item Information
CAS RN 119-36-8
Chemical Name Methyl 2-hydroxybenzoate; Methyl Salicylate
Substance ID R02-A-067-METI, MOE
Classification year (FY) FY2020
Ministry who conducted the classification Ministry of Economy, Trade and Industry (METI)/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)
-
-
- - Liquid (GHS definition)
3 Aerosols Not classified (Not applicable)
-
-
- - Not aerosol products.
4 Oxidizing gases Not classified (Not applicable)
-
-
- - Liquid (GHS definition)
5 Gases under pressure Not classified (Not applicable)
-
-
- - Liquid (GHS definition)
6 Flammable liquids Not classified
-
-
- - A flash point was 96 deg C (Closed cup) (ICSC (Accessed Sep. 2020)).
7 Flammable solids Not classified (Not applicable)
-
-
- - Liquid (GHS definition)
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
-
-
- - It is estimated that it does not ignite at normal temperatures from an autoignition temperature of 450 deg C (GESTIS (Accessed Sep. 2020)).
10 Pyrophoric solids Not classified (Not applicable)
-
-
- - Liquid (GHS definition)
11 Self-heating substances and mixtures Classification not possible
-
-
- - Classification is not possible because test methods applicable to liquid substances are not 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)
-
-
- - The substance is an organic compound containing oxygen (but not fluorine or chlorine) which is chemically bonded only to carbon or hydrogen.
14 Oxidizing solids Not classified (Not applicable)
-
-
- - Liquid (GHS definition)
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
-
-
- - No data 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) Category 4


Warning
H302 P301+P312
P264
P270
P330
P501
[Rationale for the Classification]
It was classified in Category 4 from (1) - (5).

[Evidence Data]
(1) LD50 for rats: 887 mg/kg (CLH Report (2017), EPA Pesticides RED (2005))
(2) LD50 for rats: 2,820 mg/kg (males: 3,050 mg/kg, females: 2,640 mg/kg) (CLH Report (2017))
(3) LD50 for rats: 1,250 mg/kg (CLH Report (2017), EPA Pesticides RED (2005))
(4) LD50 for rats (males): 1,220 mg/kg (CLH Report (2017))
(5) LD50 for rats (females): 1,060 mg/kg (CLH Report (2017))

1 Acute toxicity (Dermal) Not classified
-
-
- - [Rationale for the Classification]
It was classified as "Not classified" from (1), (2).

[Evidence Data]
(1) LD50 for rats: > 2,500 mg/kg (REACH registration dossier (Accessed Oct. 2020))
(2) LD50 for rabbits: > 5,000 mg/kg (EPA Pesticides RED (2005), REACH registration dossier (Accessed Oct. 2020))

1 Acute toxicity (Inhalation: Gases) Not classified
-
-
- - [Rationale for the Classification]
Liquid (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. Besides, (1), (2) could not be used for classification because the exposure time is unknown.

[Reference Data, etc.]
(1) LC50 for rats: > 400 mg/m3 (> 64.4 ppm) (REACH registration dossier (Accessed Oct. 2020))
(2) LC50 for rats: > 100 mg/m3 (> 16.1 ppm) (REACH registration dossier (Accessed Oct. 2020))
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 Not classified
-
-
- - [Rationale for the Classification]
It was classified as "Not classified" from (1).

[Evidence Data]
(1) It is reported that in a skin irritation test with rabbits (n = 4) (OECD TG 404, GLP, semi-occlusive, 4-hour application, 14-day observation), after applying 1%, 5%, 10%, 25%, and 100% solutions, no reactions were seen at concentrations of 10% or below. The mean score was 0.2 for erythema and 0 for edema after applying a 25% solution, and 1.3 for erythema and 0.6 for edema after applying a 100% solution. All reactions were fully reversed within 14 days (ECHA RAC Background Document (2019), REACH registration dossier (Accessed Oct. 2020)).
3 Serious eye damage/eye irritation Category 1


Danger
H318 P305+P351+P338
P280
P310
[Rationale for the Classification]
It was classified in Category 1 from (1).

