GHS Classification Result
GENERAL INFORMATION
REFERENCE INFORMATION
PHYSICAL HAZARDS
HEALTH HAZARDS
ENVIRONMENTAL HAZARDS
NOTE:
GENERAL INFORMATION
| Item | Information |
|---|---|
| CAS RN | 101-77-9 |
| Chemical Name | 4,4'-Methylenedianiline |
| Substance ID | H29-B-113 |
| Classification year (FY) | FY2017 |
| 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 | 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 (FY2013 revised edition (Ver. 1.1)) |
| UN GHS document (External link) | UN GHS document |
| Definitions/Abbreviations (Excel file) | Definitions/Abbreviations |
| Model Label by MHLW (External link) | |
| 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 applicable |
- |
- | - | There are no chemical groups associated with explosive properties present in the molecule. |
| 2 | Flammable gases (including chemically unstable gases) | Not applicable |
- |
- | - | Solid (GHS definition). |
| 3 | Aerosols | Not applicable |
- |
- | - | Not aerosol products. |
| 4 | Oxidizing gases | Not applicable |
- |
- | - | Solid (GHS definition). |
| 5 | Gases under pressure | Not applicable |
- |
- | - | Solid (GHS definition). |
| 6 | Flammable liquids | Not applicable |
- |
- | - | Solid (GHS definition). |
| 7 | Flammable solids | Classification not possible |
- |
- | - | There is the information that it is combustible (ICSC (J) (2013)), but the classification is not possible due to no data. |
| 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 applicable |
- |
- | - | Solid (GHS definition). |
| 10 | Pyrophoric solids | Not classified |
- |
- | - | It is estimated that it does not ignite at normal temperatures from an autoignition temperature of > 500 deg C (GESTIS (Access on August 2017)). |
| 11 | Self-heating substances and mixtures | Classification not possible |
- |
- | - | Test methods applicable to solid (melting point <= 140 deg C) substances are not available. |
| 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 |
- |
- | - | Solid (GHS definition). |
| 14 | Oxidizing solids | Not applicable |
- |
- | - | Organic compounds containing no oxygen, fluorine or chlorine |
| 15 | Organic peroxides | Not applicable |
- |
- | - | Organic compounds containing no bivalent -O-O- structure in the molecule |
| 16 | Corrosive to metals | Classification not possible |
- |
- | - | Test methods applicable to solid substances are not available. |
| Hazard class | Classification |
Pictogram Signal word |
Hazard statement (code) |
Precautionary statement (code) |
Rationale for the classification | |
|---|---|---|---|---|---|---|
| 1 | Acute toxicity (Oral) | Category 4 |
 Warning |
H302 |
P301+P312
P264 P270 P330 P501 |
Based on reports of LD50 values for rats of 335 mg/kg (ATSDR (1998)), 355 mg/kg, 475 mg/kg, 547 mg/kg (DFGOT vol. 7 (1996)), 830 mg/kg (DFGOT vol. 7 (1996), ATSDR (1998)), it was classified in Category 4. |
| 1 | Acute toxicity (Dermal) | Category 3 |
 Danger |
H311 |
P302+P352
P361+P364 P280 P312 P321 P405 P501 |
Based on a report of an LD50 value of 1,000 mg/kg for rats (EU-RAR (2001), SIDS (2002)), it was classified in Category 3. |
| 1 | Acute toxicity (Inhalation: Gases) | Not applicable |
- |
- | - | Solid (GHS definition) |
| 1 | Acute toxicity (Inhalation: Vapours) | Not applicable |
- |
- | - | Solid (GHS definition) |
| 1 | Acute toxicity (Inhalation: Dusts and mists) | Classification not possible |
- |
- | - | Classification not possible due to lack of data. Besides, there is a report that in a 4-hour inhalation with rats exposed to the particles of this substance, no case of death was observed at 0.837 mg/L corresponding to Category 3 (EU-RAR (2001), SIDS (2002)). |
| 2 | Skin corrosion/irritation | Not classified |
- |
- | - | There is a description that in a skin irritation test with rabbits, slight erythema was observed although the application time is unknown, and this substance causes slight irritation of the skin (SIDS (2002)). Therefore, it was classified as "Not Classified" (Category 3 of UN GHS classification) corresponding to slight irritation in the GHS classification guidance for the Japanese government. |
| 3 | Serious eye damage/eye irritation | Category 2 |
Warning |
H319 |
P305+P351+P338
P337+P313 P264 P280 |
