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GHS Classification Result

GENERAL INFORMATION

Item	Information
CAS RN	13838-16-9
Chemical Name	2-Chloro-1,1,2-trifluoroethyl(difluoromethyl) ether (enflurane)
Substance ID	H26-B-039, -
Classification year (FY)	FY2014
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 (FY2013 revised edition)
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 applicable	- -	-	-	There are no chemical groups associated with explosive properties present in the molecule.
2	Flammable gases (including chemically unstable gases)	Not applicable	- -	-	-	Liquid (GHS definition)
3	Aerosols	Not applicable	- -	-	-	Not aerosol products.
4	Oxidizing gases	Not applicable	- -	-	-	Liquid (GHS definition)
5	Gases under pressure	Not applicable	- -	-	-	Liquid (GHS definition)
6	Flammable liquids	Not classified	- -	-	-	Not combustible (ICSC (2002)).
7	Flammable solids	Not applicable	- -	-	-	Liquid (GHS definition)
8	Self-reactive substances and mixtures	Not applicable	- -	-	-	There are no chemical groups present in the molecule associated with explosive or self-reactive properties.
9	Pyrophoric liquids	Not classified	- -	-	-	Not combustible (ICSC (2002)).
10	Pyrophoric solids	Not applicable	- -	-	-	Liquid (GHS definition)
11	Self-heating substances and mixtures	Not classified	- -	-	-	Not combustible (ICSC (2002)).
12	Substances and mixtures which, in contact with water, emit flammable gases	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 applicable	- -	-	-	The substance is an organic compound containing fluorine, chlorine, and oxygen which are chemically bonded only to carbon or hydrogen.
14	Oxidizing solids	Not applicable	- -	-	-	Liquid (GHS definition)
15	Organic peroxides	Not applicable	- -	-	-	Organic compounds containing no bivalent -O-O- structure in the molecule
16	Corrosive to metals	Classification not possible	- -	-	-	No data available.

