NITE - Chemical Management Field

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

GENERAL INFORMATION

Item	Information
CAS RN	101-68-8
Chemical Name	Methylenebis(4,1-phenylene) diisocyanate [4'4-MDI]
Substance ID	m-nite-101-68-8_v1
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.	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
2	Flammable gases	Not classified (Not applicable)	- -	-	-	Solid (GHS definition).	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
3	Aerosols	Not classified (Not applicable)	- -	-	-	Not aerosol products.	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
4	Oxidizing gases	Not classified (Not applicable)	- -	-	-	Solid (GHS definition).	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
5	Gases under pressure	Not classified (Not applicable)	- -	-	-	Solid (GHS definition).	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
6	Flammable liquids	Not classified (Not applicable)	- -	-	-	Solid (GHS definition).	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
7	Flammable solids	Classification not possible	- -	-	-	No data available.	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
8	Self-reactive substances and mixtures	Classification not possible	- -	-	-	There is a chemical group associated with self-reactive properties (cyanate ester) present in the molecule, but the classification is not possible due to no data.	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
9	Pyrophoric liquids	Not classified (Not applicable)	- -	-	-	Solid (GHS definition).	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
10	Pyrophoric solids	Not classified	- -	-	-	It is estimated that it does not ignite at normal temperatures from an autoignition temperature of 240 deg C (ICSC (1999)).	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
11	Self-heating substances and mixtures	Classification not possible	- -	-	-	Test methods applicable to solid substances are not available.	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
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).	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
13	Oxidizing liquids	Not classified (Not applicable)	- -	-	-	Solid (GHS definition).	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
14	Oxidizing solids	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.	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
15	Organic peroxides	Not classified (Not applicable)	- -	-	-	Organic compounds containing no bivalent -O-O- structure in the molecule	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
16	Corrosive to metals	Classification not possible	- -	-	-	It is solid with a melting point of 55 deg C or lower, but the classification is not possible due to no data.	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
17	Desensitized explosives	-	- -	-	-	-	-	-