There is a description that in an eye irritation test with rabbits, mild irritation was observed but resolved within 3-7 days after application (SIDS (2002)), and it was concluded in SIDS (2002) that it causes mild to moderate irritation. Therefore, it was classified in Category 2. |
| 4 | Respiratory sensitization | Classification not possible |
- |
- | - | Classification not possible due to lack of data. |
| 4 | Skin sensitization | Category 1 |
Warning |
H317 |
P302+P352
P333+P313 P362+P364 P261 P272 P280 P321 P501 |
4,4'-Methylenedianiline (MDA) was classified in occupational skin sensitizers Group 1 by Japan Society For Occupational Health (JSOH) (Recommendation of Occupational Exposure Limits (2017)). There is a case report that among workers in a polyurethane molding factory handling this substance as a hardening agent for the polymers, eruption was seen in the body part not covered by clothes (face, neck, forearm) 1-3 weeks after the job started and the patch test for this material (1% solution) showed a strong positive, but dermatitis ceased to occur with hygiene engineering improvement (working under a hood, wearing of protection equipment, changing contaminated clothes). Other than this, there are multiple case reports which indicate sensitization potential of this substance (OEL Documentations (Japan Society For Occupational Health (JSOH), 1995), SIDS (2002), Initial Risk Assessment Report (NITE, CERI, NEDO, 2007)). Therefore, it was classified in Category 1. |
| 5 | Germ cell mutagenicity | Category 2 |
 Warning |
H341 |
P308+P313
P201 P202 P280 P405 P501 |
As for in vivo, micronucleus tests with bone marrow cells or peripheral blood of mice, a chromosomal aberration test with mouse bone marrow cells, a sister chromatid exchange test, a DNA damage test with liver cells in rats were positive, unscheduled DNA synthesis tests with the liver cells of rats or mice were negative (Initial Risk Assessment Report (NITE, CERI, NEDO, 2007), ACGIH (7th, 2001), ATSDR (1998), DFGOT vol. 7 (1996), EU-RAR (2001), Environmental Risk Assessment for Chemical Substances Vol.10 (Ministry of the Environment, 2012), NTP DB (Access on September 2017)). As for in vitro, a bacterial reverse mutation test, and a mouse lymphoma assay, a chromosomal aberration test and a sister chromatid exchange test with cultured mammalian cells, were positive (Initial Risk Assessment Report (NITE, CERI, NEDO, 2007), ATSDR (1998), EU-RAR (2001), OEL Documentations (Japan Society For Occupational Health (JSOH), 1995), ACGIH (7th, 2001), DFGOT vol. 7 (1996), NTP DB (Access on September 2017)). From the above, it was classified in Category 2 according to the GHS classification guidance for the Japanese government. |
| 6 | Carcinogenicity | Category 1B |
Danger |
H350 |
P308+P313
P201 P202 P280 P405 P501 |
In carcinogenicity tests with rats or mice dosed with the dihydrochloride of this substance (CAS RN 13552-44-8) by drinking water (concentrations: 150, 300 ppm) for 2 years, as for rats, increased incidence of neoplastic nodules in the liver, thyroid follicular cell carcinoma and pheochromocytoma of adrenal glands in males, increased incidence of thyroid follicular cell carcinoma and a dose-dependent increase of C-cell adenoma in females were observed. As for mice, increased incidence of hepatocellular carcinoma in females and males, thyroid follicular cell carcinoma in males, malignant lymphoma in females, and a dose-dependent increase of hepatocellular adenoma in females were observed (NTP TR248 (1983), IARC 39 (1986), ACGIH (7th, 2001), SIDS (2002)). Other than this, there are reports that in a test where rats were dosed by gavage with 20 mg/rat of this substance for 8 months and observed for a lifetime, hepatoma and a hemangioma-like tumors of the kidneys were observed after 18 months in a male rat (1/8), and adenocarcinoma of the uterus was observed after 24 months in a female rat (1/8) and so on (IARC 39 (1986), ACGIH (7th, 2001)). IARC classified this substance in Group 2B as there is sufficient evidence for carcinogenicity in experimental animals (IARC 39 (1986), IARC Suppl. 