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GHS Classification Results by the Japanese Government

GENERAL INFORMATION

Item	Information
CAS RN	108-11-2
Chemical Name	4-methyl-2-pentanol
Substance ID	R03-B-004-MHLW
Classification year (FY)	FY2021
Ministry who conducted the classification	Ministry of Health, Labour and Welfare (MHLW)
New/Revised	Revised
Classification result in other fiscal year	FY2014 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.
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	Category 3	Warning	H226	P303+P361+P353 P370+P378 P403+P235 P210 P233 P240 P241 P242 P243 P280 P501	It was classified in Category 3 based on a flash point of 40.5 deg C (closed cup) (GESTIS (Accessed Sep. 2021)). Besides, it is classified in Class 3, PG III in UNRTDG (UN2053).
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 335 deg C (GESTIS (Accessed Oct. 2021)).
10	Pyrophoric solids	Not classified (Not applicable)	- -	-	-	Liquid (GHS definition)
11	Self-heating substances and mixtures	Classification not possible	- -	-	-	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)	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) to (4), it was classified as "Not classified" (Category 5 in the UN GHS classification). [Evidence Data] (1) LD50 for rats (males): between 2,260 to 2,970 mg/kg (SIAR (2005)) (2) LD50 for rats: 2,260 mg/kg (AICIS IMAP (2013)) (3) LD50 for rats: 2,590 mg/kg (ACGIH (8th, 2020)) (4) LD50 for rats: between 2,590 to 2,950 mg/kg (ACGIH (8th, 2020))
1	Acute toxicity (Dermal)	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) and (2), it was classified as "Not classified" (Category 5 in the UN GHS classification). [Evidence Data] (1) LD50 for rabbits: 3.56 ml/kg (approx. 2,870 mg/kg) (SIAR (2005), AICIS IMAP (2013), ACGIH (8th, 2020)) (2) LD50 for rabbits: 2,880 mg/kg (Patty (6th, 2012))
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.
1	Acute toxicity (Inhalation: Dusts and mists)	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) and (2), it was classified as "Not classified." Besides, the exposure concentration was higher than the saturated vapor pressure concentration (15.4 mg/L) and it was judged as mist. Also, based on the new findings, the classification result was changed. [Evidence Data] (1) LC50 (4 hours) for rats: > 16 mg/L (SIAR (2005), AICIS IMAP (2013), ACGIH (8th, 2020)) (2) LC50 (2 hours) for rats: > 19 mg/L (converted 4-hour equivalent value: ＞ 9.5 mg/L) (SIAR (2005) , ACGIH (8th, 2020))
2	Skin corrosion/irritation	Category 2	Warning	H315	P302+P352 P332+P313 P362+P364 P264 P280 P321	[Rationale for the Classification] Based on (1) and (2), it was classified in Category 2. Also, based on the new findings, the classification result was changed. [Evidence Data] (1) In an acute dermal irritation/corrosion test (OECD TG 404, GLP, semiocclusive, 4-hour application, observation for 14 days) with rabbits (n = 3), well-defined erythema with slight edema, desquamation of the stratum corneum, and dryness and sloughing of the skin were observed in all animals, and thickening of the skin was also observed in 1 animal. It was reported that the effects in 2 animals were fully reversible within 14 days, but very slight erythema was still observed in 1 animal on day 14 (erythema score: 2/2/2, edema score: 2/1/1.7) (REACH registration dossier, AICIS IMAP (2013), ACGIH (8th, 2020)). (2) This substance was irritating to the skin, eyes, and respiratory tract (ACGIH (8th, 2020)).
3	Serious eye damage/eye irritation	Category 2A	Warning	H319	P305+P351+P338 P337+P313 P264 P280	[Rationale for the Classification] Based on (1) to (3), it was classified in Category 2A. [Evidence Data] (1) In an acute eye irritation/corrosion test (OECD TG 405, GLP, observation for 14 days) with rabbits (n = 3), corneal opacification, iridial inflammation, diffuse coloration of the conjunctivae, and swelling with eyelids about half-closed were observed in all animals. It was reported that all effects were reversible within 14 days (corneal opacity score: 1/0.7/2, iritis score: 0.7/0.7/0.3, conjunctival redness score: 2.3/1.3/1.3, chemosis score: 1/0.3/0.3) (AICIS IMAP (2013), ACGIH (8th, 2020), REACH registration dossier (Accessed Oct. 2021)). (2) It was reported that a study with human volunteers (12/sex) indicated that vapor exposure to this substance at 50 ppm for 15 minutes resulted in eye irritation in most subjects with nose and throat irritation experienced at higher concentrations, and the maximum tolerable concentration was considered to be 25 ppm (SIAR (2005), AICIS IMAP (2013), ACGIH (8th, 2020), REACH registration dossier (Accessed Oct. 2021)). (3) In an eye irritation test with rabbits (n = 3), Draize scores (maximum score: 110) were 11, 25, and 17 at 1, 24, and 72 hours after instillation, respectively. It was reported that conjunctivitis, edema, and corneal injury were observed, but all were reversible within 7 days, and the result was a moderate irritation (SIAR (2005), AICIS IMAP (2013), ACGIH (8th, 2020)).