[Evidence Data]
(1) It is reported that in an in-vitro eye irritation test (OECD TG 491, GLP), cell viability was 25.5%, 26.8%, 31.0% at a 5% concentration, and 11.6%, 3.9%, 19.9% at a 0.05% concentration (REACH registration dossier information (Accessed Oct. 2020)).
4 Respiratory sensitization Classification not possible
-
-
- - [Rationale for the Classification]
Classification not possible due to lack of data.
4 Skin sensitization Category 1B


Warning
H317 P302+P352
P333+P313
P362+P364
P261
P272
P280
P321
P501
[Rationale for the Classification]
It was classified in Category 1B from (1) - (5).

[Evidence Data]
(1) It is reported that in a patch test in 585 eczema patients (2% of this substance), a positive rate was 1% in the survey in 1978-1979 and 2% in the survey in 1979-1980 (ECHA RAC Opinion (2019), CLH Report (2018)).
(2) It is reported that in a patch test (multicenter study, 2% of this substance), a positive rate was 0.4% (7/1,825) (ECHA RAC Opinion (2019), CLH Report (2018)).
(3) This substance was shown to be a skin sensitizer in multiple diagnostic studies including (1) and (2), with an incidence of < 1% in unselected patients and <= 2% in selected patients (ECHA RAC Opinion (2019), CLH Report (2018)).
(4) It is reported that in a local lymph node assay (LLNA) with mice (n = 4/group) (equivalent to OECD TG 429, solvent: DMF), stimulation index (SI values) was 1.5 (12.5%), 1.7 (25%), 5.9 (50%), 7.1 (100%), and the EC3 value was calculated as 33% (ECHA RAC Opinion (2019), CLH Report (2018), REACH registration dossier (Accessed Oct. 2020)).
(5) It is reported that in a local lymph node assay (LLNA) with mice (n = 4/group) (equivalent to OECD TG 429, solvent: MEK), stimulation index (SI values) was 2.0 (12.5%), 2.4 (25%), 7.6 (50%), 9.4 (100%), and the EC3 value was calculated as 28% (ECHA RAC Opinion (2019), CLH Report (2018), REACH registration dossier (Accessed Oct. 2020)).
5 Germ cell mutagenicity Not classified
-
-
- - [Rationale for the Classification]
Based on (1) and (2), it was classified as "Not classified."

[Evidence Data]
(1) In a bacterial reverse mutation test (equivalent to OECD TG 471), negative results were reported (REACH registration dossier (Accessed Oct. 2020), RIFM Expert Panel Report (2007), Patty (6th, 2012)).
(2) In an in vitro mammalian chromosome aberration test (equivalent to OECD TG 473), negative results were reported (REACH registration dossier (Accessed Oct. 2020), RIFM Expert Panel Report (2007), Patty (6th, 2012)).
6 Carcinogenicity Classification not possible
-
-
- - [Rationale for the Classification]
Classification was not possible due to lack of data.

[Evidence Data]
(1) In a two-year chronic toxicity study with rats dosed by feeding, no evidence of carcinogenicity was observed (REACH registration dossier (Accessed Oct. 2020), RIFM Expert Panel Report (2007)). However, this was an old chronic toxicity study and the number of animals was limited. Therefore, it did not meet the standard for carcinogenicity studies. No standard carcinogenicity study result was available for any of 18 salicylates (salts, esters) (RIFM Expert Panel Report (2007)).
(2) In a screening test using mice of the A strain susceptible to lung tumorigenesis, there was no increase in lung tumorigenesis under the test conditions (intraperitoneal administration of up to 500 mg/kg, 3 times/week, for 8 weeks) of this substance (RIFM Expert Panel Report (2007)).
(3) In a screening test for carcinogenic potential of salicylic acid, which is a hydrolysate of this substance, rats were fed or injected with sodium salicylate. As a result, none of the animals developed tumors in any organs (REACH registration dossier (Accessed Oct. 2020)).
(4) A two-year chronic toxicity study with rats and a test using mice of the A strain provided no evidence to indicate that this substance was carcinogenic. Given the results of the genotoxicity tests and the well-known metabolism of the salicylates and related compounds, it was considered that this substance was unlikely to be carcinogenic (RIFM Expert Panel Report (2007)).
7 Reproductive toxicity Category 1B


Danger
H360 P308+P313
P201
P202
P280
P405
P501
[Rationale for the Classification]
Based on (1) and (2), it was classified in Category 1B. In (1), at the dose at which slight maternal toxicity was observed, malformations and visceral anomalies were observed in pups, and in (2), effects such as a decrease in birth index were observed.