7 (1987)). On the other hand, EU considered that association with the oral dose of this substance and the incidence of tumors in the thyroid or liver was shown in the long-term experiments with rats or mice, it regarded that there is a concern about carcinogenicity of this substance in humans from animal studies, and classified it in Category 2 (SIDS (2002)). This EU classification is the previous DSD classification, corresponding to Carc. 1B in the present CLP classification (ECHA CL Inventory (Access on August 2017)). Other than this, NTP classified it in R (NTP RoC (14th, 2016)), ACGIH classified it in A3 (ACGIH (7th, 2001)) and Japan Society For Occupational Health (JSOH) classified it in Group 2B (Recommendation of Occupational Exposure Limits (2017): proposed in 1995), respectively. From the above, it was classified in Category 1B for this hazard class based on the fact that the multiple organs carcinogenesis including malignant tumors was observed in two species of experimental animals and the classification result of EU. Besides, category was changed from that of the previous classification. |
| 7 | Reproductive toxicity | Classification not possible |
- |
- | - | Classification not possible due to lack of data. Besides, there is a description that as a result of administration of the hydrochloride of this substance to pregnant rats (n= 5 or 10) by gavage at 300 mg/kg/day during gestation day 7-20 or at 50 mg/kg during gestation day 14-20, a maternal animal (1/5) delivered abiotrophic and abnormal pups in the former (there is no description of maternal toxicity), and abnormal findings in the liver in both maternal and fetal animals (proliferation in the bile ducts and in the periportal region in maternal animals, fatty infiltration of the liver parenchyma in fetal animals) were observed in the latter, but including this test, there are no tests which meet the current requirements for a teratogenicity test (DFGOT vol. 7 (1996)). In the previous classification, it was classified in Category 2 by using this data, but this was judged inadequate to use for classification. |
| 8 | Specific target organ toxicity - Single exposure | Category 1 (central nervous system, liver, kidney, heart, visual organs) |
Danger |
H370 |
P308+P311
P260 P264 P270 P321 P405 P501 |
In humans, intoxification cases of 84 people who ate bread made from flour contaminated with this substance were reported. It was reported that as symptoms, right upper abdominal pains, jaundice, fever, liver enlargement, and an increase in liver enzyme activity were observed, and as for liver biopsy, inflammation of the portal zone and cholestasis were found (Initial Risk Assessment Report (NITE, CERI, NEDO, 2007), DFGOT vol. 7 (1996), ATSDR (1998), EU-RAR (2001), SIDS (2002)). In addition, there is a report that 5 men and a woman who drank an alcoholic beverage spiked with this substance showed colicky abdominal pain, jaundice, increases in blood bilirubin and liver enzyme activity indicating cholestasis, fever, pain of muscle and joints, and one man among them developed proteinuria and hematuria (Initial Risk Assessment Report (NITE, CERI, NEDO, 2007), ATSDR (1998), EU-RAR (2001), SIDS (2002)). In addition, one case is reported that in a man accidentally drinking a solution containing this substance (unknown quantity), potassium carbonate and butyrolactone, jaundice, elevated serum aminotransferase and bilirubin levels, hematuria, glycosuria, myocardial effects (ECG changes, bradycardia, hypotension), and retinal damage in the eyes were observed (Initial Risk Assessment Report (NITE, CERI, NEDO, 2007), SIDS (2002), EU-RAR (2001), ATSDR (1998), DFGOT vol. 7 (1996)). Furthermore, there is a report that in a factory handling this substance, a man exposed to dust containing this substance by oral, dermal, and inhalation due to an air filter malfunction, had severe upper abdominal pain, eruption in upper arms, jaundice, and ECG abnormality which is considered to indicate myocardial lesions on the next morning (Initial Risk Assessment Report (NITE, CERI, NEDO, 2007), SIDS (2002), EU-RAR (2001), ATSDR (1998), DFGOT vol. 7 (1996)). As for experimental animals, there are reports that in a single oral dose test with rats, at 100 mg/kg, hepatocellular necrosis with bleeding and moderate neutrophilic infiltration was observed and that the most remarkable effects at 100 mg/kg or more were lesions in the liver and kidney (EU-RAR (2001), SIDS (2002)). In addition, as for