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Latest GHS Classification Results by the Japanese Government (edited by NITE)

GENERAL INFORMATION

Item	Information
CAS RN	54-11-5
Chemical Name	3-(1-Methyl-2-pyrrolidinyl)pyridine; Nicotine
Substance ID	m-nite-54-11-5_v2
Download of Excel format	Excel file

REFERENCE INFORMATION

Item	Information
Guidance used for the classification (External link)	To Guidance List
UN GHS document (External link)	To UN GHS document
FAQ（GHS classification results by the Japanese Government）	To FAQ
List of Information Sources (Excel file)	List of Information Sources
List of Definitions/Abbreviations	Definitions/Abbreviations
Sample Label by MHLW (External link)	MHLW Website (in Japanese Only)
Sample SDS by MHLW (External link)	MHLW Website (in Japanese Only)
OECD/eChemPortal (External link)	To OECD/eChemPortal (External link)

PHYSICAL HAZARDS

Hazard class		Classification	Pictogram Signal word	Hazard statement (code)	Precautionary statement (code)	Rationale for the classification	Classification year (FY)	GHS Classification Guidance for the Japanese Government
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."	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
2	Flammable gases	Not classified (Not applicable)	- -	-	-	Liquid (GHS definition). It was classified as "Not classified."	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
3	Aerosols	Not classified (Not applicable)	- -	-	-	Not aerosol products. It was classified as "Not classified."	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
4	Oxidizing gases	Not classified (Not applicable)	- -	-	-	Liquid (GHS definition). It was classified as "Not classified."	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
5	Gases under pressure	Not classified (Not applicable)	- -	-	-	Liquid (GHS definition). It was classified as "Not classified."	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
6	Flammable liquids	Not classified	- -	-	-	It was classified as "Not classified" from a flash point of 101 deg C (closed cup) (NFPA (14th, 2010)).	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
7	Flammable solids	Not classified (Not applicable)	- -	-	-	Liquid (GHS definition). It was classified as "Not classified."	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
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."	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
9	Pyrophoric liquids	Not classified	- -	-	-	It was classified as "Not classified" because it is estimated that it does not ignite at normal temperatures from an autoignition temperature of 244 deg C (NFPA (14th, 2010)).	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
10	Pyrophoric solids	Not classified (Not applicable)	- -	-	-	Liquid (GHS definition). It was classified as "Not classified."	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
11	Self-heating substances and mixtures	Classification not possible	- -	-	-	Classification is not possible because test methods applicable to liquid substances are not available.	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
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."	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
13	Oxidizing liquids	Not classified (Not applicable)	- -	-	-	Organic compounds containing no oxygen, fluorine or chlorine. It was classified as "Not classified."	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
14	Oxidizing solids	Not classified (Not applicable)	- -	-	-	Liquid (GHS definition). It was classified as "Not classified."	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
15	Organic peroxides	Not classified (Not applicable)	- -	-	-	Organic compounds containing no bivalent -O-O- structure in the molecule. It was classified as "Not classified."	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
16	Corrosive to metals	Classification not possible	- -	-	-	No data available.	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
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."	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))