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 Maximization test (OECD TG 406, GLP, intradermal injection: 1% solution) with guinea pigs (n = 20), the skin reaction positive rate was 0% (0/20 animals) both at 24 and 48 hours after challenge (SIAR (2005), AICIS IMAP (2013), ACGIH (8th, 2020), REACH registration dossier (Accessed Oct. 2021)).
5	Germ cell mutagenicity	Not classified	- -	-	-	[Rationale for the Classification] Based on (1) to (3), it was classified as "Not classified." [Evidence Data] (1) As for in vitro, negative results were obtained in a bacterial reverse mutation assay, a mammalian cell (mouse lymphoma cells) gene mutation test (OECD TG 476, GLP), and a chromosomal aberration test using the rat liver cells (RL4) (Mutagenicity Test Data of Existing Chemical Substances based on the toxicity investigation system of the Industrial Safety and Health Law (Accessed Sep. 2021), SIAR (2005), AICIS IMAP (2013), Patty (6th, 2012), REACH registration dossier (Accessed Sep. 2021)). (2) Negative results were obtained in an in vivo micronucleus test with mice and hamsters using methyl isobutyl ketone (MIBK, CAS RN 108-10-1), which is the major metabolite of this substance, as the test substance (ACGIH (8th, 2020)). (3) As for in vitro test for MIBK, negative results were obtained in a bacterial reverse mutation test, and a chromosomal aberration test using the rat liver cells (RL4), and positive, uncertain (-S9), or negative results (+S9) were obtained in a mouse lymphoma assay (ACGIH (8th, 2020)).
6	Carcinogenicity	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data. In the latest assessment by the ACGIH, based on (1) to (4), the applicability of the carcinogenicity data of the main metabolite MIBK to this substance was examined, and it was concluded to be inapplicable because the carcinogenicity induction concentration (calculated value) converted into the concentration of this substance was estimated to be near the lethal concentration (measured value) of this substance. [Reference Data, etc.] (1) Toxicokinetics tests showed similar levels of in vivo exposure after administration of this substance and its main metabolite, Methyl isobutyl ketone (MIBK, CAS RN 108-10-1). It was reported that the use of the data for MIBK as well as the data for the final metabolite, 4-hydroxy-4-methyl-2-pentanone (HMP; CAS RN 123-42-2), was found to be appropriate for the evaluation of potential hazards from this substance (SIAR (2005), ACGIH (8th, 2020)). (2) As for the carcinogenicity classification of MIBK, it was classified in Group 2B by the IARC (IARC 101 (2012)), in A3 by the ACGIH (ACGIH (8th, 2010)), in Group 2B by the Japan Society For Occupational Health (JSOH) (Recommendation of Occupational Exposure Limits (Japan Society For Occupational Health (JSOH)) (proposed in 2015)), and in Category 2 by the Japanese Government (GHS Classification Result in FY2015). (3) The basis for the carcinogenicity classification of MIBK in (2) was that a certain degree of evidence of carcinogenicity was obtained in a group exposed to the highest concentration (1,800 ppm) in a 2-year inhalation exposure test with rats and mice. In rats, kidney tumors observed in males were attributed to alpha 2mu-globulin nephropathy, which was not applicable for humans, based on the increased incidences of mononuclear cell leukemia in males and renal mesenchymal tumors in females in the 1,800 ppm group, and an increase in liver tumors in males and females in the 1,800 ppm group in mice (ACGIH (8th, 2020)). (4) The ACGIH classified MIBK in A3, but did not recommend a carcinogenicity notation for this substance. The rationale for this was that, based on the acute inhalation toxicity test results (5) of this substance, the concentrations of this substance (1,800 to 2,250 ppm) corresponding to the high concentration (1,800 ppm) at which carcinogenicity occurred in animal studies for MIBK, corresponded to the concentration at which animals were anesthetized and died, and it was assumed that continuous exposure became impossible before the development of carcinoma in animal studies for this substance, and therefore, it was considered to be inappropriate to apply the same carcinogenicity classification as MIBK to this substance (ACGIH (8th, 2020)). (5) In an acute oral inhalation toxicity test with rats using this substance, all animals were anesthetized at 2,400 and 3,840 ppm, but death was observed only in 1 female at 3,840 ppm. After 2-hour exposure of rats to saturated vapor (approx. 3,700 ppm), there was no death, but after 8-hour exposure at 2,000 ppm, death was observed in 5/6 animals (ACGIH (8th, 2020)). (6) Toxicokinetics tests by oral administration of this substance and MIBK to rats (analysis results of the blood concentration changes over time of unchanged drug and metabolites (including the final metabolite HMP (4-Hydroxy-4-methyl-2-pentenone))) showed similar levels of in vivo exposure after administration of this substance and its main metabolite, MIBK. It was found to be appropriate to use the extensive toxicity database for MIBK and the data for HMP for the evaluation of potential hazards from this substance (SIAR (2005), ACGIH (8th, 2020)).