cats, there is a report that a single oral dose at 25-100 mg/kg caused blindness due to retinal atrophy (EU-RAR (2001), SIDS (2002)). As for dermal route, there is a report in a single dermal exposure to rats at 1,000 mg/kg, indifference, chromodacryorrhea, and jaundice were observed, and 5 of 10 rats died within 7 days (EU-RAR (2001), SIDS (2002)). As for the inhalation route, there is a report in a 4-hour single inhalation test with rats exposed to dust of this substance at 0.837 mg/L, exophthalmos, tremors, curved hunched body position, and ruffled fur were observed, but there was no death, and they recovered within 2 days (SIDS (2002)). All the above doses which caused effects on experimental animals correspond to Category 1. From the above information, it is considered that this substance causes effects on the central nervous system, liver, kidney, heart and visual organs. Visual organs were adopted for the target organs because atrophy of the retina was also observed in experimental animals although there is only one case in which damage of the retina was observed in humans. Therefore, it was classified in Category 1 (central nervous system, liver, kidney, heart, visual organs). |
| 9 | Specific target organ toxicity - Repeated exposure | Category 1 (heart, liver, kidney), Category 2 (haemal system) |
Danger Warning |
H372
H373 |
P260
P264 P270 P314 P501 |
As for humans, 12 male workers handling this substance developed acute hepatitis with main symptoms of upper abdominal pain, fever, chills, and jaundice, for which the main exposure route was considered to be dermal absorption, 1-2 weeks after starting the work, and all 12 recovered within 7 weeks. In addition, there is the following report: acute hepatitis was caused in 6 out of 300 workers who engaged in work of mixing the powders containing this substance with liquid epoxy resin and applying the mixture to the wall with a spray gun or by hand; the onset was within 2 days to 2 weeks after starting the work for all of them; and it was considered that there were exposures by all through the inhalation, oral, dermal routes in this operation (Environmental Risk Assessment for Chemical Substances Vol.10 (Ministry of the Environment, 2012)). Also, although they are acute effects, it is reported that by exposure by oral, dermal and inhalation, spot, eruption in both arms, jaundice and electrocardiogram abnormality indicating cardiac muscle lesion were observed the next morning after exposure, and the electrocardiogram became normal again one year later (Environmental Risk Assessment for Chemical Substances Vol.10 (Ministry of the Environment, 2012), Initial Risk Assessment Report (NITE, CERI, NEDO, 2007)). As for experimental animals, in a 13-week test with rats dosed by drinking water, at or above 400 ppm (male: 25.7 mg/kg/day, female: 20.4 mg/kg/day) within the guidance value range for Category 2, decreased weight gain, bile duct hyperplasia, thyroid follicle epithelium cell hyperplasia were observed, and at 800 ppm (male: 38.7 mg/kg/day, female: 44.4 mg/kg/day) hypertrophy of pituitary basophilic cells in the brain was observed. In a 3-month test with rats dosed by drinking water, at or above 80 ppm (male: 7.5 mg/kg/day, female: 8 mg/kg/day) within the guidance value range for Category 1, kidney calcification and thyroid follicular cell degeneration were observed, at or above 400 ppm (male: 23 mg/kg/day, female: 22 mg/kg/day) within the guidance value range for Category 2, decreased weight gain, anemia, increased levels of serum alkaline phosphatase, ALT, AST, urea nitrogen, bile pigment, cholesterol, and focal and nodular hyperplasia of the thyroid follicle epithelium cells were observed, and at 800 ppm (male: 31 mg/kg/day, female: 32 mg/kg/day), leukocytosis, neutrophilic increase, prothrombin time extension, hyperplasia of the liver small bile duct, and hypertrophy of the thyroid follicle epithelium cells were observed. In a 103-week test with rats dosed by drinking water, at or above 150 ppm (male: 9 mg/kg/day, female: 10 mg/kg/day) within the guidance value range for Category 1, fatty liver, cysts and hyperplasia of the thyroid follicle epithelium cells were observed, and at 300 ppm (male: 16 mg/kg/day, female: 19 mg/kg/day) within the guidance value