HEALTH HAZARDS

Hazard class		Classification	Pictogram Signal word	Hazard statement (code)	Precautionary statement (code)	Rationale for the classification	Classification year (FY)	GHS Classification Guidance for the Japanese Government
1	Acute toxicity (Oral)	Category 1	Danger	H300	P301+P310 P264 P270 P321 P330 P405 P501	[Rationale for the Classification] There are descriptions that the lethal dose by oral ingestion in humans was estimated as 30-60 mg (CLH Report (2015)), 50-60 mg (ACGIH (7th, 2001)), or about 60 mg (MAK (DFG) (2014)). Because it was judged that an oral lethal dose for humans was below 1 mg/kg, it was classified in Category 1. [Evidence Data] (1) Estimated lethal dose for humans: 30-60 mg (CLH Report (2015)) (2) Estimated lethal dose for humans: 50-60 mg (ACGIH (7th, 2001)) (3) Estimated lethal dose for humans: about 60 mg (MAK (DFG) (2014))	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
1	Acute toxicity (Dermal)	Category 1	Danger	H310	P302+P352 P361+P364 P262 P264 P270 P280 P310 P321 P405 P501	[Rationale for the Classification] It was classified in Category 1 from (1) - (5). [Evidence Data] (1) LD50 for rabbits: 50 mg/kg (EU CLP CLH (2015), MAK (DFG) (2014), GESTIS (Access on June 2020), HSDB (Access on June 2020)) (2) LD50 for rabbits: 140 mg/kg (EU CLP CLH (2015)) (3) LD50 for rats: 140 mg/kg (CLH Report (2015), MAK (DFG) (2014), HSDB (Access on June 2020)) (4) LD50 for rats: 150 mg/kg (GESTIS (Access on June 2020)) (5) LD50 for rats: > 360 mg/kg (CLH Report (2015))	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
1	Acute toxicity (Inhalation: Gases)	Not classified	- -	-	-	[Rationale for the Classification] Liquid (GHS definition). It was classified as "Not classified."	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
1	Acute toxicity (Inhalation: Vapours)	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data. There were data of (1), but it was listed as reference data because the value was calculated from the result of a test by 20-minute exposure to tobacco. Besides, because an exposure concentration was lower than 90% of the saturated vapor pressure concentration (50 ppm), a reference value in the unit of ppm was applied as a vapor with little mist. [Reference Data, etc.] (1) LC50 for rats (4 hours): > 0.114 mg/L (> 17 ppm) (EU CLP CLH (2015)) (2) Vapor pressure of this substance: 0.038 mmHg (25 deg C) (HSDB (Access on May 2020)) (converted value for the saturated vapor pressure concentration: 50 ppm)	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
1	Acute toxicity (Inhalation: Dusts and mists)	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
2	Skin corrosion/irritation	Category 2	Warning	H315	P302+P352 P332+P313 P362+P364 P264 P280 P321	[Rationale for the Classification] It was classified in Category 2 from (1) - (3). Because new data (1) - (3) were obtained, the classification result was changed. [Evidence Data] (1) This substance was locally irritating to the skin (Patty (6th, 2012)). (2) This substance was irritating to the skin (GESTIS (Access on June 2020)). (3) In an acute dermal administration toxicity test with rabbits according to OECD TG 402 on this substance, slight to severe erythema was observed, and it was concluded that it was not corrosive but irritating (REACH registration dossier (Access on September 2020)). [Reference Data, etc.] (4) It is reported that erythema was found due to patches containing this substance (smoking cessation drug) in some volunteers (MAK (DFG) (2014)).	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
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) - (4). Because new data (1) - (4) were obtained, the classification result was changed. [Evidence Data] (1) In an eye irritation test according to OECD TG 405 on this substance, conjunctival redness and chemosis, iritis, and corneal opacity were observed, conjunctival inflammation and corneal opacity persisted by 21 days after application, and it was concluded to be corrosive (REACH registration dossier (Access on September 2020)). (2) This substance caused inflammation of the anterior segment of the eye and miosis (Patty (6th, 2012)). (3) Eye contact with this substance caused pain, pronounced conjunctivitis, and inflammation and partial turbidity of the cornea (GESTIS (Access on June 2020)). (4) In an in-vitro eye irritation test with reconstructed human cornea-like epithelium (EpiOcular TM) according to OECD TG 492, the mean cell viability was 3.1%, and it was estimated to correspond to Category 1 or 2 (REACH registration dossier (Access on September 2020)). [Reference Data, etc.] (5) In an in-vitro eye damage test with the bovine cornea (BCOP) according to OECD TG 437, the in vitro irritancy score (IVIS) was 29.518, and Category 1 was denied (REACH registration dossier (Access on September 2020)).	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
4	Respiratory sensitization	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
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 (LLNA) according to TG 429, the SI value did not exceed 3, and it was judged as negative (REACH registration dossier (Access on September 2020)).	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
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). The classification result was changed based on newly obtained data. [Evidence Data] (1) As for in vivo, it was reported to be negative in a dominant lethal test in mice but positive in a micronucleus test with mouse bone marrow cells (MAK (DFG) (2014), Patty (6th, 2012)). (2) As for in vitro, it was reported to be negative in a bacterial reverse mutation test but positive and negative in chromosomal aberration tests and sister chromatid exchange tests using cultured mammalian cells (same as the above).	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
6	Carcinogenicity	Classification not possible	- -	-	-	[Rationale for the Classification] No data available.	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
7	Reproductive toxicity	Category 2,	Warning	H361 H362	P308+P313 P201 P202 P260 P263 P264 P270 P280 P405 P501	[Rationale for the Classification] Based on (1) to (4), it was classified in Category 2. In addition, based on (5), "effects on or via lactation" was added. As a result of a review, the classification result was changed from the previous classification. [Evidence Data] (1) In a combined study of repeated dose toxicity test and reproduction/developmental toxicity screening test (OECD TG 422) by inhalation exposure in rats, at a dose at which parental toxicity (decreased body weight gain, decreased food consumption, hepatocellular necrosis and hydropic degeneration in the liver, stress-related adrenal cortical hypertrophy, thymic atrophy and uterine atrophy) was observed, no reproductive effects were observed, but irregular estrous cycle and lower body weight in pups were observed (REACH registration dossier (Access on October 2020)). (2) In subcutaneous administration tests with female mice, rats, and rabbits during the organogenesis period, at doses where maternal toxicity (reduced body weight gain, decreased food consumption) was observed, unossified bones were observed in fetuses of mice and rats, but no effect was observed in fetuses of rabbits (Patty (6th, 2012)). (3) In a subcutaneous administration test with female rats dosed at 6 mg/kg/day on days 4 to 20 of gestation, reduced body weight gain was observed in dams, and reduced body weight and brain development were observed in pups (ACGIH (7th, 2001)). (4) Female rats were dosed at 6 mg/kg/day from 6 weeks before mating and during gestation period and newborns were cross-fostered to control dams for nursing 12 hours after birth. Reduced adrenal weight were observed in males and increased adrenal weight were observed in females, and a decrease in birth weight, a decrease in the number of fetuses/litter, and a decrease in activity were observed in males (MAK (DFG) (2014)). (5) In a test with rats dosed in the gestation and lactation period, most pups died because mothers produced very little milk (Patty (6th, 2012)).	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
8	Specific target organ toxicity - Single exposure	Category 1 (nervous system, cardiovascular system, gastrointestinal tract)	Danger	H370	P308+P311 P260 P264 P270 P321 P405 P501	[Rationale for the Classification] Based on (1) to (6), it was classified in Category 1 (nervous system, cardiovascular system, gastrointestinal tract). Target organs were reviewed and the classification result was changed from the previous classification. [Evidence Data] (1) Numerous cases of green tobacco sickness, a form of acute nicotine poisoning, were reported after dermal exposure to nicotine absorbed by workers while harvesting tobacco leaves. The illness may occur after only a few hours and is of short duration. It is characterized by nausea, vomiting, weakness, dizziness, and changes in blood pressure or heart rate (MAK (DFG) (2014)). (2) Transdermal patches containing 78 mg of this substance were applied alternately to the arm, chest, and back of 12 male volunteers within a period of 24 hours. As a result, heart rate and systolic blood pressure increased significantly after 4 hours (MAK (DFG) (2014)). (3) Fatal occupational poisoning was relatively uncommon. However, milder cases, with the predominant symptoms of vomiting and diarrhea, were not unusual among chemical processors and insecticide applicators. Autopsies of those who died from acute poisoning with this substance showed marked dilatation of the right side of the heart, mild pulmonary edema, hemorrhagic gastritis, acute passive congestion of most internal organs, brain edema, and marked renal hyperemia (ACGIH (7th, 2001)). (4) This substance has an effect on the heart rate and blood pressure, with the stimulating effect prevailing at low doses. Furthermore, it acts on the gastrointestinal tract and central nervous system. At toxic doses, central stimulation is followed by inhibition, e.g. central inhibition of respiration. About 60 mg is fatal for humans. Death from respiratory paralysis occurs after only a few minutes (MAK (DFG) (2014)). (5) This substance binds to the so-called nicotine receptors that are present in many neurons. It then induces different reactions in the cardiovascular system, central nervous system, and gastrointestinal tract depending on the dose. Nicotine can readily pass the blood-brain barrier (MAK (DFG) (2014)). (6) A TLV-TWA 0.5 mg/m3 is recommended for occupational exposure to this substance. This value is intended to minimize the potential for gastrointestinal disturbances such as nausea, vomiting, diarrhea and hemorrhagic gastritis, cardiovascular effects such as increased blood pressure and heart rate, and adverse central nervous system effects such as headache, dizziness, depression, respiratory, hypertension, sweating and salivation (ACGIH (7th, 2001)).	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
9	Specific target organ toxicity - Repeated exposure	Classification not possible	- -	-	-	[Rationale for the Classification] Classification was not possible due to lack of data. [Reference Data, etc.] (1) There was only one that reported that, in an inhalation exposure test with rats by nasal exposure to aerosol (males: for up to 35 days, females: for about 70 days), hepatocellular necrosis and hydropic degeneration were observed at 10 microg/L (REACH registration dossier (Access on October 2020)). (2) Chronic consumption of this substance may result in intoxication and addiction (HSDB (Access on June 2020)). (3) It was reported that, when near-lethal doses were administered to rabbits daily for 80 days, this substance produced mydriasis and poor response of pupils to light attributable to degeneration in retinal ganglion cells (HSDB (Access on June 2020)).	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
10	Aspiration hazard	Classification not possible	- -	-	-	[Rationale for the Classification] Classification not possible due to lack of data.	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))