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)	Not classified	- -	-	-	Based on an LD50 value of 31,600 mg/kg (CICAD 27 (2000)) for rats, it was classified as "Not classified."	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
1	Acute toxicity (Dermal)	Classification not possible	- -	-	-	Classification not possible due to lack of data.	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
1	Acute toxicity (Inhalation: Gases)	Not classified (Not applicable)	- -	-	-	Solid (GHS definition)	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
1	Acute toxicity (Inhalation: Vapours)	Not classified (Not applicable)	- -	-	-	Solid (GHS definition)	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
1	Acute toxicity (Inhalation: Dusts and mists)	Category 2	Danger	H330	P304+P340 P403+P233 P260 P271 P284 P310 P320 P405 P501	Based on reports of LC50 values (4 hours) for rats of 0.369 mg/L (male), 0.380 mg/L (female) (ACGIH (7th, 2001)), it was classified in Category 2. Besides, the reference value for dust was applied because the test substance is a solid.	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
2	Skin corrosion/irritation	Category 2	Warning	H315	P302+P352 P332+P313 P362+P364 P264 P280 P321	There is a report that this substance was irritating to human skin (EU-RAR (2005)). In addition, there are reports that this substance was irritating to rabbit skin (EU-RAR (2005), IARC 71 (1999)), and that it was slightly irritating (EU-RAR (2005)). From the above, it was classified in Category 2. Besides, this substance was classified as "Skin. Irrit. 2 H315" in EU CLP classification (ECHA CL Inventory (Access on September 2015)).	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
3	Serious eye damage/eye irritation	Category 2B	- Warning	H320	P305+P351+P338 P337+P313 P264	There are reports in eye irritation tests with rabbits that slight irritation was observed (EU-RAR (2005)), and that it was not irritating (EU-RAR (2005)). From the above, it was classified in Category 2B. Besides, this substance was classified as "Eye. Irrit. 2 H319" in EU CLP classification (ECHA CL Inventory (Access on September 2015)).	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
4	Respiratory sensitization	Category 1	Danger	H334	P304+P340 P342+P311 P261 P284 P501	There is a report that this substance causes asthma in humans (IARC 71 (1999)), and there is a description that this substance causes respiratory tract sensitization in humans and animals (ECETOC TR 77 (1999)). In addition, Japan Society For Occupational Health (JSOH) classified it in occupational sensitizers to the airway Group 1 (Recommendation of Occupational Exposure Limits (2015)), and DFG as Sah (DFGOT Vol. 14 (2000)). From the above, it was classified in Category 1. Besides, this substance was classified as "Resp. Sens. 1 H334" in EU CLP classification (ECHA CL Inventory (Access on September 2015)).	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
4	Skin sensitization	Category 1	Warning	H317	P302+P352 P333+P313 P362+P364 P261 P272 P280 P321 P501	There is a report that in a maximization test with guinea pigs, as a result of an application of this substance (95%), sensitization was observed (EU-RAR (2005)). In addition, there is a report that in a patch test in humans, sensitization was shown by an application of this substance (EU-RAR (2005)). It is concluded in EU-RAR (2005) that this substance is a skin sensitizer (EU-RAR (2005)). From the above, it was classified in Category 1. Besides, this substance was classified as "Skin sens. 1 H317" in EU CLP classification (ECHA CL Inventory (Access on September 2015)).	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
5	Germ cell mutagenicity	Classification not possible	- -	-	-	The substance 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, a micronucleus test with mice was negative (DFGOT Vol. 8 (1997)). As for in vitro, bacterial reverse mutation tests gave positive and negative results, a mouse lymphoma test with mammalian cultured cells was positive, a chromosomal aberration test and a sister chromatid exchange test with human cultured lymphocytes were positive and negative, and a micronucleus test with cultured human lymphocytes was negative (CICAD 27 (2000), ACGIH (7th, 2001), OEL Documentations (Japan Society For Occupational Health (JSOH), 1993), DFGOT vol. 8 (1997), IARC 71 (1999), NTP DB (Access on October 2015)).	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
6	Carcinogenicity	Classification not possible	- -	-	-	As for humans, International Agency for Research on Cancer (IARC) evaluated three cohort studies and one case-control study on the carcinogenic risks associated with occupational exposures to isocyanates. As a result, neither a strong association nor consistent pattern was shown for the carcinogenic risk in any of the sites investigated, and it was concluded that there was inadequate evidence of carcinogenicity in humans for both the monomer and the polymer (PMDI) of this substance (IARC 71 (1999)). As for experimental animals, there is a description that as a result of 2-year inhalation exposure to this substance (4,4'-MDI) in rats, at the high dose (2.05 mg/m3), a bronchiolar/alveolar adenoma was found in one animal (CICAD 27 (2000), IRIS Summary (Access on August 2015)), in addition, proliferation of the alveolar epithelium considered to be a preneoplastic lesion was observed (IRIS Summary (Access on August 2015)). In addition, there is a description that as a result of 2-year inhalation exposure to the polymer of this substance (PMDI) in rats, pulmonary adenomas were observed in males (6/60) and females (2/59) at the high dose (6.03 mg/m3) (CICAD 27 (2000), IRIS Summary (Access on August 2015)). IARC used only the latter polymer data for evaluation, and it was concluded that there is limited evidence for carcinogenicity of a mixture containing this substance and the polymer of this substance in experimental animals (IARC 71 (1999)). As for classification results by other organizations, IARC, as mentioned above, classified it in Group 3 in 1999 due to insufficient evidence in humans and limited evidence in experimental animals (IARC 27 (1999)), and US EPA classified MDI and MDI polymers (PMDI) as "CBD (cannot be determined)" in 1998. On the other hand, EU conducted a risk assessment of a mixture of isomers of this substance (MDI), and it was concluded just as IARC, that the evidence for carcinogenicity in humans was insufficient, and the evidence for carcinogenicity in experimental animals was limited. Nevertheless, it is described in the section on the classification in the evaluation document that the CMR working group proposed Carc. Cat. 3 (EU-RAR (2005)). Currently it corresponds to Carc. 2 in CLP classification, but evidence for classification was unknown from available documents. From the above, it is not appropriate to adopt Category 2 because the evidence for the classification in EU is unknown. According to the GHS classification guidance for the Japanese government which was revised after the classification, based on the previous classification results by IARC and EPA, it was classified as "Classification not possible" for this hazard class.	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