7	Reproductive toxicity	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data. Besides, there was no data for the substance itself, but based on (1) to (3), in an inhalation exposure test using methyl isobutyl ketone, which is a related substance and a main metabolite, there were no effects on fertility even at a concentration at which general toxicity effects were observed in parent animals, and developmental toxicity effects were also within the range of minor effects except for an increase in fetal death in mice. [Reference Data, etc.] (1) Toxicokinetics tests showed similar levels of in vivo exposure after administration of this substance and its main metabolite, Methyl isobutyl ketone (MIBK, CAS RN 108-10-1). It was reported that the use of the data for MIBK as well as the data for the final metabolite, 4-hydroxy-4-methyl-2-pentanone (HMP; CAS RN 123-42-2), was found to be appropriate for the evaluation of potential hazards from this substance (SIAR (2005), ACGIH (8th, 2020)). (2) In a two-generation reproduction toxicity study by inhalation exposure of rats to MIBK as the test substance, no effects on fertility were observed in parent animals at doses up to the highest dose of 2,000 ppm at which reduced body weight gain and slightly decreased food consumption were observed in F0 and F1 parent animals. Besides, it was reported that, at or above 1,000 ppm, a transient reduced acoustic startle response and a sedative effect (which disappeared within 1 hour) were observed in parent animals, and CNS depression symptoms were observed in pups (SIAR (2005), AICIS IMAP (2013), ACGIH (8th, 2020), REACH registration dossier (Accessed Sep. 2021)). (3) It was reported that, in a developmental toxicity study by inhalation exposure of pregnant rats and mice to MIBK as the test substance (days 6 to 15 of gestation), developmental toxicity (lower fetal body weight and delayed ossification (both species), an increase in the incidence of dead fetuses (mice only)) was observed in fetuses at the highest concentration (3,000 ppm) at which maternal toxicity (neuromuscular symptoms, lower body weight/food consumption (rats only), increased liver weight) was observed in both species (SIAR (2005), AICIS IMAP (2013), ACGIH (8th, 2020), REACH registration dossier (Accessed Sep. 2021)). (4) It was reported that, in a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD TG 422) with rats dosed by gavage using HMP as the test substance, at the highest dose (1,000 mg/kg/day) at which reduced body weight gain (females) and general toxicity effects, such as histopathological changes to the liver, kidneys, and adrenals, were unequivocal in parent animals, a trend towards lower reproductive indices (fertilization rate, number of implantations) was observed; and in offspring, a trend towards lower developmental indices (number of liveborn pups, birth rate, survival rate on postnatal day 4, etc.) was observed (SIAR (2005), AICIS IMAP (2013), REACH registration dossier (Accessed Oct. 2021)).