ENVIRONMENTAL HAZARDS

Hazard class		Classification	Pictogram Signal word	Hazard statement (code)	Precautionary statement (code)	Rationale for the classification	Classification year (FY)	GHS Classification Guidance for the Japanese Government
11	Hazardous to the aquatic environment Short term (Acute)	Category 2	- -	H401	P273 P501	It was classified in Category 2 from 48-hour EC50 = 3 mg/L for crustacea (Daphnia magna) (REACH registration dossier, 2020). The classification result was changed from the previous classification by using new information.	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
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 as "Not classified" because it is not rapidly degradable (BIOWIN) and due to 72-hour NOEC = 3.2 mg/L for algae (Desmodesmus subspicatus) (REACH registration dossier, 2020). If acute toxicity data are used for a trophic level for which chronic toxicity data are not obtained, then it is classified in Category 2 because it is not rapidly degradable (BIOWIN) and due to 48-hour EC50 = 3 mg/L for crustacea (Daphnia magna) (REACH registration dossier, 2020). By drawing a comparison between the above results, it was classified in Category 2. The classification result was changed from the previous classification by using new information.	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))
12	Hazardous to the ozone layer	Classification not possible	- -	-	-	This substance is not listed in the Annexes to the Montreal Protocol.	FY2020	GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0))

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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