7	Reproductive toxicity	Classification not possible	- -	-	-	There is no information on reproductive effects in humans. As for experimental animals, in a developmental toxicity test in which pregnant rats were exposed by inhalation to this substance (4,4'-MDI) during the organogenesis period (gestational days 6-15), at the high dose group (9 mg/m3), increases in absolute and relative weight of the lung in maternal animals, and a slight increase in asymmetric sternebrae in fetuses were observed (CICAD 27 (2000), IRIS Tox Review (1998), EU-RAR (2005)). From the result of this test, because merely a skeletal variation was observed in the fetuses at the dose where adverse effects were observed in the maternal animals, it is not appropriate to classify in Category due to minor developmental effects. Other than this, there is no test result for evaluating the effects on sexual function and fertility and developmental effects of this substance. Therefore, classification was not possible due to lack of data for this hazard class. Besides, for the polymer of isomeric mixture of this substance (PMDI), there are two reports of developmental toxicity tests with pregnant rats (Wistar) exposed by inhalation during the organogenesis period (gestational days 6-15). In one report, it is reported that no abnormality was observed in the fetuses at 12 mg/m3 where maternal toxicity (decreased food consumption, increased lung weight) was observed (CICAD 27 (2000), EU-RAR (2005)). In the other report, it is reported that a low value of body weight, an increase in frequency of skeletal variations, and retarded ossification were observed in the fetuses at 12 mg/m3 where deaths (2/25) and decreased placenta weight were observed in maternal animals (CICAD 27 (2000), IRIS Tox Review (1998), EU-RAR (2005)).	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
8	Specific target organ toxicity - Single exposure	Category 1 (respiratory organs)	Danger	H370	P308+P311 P260 P264 P270 P321 P405 P501	This substance is irritating to the respiratory tract (DFGOT Vol. 8 (1997), IARC 71 (1999)). As for experimental animals, a decreased respiratory rate and an increased respiratory volume in an inhalation exposure (doses corresponding to Category 1) in guinea pigs, and in an inhalation exposure (doses corresponding to Category 1) in rats, at autopsy just after exposure, hemorrhage and oedema in the lungs were observed (CICAD 27 (2000)). From the above, this substance was classified in Category 1 (respiratory organs) because it has effects on the respiratory organs.	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
9	Specific target organ toxicity - Repeated exposure	Category 1 (respiratory organs)	Danger	H372	P260 P264 P270 P314 P501	There is a description that in research on 18 workers at a timber product plant using heated MDI, lower respiratory tract symptoms were observed, and later, after the symptom onset time was corrected for confounding factors, it was shown that they were occupational asthma and developed due to exposure to the vapor from heating this substance over 2.5 years or longer. The causative agent of sensitization by MDI is assumed to be either reaction products of the vapour and polymers of MDI, MDI alone, or a mixture of MDI and the reactive products (CICAD 27 (2000)). In addition, it is reported that as a result of necropsy of a foundry worker who was diagnosed with asthma induced by this substance five years before the death, and continued exposure to this substance, morphological changes such as epithelial desquamation, eosinophilic and neutrophilic infiltration, oedema, and dilatation of the bronchial vessels were observed in the lung (CICAD 27 (2000)). As for experimental animals, there is a description that in a 2-year test in which female rats were exposed by inhalation to this substance (purity 99.5%), increased lung weight, focal or multifocal alveolar/bronchiolar epithelial hyperplasia, interstitial fibrosis, an accumulation of particle-laden macrophages, and decreased pulmonary function were observed at doses within the range of Category 1 (0.23-2.05 mg/m3: (converted guidance value: 0.00047-0.0041 mg/L/6 hr/day)) (CICAD 27 (2000)). In addition, there are the following descriptions on a study in which rats were exposed by inhalation to PMDI containing 52% MDI monomer and 30% isocyanate for 13 weeks or 2 years: in the 13-week test, atrophy and degeneration of nasal cavity tissues, and an accumulation of macrophages in the lungs and mediastinal lymph nodes were observed at 4.1-12.3 mg/m3 corresponding to Category 1, and at high concentrations, severe respiratory symptoms occurred, and 25% (15/60) of animals died (CICAD 27 (2000), DFGOT Vol. 8 (1997)); and in the 2-year exposure, at or above 0.98 mg/m3, the effects were seen only in the respiratory organs, and findings were observed in the nasal cavity (degeneration of the olfactory epithelia, hyperplasia of the basal cells), lung (fibrosis, interstitial pneumonitis), and mediastinal lymph nodes (CICAD 27 (2000), DFGOT Vol. 8 (1997)). From the above, it was classified in Category 1 (respiratory organs).	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
10	Aspiration hazard	Classification not possible	- -	-	-	Classification not possible due to lack of data. Besides, the kinematic viscosity of this substance is calculated to be 3.547 mm2/sec (50/20 deg C) from the numerical data (viscosity: 4.7 mPa*s (50 deg C), density (specific gravity): 1.325 (20 deg C)) listed on EU-RAR (2005).	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))

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)	Classification not possible	- -	-	-	No data available.	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
11	Hazardous to the aquatic environment Long term (Chronic)	Classification not possible	- -	-	-	No data available.	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))
12	Hazardous to the ozone layer	Classification not possible	- -	-	-	No data available.	FY2015	GHS Classification Guidance for the Japanese Government (FY2013 revised edition (Ver. 1.1))

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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