[Evidence Data]
(1) It was reported that in a developmental toxicity study with rats by subcutaneous administration (GLP, days 6 to 17 of gestation), at 200 mg/kg/day, reduced body weight gain and a reduction in food consumption were observed in parental animals; and lower body weight, an increase in the incidence of external malformations (craniorachischisis, gastroschisis), and visceral anomalies (ventricular septal defect, dilatation of the ureter, thymic remnant in the neck) were observed in pups (CLH Report (2018)).
(2) It was reported that in a developmental toxicity study with rats by subcutaneous administration (GLP, day 6 of gestation to lactation day 21), at 200 mg/kg/day, general toxicity effects (death (2/20 cases), a decrease in body weight and a reduction in food consumption) were observed in parental animals; and decreased birth index, delayed preputial separation, delayed incisor eruption, and increases in skeletal variations and anomalies (fusion of the cervical vertebra, misshapen sternebra) were observed in pups (CLH Report (2018)).

[Reference Data, etc.]
(3) It was reported that in a developmental toxicity study with rabbits by subcutaneous administration (GLP, days 6 to 18 of gestation), no developmental toxicity was observed (CLH Report (2018)).
(4) There was no data available on effects of this substance on humans, but there were many reports on an analogous compound, acetyl salicylic acid (ASA). Both ASA and this substance were rapidly decomposed into salicylic acid in the body. Many of the reports did not show adverse effects on pregnancy at low ASA doses in humans, while there were some reports suggesting effects on maternal bleeding, pregnancy duration, and labor. However, no detailed information was known, and it was considered that no conclusion could be drawn based on the data on humans (CLH Report (2018)).
(5) The result of a large cohort study of ASA in the U.S. showed that there was no statistical difference in the incidence of delivery of malformed infants between the pregnant women dosed with ASA during gestation and those not dosed, and ASA was not considered to be teratogenic. Nowadays, it has been recognized that ASA has a preventive effect of pre-eclampsia, and the prophylactic daily use of low-dose aspirin in pregnant women who are considered to be at risk for pre-eclampsia has been recommended. It was considered that no such teratogenic effect that was observed in experimental animals dosed with ASA was caused in humans by this substance which was an analogous compound of ASA (ECHA RAC Opinion (2019)).
(6) In the developmental toxicity study with rats, external malformations and visceral anomalies were observed in fetuses with a slight maternal toxicity; and also in hamsters, malformations were observed in a high dose of this substance (Patty (2012)). Based on these findings, CLH Report concluded that it was appropriate to classify it as Repr. 1B for reproductive toxicity. RAC determined that based on the study result of ASA, this substance was not teratogenic to humans, and in a weighted evidence evaluation, it concluded that this substance should be classified as Repr. 2 based on the positive results with experimental animals and the negative results with humans (ECHA RAC Opinion (2019)).
8 Specific target organ toxicity - Single exposure Category 1 (central nervous system, gastrointestinal tract), Category 3 (narcotic effects)



Danger
Warning
H370
H336
P308+P311
P260
P264
P270
P321
P405
P501
P304+P340
P403+P233
P261
P271
P312
[Rationale for the Classification]
Based on (1) to (4), it was considered that the central nervous system and the gastrointestinal tract were the major target organs and it was classified in Category 1 (central nervous system, gastrointestinal tract). Since lethargy and coma were observed, it was also considered to be classified in Category 3 (narcotic effects). Therefore, it was classified in Category 1 (central nervous system, gastrointestinal tract) and Category 3 (narcotic effects).

