Item | Information |
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CAS RN | 54-11-5 |
Chemical Name | 3-(1-Methyl-2-pyrrolidinyl)pyridine; Nicotine |
Substance ID | R02-B-101-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 |
Item | Information |
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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 |
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) |
- |
- | - | Liquid (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) |
- |
- | - | Liquid (GHS definition). It was classified as "Not classified." |
5 | Gases under pressure | Not classified (Not applicable) |
- |
- | - | Liquid (GHS definition). It was classified as "Not classified." |
6 | Flammable liquids | Not classified |
- |
- | - | It was classified as "Not classified" from a flash point of 101 deg C (closed cup) (NFPA (14th, 2010)). |
7 | Flammable solids | Not classified (Not applicable) |
- |
- | - | Liquid (GHS definition). It was classified as "Not classified." |
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 |
- |
- | - | 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)). |
10 | Pyrophoric solids | Not classified (Not applicable) |
- |
- | - | Liquid (GHS definition). It was classified as "Not classified." |
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). It was classified as "Not classified." |
13 | Oxidizing liquids | Not classified (Not applicable) |
- |
- | - | Organic compounds containing no oxygen, fluorine or chlorine. It was classified as "Not classified." |
14 | Oxidizing solids | Not classified (Not applicable) |
- |
- | - | Liquid (GHS definition). 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 |
- |
- | - | No data 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." |
Hazard class | Classification | Pictogram Signal word |
Hazard statement (code) |
Precautionary statement (code) |
Rationale for the classification | |
---|---|---|---|---|---|---|
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)) |
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)) |
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. 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) |
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 | 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)). |
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)). |
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 (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)). |
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). |
6 | Carcinogenicity | Classification not possible |
- |
- | - | [Rationale for the Classification] No data available. |
7 | Reproductive toxicity | Category 2, Additional category for effects on or via lactation |
Warning |
H361 | P308+P313 P201 P202 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)). |
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)). |
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)). |
10 | Aspiration hazard | Classification not possible |
- |
- | - | [Rationale for the Classification] Classification not possible due to lack of data. |
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 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. |
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. |
12 | Hazardous to the ozone layer | Classification not possible |
- |
- | - | This substance is not listed in the Annexes to the Montreal Protocol. |
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