HEALTH HAZARDS

Hazard class		Classification	Pictogram Signal word	Hazard statement (code)	Precautionary statement (code)	Rationale for the classification
1	Acute toxicity (Oral)	Not classified	- -	-	-	Based on a report of an LD50 value of 5,450 mg/kg for rats (DFGOT vol. 9 (1998)), it was classified as "Not classified."
1	Acute toxicity (Dermal)	Classification not possible	- -	-	-	Classification not possible due to lack of data.
1	Acute toxicity (Inhalation: Gases)	Not applicable	- -	-	-	Liquid (GHS definition)
1	Acute toxicity (Inhalation: Vapours)	Category 4	Warning	H332	P304+P340 P261 P271 P312	Based on a report of an LC50 value (3 hours) of 14,000 ppm for rats (converted 4-hour equivalent value: 12,100 ppm) (DFGOT vol. 9 (1998)), it was classified in Category 4. Since the LC50 value was lower than 90% of the saturated vapor concentration (230,010 ppm), the reference value in units of ppm was applied as a vapour without a mist. By correcting "Not classified" in the previous classification, it was classified in Category 4.
1	Acute toxicity (Inhalation: Dusts and mists)	Classification not possible	- -	-	-	Classification not possible due to lack of data.
2	Skin corrosion/irritation	Classification not possible	- -	-	-	Classification not possible due to lack of data. According to the revision of the GHS classification guidance for the Japanese Government, the information in List 3 was deleted and the category was changed.
3	Serious eye damage/eye irritation	Category 2	Warning	H319	P305+P351+P338 P337+P313 P264 P280	Based on a description that it was irritating to the eyes (HSDB (Access on June 2014)), it was classified in Category 2.
4	Respiratory sensitization	Classification not possible	- -	-	-	Classification not possible due to lack of data. Besides, there is a report of one person who developed allergic asthma (DFGOT vol. 9 (1998)), but it could not be determined whether the induction of symptoms was limited to people with bronchial hypersensitivity. From the above, it was judged that the data was inadequate to be used in the classification.
4	Skin sensitization	Classification not possible	- -	-	-	Classification not possible due to lack of data.
5	Germ cell mutagenicity	Classification not possible	- -	-	-	It was classified as "Classification not possible" because it was not possible to classify a substance as "Not classified" according to the revised GHS classification guidance for the Japanese government. As for in vivo, there is a description that no chromosomal aberrations in the spermatogonia were observed in a 78-week inhalation test with mice (DFGOT vol. 9 (1998)). As for in vitro, it was negative in bacterial reverse mutation tests, and a gene mutation test and a sister chromatid exchange test with cultured mammalian cells (DFGOT vol. 9 (1998)).
6	Carcinogenicity	Classification not possible	- -	-	-	Since it was classified in A4 by ACGIH (ACGIH (2010)), it was classified as "Classification not possible."
7	Reproductive toxicity	Category 2	Warning	H361	P308+P313 P201 P202 P280 P405 P501	Effects on fertility were not observed in reproductive toxicity tests with rats and mice by the inhalation route (DFGOT vol. 9. (1998)). In a teratogenicity test with rats by the inhalation route, reduced birth weights were observed at a dose (3,200 ppm) where narcotic effects were observed in maternal animals, however, no teratogenicity was observed. This test was not adopted since the effect on pups was slight. In a teratogenicity test with mice by the inhalation route, although there was no description on parental toxicity, there is a report that cleft palate and slight skeletal and visceral anomalies were observed by exposure to 10,000 mg/m3 for 4 hours/day on 6-15 days of gestation (DFGOT vol. 9 (1998)). In humans, there are reports that increases in spontaneous abortions and congenital anomalies were observed by the exposure in operating theatres, no clear relationship with exposure to this substance was identified (DFGOT vol. 9 (1998)). Besides, it is described in DFGOT vol. 9 (1998) that the reduced birth weight observed in rats was, in general, a rapidly reversible weak reproductive effect, and the cleft palate observed in mice was readily induced by exposure to many substances at high concentrations. As above, although there was no description of maternal toxicity, there is a report that cleft palates and slight skeletal and visceral anomalies were observed in the fetuses. Therefore, it was classified in Category 2 according to the GHS Classification Guidance for the Japanese Government.
8	Specific target organ toxicity - Single exposure	Category 1 (central nervous system, cardiovascular system), Category 3 (narcotic effects, respiratory tract irritation)	Danger Warning	H370 H336 H335	P308+P311 P260 P264 P270 P321 P405 P501 P304+P340 P403+P233 P261 P271 P312	This substance had been used as a pharmaceutical (inhalational anesthetic), but it is also said that twitching is also likely to be induced and it is rarely used at present. In humans, it had narcotic effects and was irritating to the respiratory tract. In addition, there is a report that it caused deterioration in reaction time and memory (DFGOT vol. 9 (1998), ACGIH (7th, 2001), HSDB (Access on June 2014)). It is reported that when this substance is used for therapeutic purposes in humans, it may cause increased locomotor activity, tremors, severe headache, dizziness, sleepiness, lightheadedness, respiratory depression, tachypnea, hypotension, tachycardia, cough, laryngospasm, acute asthma, nausea, vomiting, malignant hyperthermia, hepatotoxicity, nephrotoxicity and seizures. In addition, it is reported that arrhythmia and cyanosis with narcotic effects, and metabolic acidosis, hyperkalemia, hypokalemia, skeletal muscle rigidity and rhabdomyolysis with abnormal hyperthermia may occur (HSDB (Access on June 2014)). As for experimental animals, narcotic effects were observed in rats and mice (exposure concentration unknown) (DFGOT vol.9 (1998)、ACGIH (7th, 2001)). In addition to central nervous system depression, there is a report of depression of myocardial mechanics although the concentration was not described (ACGIH (7th, 2001)). From the above, in addition to narcotic effects and respiratory tract irritation, this substance was considered to affect the central nervous system and cardiovascular system. Therefore, it was classified in Category 1 (central nervous system, cardiovascular system), Category 3 (narcotic effects, respiratory tract irritation). Besides, although hepatotoxicity and renal toxicity were described in the findings of therapeutic uses in humans, they were not adopted for classification since it was judged that they could not be generalized due to no concrete findings. In the previous classification, SITTIG and ICSC (J) were cited, however, they were not adopted this time because they were information sources in List 3 in the GHS classification guidance for the Japanese government.
9	Specific target organ toxicity - Repeated exposure	Classification not possible	- -	-	-	Although no abnormalities were observed in liver function values or hematological parameters in operating theatre personnel at concentrations up to approximately 20 ppm in case of using this substance in the operating theatre as an anesthetic (DFGOT vol. 9 (1998)), there is a description that the effects of long-lasting exposure in humans were not clear (ACGIH (7th, 2001)). As for experimental animals, no abnormalities including those in liver function and the hemal system were observed by inhalation exposure to 200 ppm of this substance with rats for 100 days, and to 33,000 ppm with dogs and to 22,000 ppm with monkeys for 3 days/week for 4 weeks (DFGOT vol. 9 (1998)). However, it is described that in mice, liver cell degeneration and necrosis occurred, and death animals appeared by the inhalation exposure to 700 ppm for 35 days (converted guidance value as mist: 2.08 mg/L) (DFGOT vol. 9 (1998)), and some effects were observed in sensitive mice at the high concentrations corresponding to "Not classified." On the other hand, there is also a report that no general toxicological effects were observed in maternal animals even when pregnant female mice were exposed by inhalation at up to 10,000 ppm for 8 days of gestation and 68 days after delivery (DFGOT vol. 9 (1998)). From the above, in experimental animals, although no toxic effects were observed within and lower than the range of Category 2, therefore, it was considered to correspond to "Not classified," it was judged that the findings about the presence or absence of repeated exposure effects in humans were still inadequate, and it was classified as "Classification not possible." Besides, although in this classification, it was classified by adopting the information sources in List 1, no data could be obtained as the evidence in the previous classification result (Category 2 (central nervous system, liver)).
10	Aspiration hazard	Classification not possible	- -	-	-	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 (Acute)	-	- -	-	-	-
11	Hazardous to the aquatic environment (Long-term)	-	- -	-	-	-
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.

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