8	Specific target organ toxicity - Single exposure	Category 3 (respiratory tract irritation, narcotic effects)	Warning	H335 H336	P304+P340 P403+P233 P261 P271 P312 P405 P501	[Rationale for the Classification] Based on (1) to (3), it was classified in Category 3 (respiratory tract irritation, narcotic effects). [Evidence Data] (1) It was reported that a study with human volunteers (12/sex) indicated that vapor exposure to this substance at 50 ppm for 15 minutes resulted in eye irritation in most subjects with nose and throat irritation experienced at higher concentrations, and the maximum tolerable concentration was considered to be 25 ppm (SIAR (2005), AICIS IMAP (2013), ACGIH (8th, 2020)). (2) It was reported that, in an acute inhalation exposure test with rats (4 hours), anesthetic symptoms were observed in all animals (5 males and 5 females/group) within 1 hour after the start of exposure at 10 to 16 mg/L or higher (in the range corresponding to "Not classified"), but animals regained consciousness within 30 minutes after cessation of the exposure at 10 mg/L and within 2 hours after cessation of the exposure at 16 mg/L (SIAR (2005), AICIS IMAP (2013), ACGIH (8th, 2020)). (3) It was reported that, in an acute inhalation exposure test with mice (4 to 15 hours), at 20 mg/L, signs of respiratory tract irritation within 5 minutes and signs of lethargy within 1 hour were observed after administration, and ataxia and hind-limb paralysis were observed as the exposure continued (SIAR (2005), ACGIH (8th, 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), as for this hazard class, this substance was classified based on the data of methyl isobutyl ketone, which is a major metabolite. Based on (2) and (3), CNS symptoms (headache, weakness, insomnia, somnolence, etc.) were observed as health effects on humans, and therefore, it was classified in Category 1 (central nervous system). Also, based on the new findings, the classification result was changed. [Evidence Data] (1) Toxicokinetics tests showed similar levels of in vivo exposure after administration of this substance and its main metabolite, Methyl isobutyl ketone (MIBK, CAS RN 108-10-1), and the use of the data for MIBK and HMP (final metabolite) were found to be appropriate for the evaluation of potential hazards from this substance (SIAR (2005), ACGIH (8th, 2020)). (2) Irritation of the eyes, nose, and throat was reported in over two-thirds of a 19-person workforce exposed to MIBK for 20 to 30 minutes daily during the operation of a centrifuge, and more than half of the 19 workers involved complained of weakness, loss of appetite, headache, burning in the eyes, stomach ache, nausea, and vomiting. Also, it was reported that a few workers experienced sore throat, insomnia, somnolence, heartburn, and intestinal pain, 4 had slightly enlarged livers, and 6 complained mainly of nonspecific colitis. Besides, it was reported that workers near the centrifuge were exposed at 500 ppm, and the workplace air concentration was 80 ppm elsewhere in the room (ACGIH (8th, 2020)). (3) A follow-up study conducted 5 years after (2) identified air concentrations of MIBK of 100 to 105 ppm in the vicinity of the centrifuge and 50 ppm elsewhere in the room during the operation of the centrifuge. Only 1 of the 14 workers who continued working there from the previous study reported eye irritation. It was reported that a few workers still complained of gastrointestinal and CNS disturbances, and slight liver enlargement persisted in 2 workers, but other earlier symptoms had been reduced to the point of disappearing (ACGIH (8th, 2020)). [Reference Data, etc.] (4) In a 6-week repeated inhalation (vapor) exposure test with rats using this substance as the test substance (6 hours/day, 5 days/week), at 0.211 mg/L (converted guidance value: 0.070 mg/L: within the range for Category 1) to 3.70 mg/L (converted guidance value: 1.23 mg/L, in the range corresponding to "Not classified"), increased levels of ketone bodies in the urine, increased kidney weight, and proteinuria (males), and increased plasma ALP (females) were observed, but it was judged that these were not toxicity findings (SIAR (2005), AICIS IMAP (2013), ACGIH (8th, 2020)). (5) It was reported that, in a 14-week inhalation (vapor) exposure test with rats and mice using MIBK as the test substance (6 hours/day, 5 days/week), at or above 250 ppm (1.02 mg/L) (converted guidance value: 0.79 mg/L, within the range for Category 2), an increase in hyaline droplets within the proximal tubule cells of the kidney was observed in rats (males), and an increase in liver weight was observed in mice (males) (SIAR (2005), AICIS IMAP (2013), ACGIH (8th, 2020)). (6) It was reported that, in a 2-year repeated inhalation exposure test with rats and mice using MIBK as the test substance, at 450 ppm (1.88 mg/L, in the range corresponding to "Not classified"), effects on the kidney were observed in rats (males), and liver preneoplastic lesions (eosinophilic foci of altered hepatocytes) were observed in mice (ACGIH (8th, 2020), REACH registration dossier (Accessed Oct. 2021)).
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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