[Evidence Data]
(1) It was reported that when this substance was used in large amounts, side effects such as headache, nausea or vomiting, anorexia and tachycardia occured (JAPIC (2019)).
(2) This substance is well absorbed by oral route. This substance is rapidly and extensively hydrolyzed to salicylic acid and methanol. It was reported that after oral administration, 80% of this substance was hydrolyzed within 90 minutes in humans (CLH Report (2018)).
(3) There are many reports on acute salicylate poisoning caused by overdose of acetylsalicylic acid (aspirin), excessive application of topical agents, ingestion of salicylic acid ointment, etc. In 2004, 40,405 cases of human exposure to salicylates were reported to poison control centers in the U.S. Of these cases, this substance was involved in 12,500 cases (30%). It was reported that the typical symptoms of salicylate poisoning were hematemesis, tachypnea, hyperpnea, dyspnea, tinnitus, deafness, lethargy, seizures, and confusion (CLH Report (2018)).
(4) Cardinal symptoms of salicylate poisoning after oral ingestion are nausea, vomiting and epigastric pain, and occasionally hematemesis. The common clinical symptoms of mild to moderate salicylate poisoning are hyperventilation, sweating, flushing, fever, hyperirritability, tinnitus, and deafness. In severe intoxication, dyspnea, stupor, hallucination, convulsions, papilloedema, and coma particularly in children may occur. It was reported that metabolic acidosis, non-cardiogenic pulmonary edema, hepatotoxicity, and cardiac dysrhythmia might also occur (IPCS PIM 642 (Accessed Oct. 2020)).

[Reference Data, etc.]
(5) In an acute oral toxicity test with rats, depression was observed soon after the treatment and death was observed 4 to 18 hours after the treatment. The LD50 was reported to be 887 mg/kg (CLH Report (2018), REACH registration dossier (Accessed Oct. 2020)).
9 Specific target organ toxicity - Repeated exposure Category 1 (central nervous system)


Danger
H372 P260
P264
P270
P314
P501
[Rationale for the Classification]
Based on (1) and (2), it was classified in Category 1 (central nervous system). Based on (3) and (4), no specific target organ toxicity was observed in experimental animals at doses of up to the range for Category 2.

[Evidence Data]
(1) This substance is well absorbed by oral route. This substance is rapidly and extensively hydrolyzed to salicylic acid and methanol. It was reported that after oral administration, 80% of this substance was hydrolyzed within 90 minutes in humans (CLH Report (2018)).
(2) It was reported that the signs of chronic salicylate poisoning included metabolic acidosis, hypoglycemia, lethargy, coma, and fits (IPCS PIM 642 (Accessed Oct. 2020)).
(3) It was reported that in a two-year oral toxicity study with rats dosed by feeding, no effect was observed at 50 mg/kg/day (within the range for Category 2), and although toxic effects were observed at 250 mg/kg/day (in the range corresponding to "Not classified"), the targets organs could not be identified (RIFM Expert Panel Report (2007), REACH registration dossier (Accessed Oct. 2020).
(4) It was reported that in a two-year oral toxicity study with dogs dosed by gavage, no effect was observed at 50 mg/kg/day (within the range for Category 2) and liver effects (an increase in relative weight, an enlargement, hepatocellular hypertrophy) were observed at 150 mg/kg/day (in the range corresponding to "Not classified") (RIFM Expert Panel Report (2007), REACH registration dossier (Accessed Oct. 2020)).
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 2
-
-
H401 P273
P501
It was classified in Category 2 from 72-hour ErC50 = 1.6 mg/L for algae (Desmodesmus subspicatus) (EU CLP CLH, 2018).
11 Hazardous to the aquatic environment Long term (Chronic) Category 2


-
H411 P273
P391
P501
If chronic toxicity data are used, then it is classified in Category 2 because sufficient data on rapid degradability were not obtained and due to 72-hour NOErC = 0.79 mg/L for algae (Desmodesmus subspicatus) (EU CLP CLH, 2018).
If acute toxicity data are used for a trophic level for which chronic toxicity data are not obtained, then it is classified in Category 3 because sufficient data on rapid degradability were not obtained and due to 96-hour LC50 = 19.8 mg/L for fish (Pimephales promelas) (EU CLP CLH, 2018).
By drawing a comparison between the above results, it was classified in Category 2.
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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