range for Category 2, mineralization in the kidney (male) was observed (Initial Risk Assessment Report (NITE, CERI, NEDO, 2007)). Other than these, there is a report that in a test in which guinea pigs were exposed to the aerosol at 440 mg/m3 in the nose for 2 weeks (4 hours/day, 5 days/week) and were challenged on the skin or trachea 2 weeks later, no irritative or allergic response to the skin or respiratory organs was observed, but a degenerative change to the visual cells and retinal pigment epithelium cells in the eyes and slight granulomatous inflammation in the lung were observed (OEL Documentations (Japan Society For Occupational Health (JSOH), 1995), Environmental Risk Assessment for Chemical Substances Vol.10 (Ministry of the Environment, 2012)). From the above, acute hepatitis was mainly observed in humans, and the substance is considered to also affect the heart. As for experimental animals, effects on the thyroid, liver and kidney within the guidance value range for Category 1 and effects on the blood, and pituitary gland in the brain within the range of the guidance value of Category 2 were observed. Also, it may affect the eyes or respiratory organs. Among these, hypertrophy of the pituitary basophilic cells was considered to indicate increased production of thyroid stimulating hormone, and the finding on the thyroid gland was considered to be a secondary finding for hypermetabolism by the liver. In addition, as for the test with guinea pigs, in which effects on the eye or respiratory organs were observed, it is not possible to convert to the guidance value because the exposure time was as short as 10 times, and the dermal dose or inhalation exposure was done for the challenge after repeated exposures, therefore, it was not adopted as evidence of the classification. Accordingly, it was classified in Category 1 (heart, liver, kidney), Category 2 (haemal system). Besides, the classification result was different from the previous one since a new information source was used and effects on the thyroid were regarded as secondary effects. |
| 10 | Aspiration hazard | Classification not possible |
- |
- | - | 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 (Acute) | Category 1 |
 Warning |
H400 |
P273
P391 P501 |
From 48-hour EC50 = 0.105 mg/L for crustacea (Daphnia magna) (Initial Risk Assessment (NITE, CERI, NEDO, 2007)), it was classified in Category 1. |
| 11 | Hazardous to the aquatic environment (Long-term) | Category 1 |
Warning |
H410 |
P273
P391 P501 |
If chronic toxicity data are used, then it is classified in Category 1 due to being not rapidly degradable (non-biodegradable, a degradation rate by BOD: 0% (J-CHECK, 1982)), and 21-day NOEC (reproduction inhibition) = 0.00525 mg/L for crustacea (Daphnia magna) (Environmental Risk Assessment for Chemical Substances vol. 10 (Ministry of the Environment, 2012), Initial Risk Assessment (NITE, CERI, NEDO, 2007)). If acute toxicity data are used for a trophic level for which chronic toxicity data are not obtained, then it is classified in Category 3 due to being not rapidly degradable (non-biodegradable, a degradation rate by BOD: 0% (J-CHECK, 1982)), and 96-hour LC50 = 20.6 mg/L for fish (Oryzias latipes) (Environmental Risk Assessment for Chemical Substances vol. 10 (Ministry of the Environment, 2012)). From the above results, it was classified in Category 1. |
| 12 | Hazardous to the ozone layer | Classification not possible |
- |
- | - | No data available. |
NOTE:
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* A blank or "-" in a cell of classification denotes that the classification of the hazard class was not conducted. * Hazard_statement_and/or_Precautionary_statement will show when hovering the mouse over a code of Hazard_statement_and/or_Precautionary_statement. Hazard_statement_and/or_Precautionary_statement are also provided in the Excel file. * Classification was conducted by relevant Japanese Ministries in accordance with GHS Classification Guidance for the Japanese Government, and is intended to provide a reference for preparing GHS labelling and SDS for users. * This is a provisional English translation of classification results and is subject to revision without notice. * The responsibility for any resulting GHS labelling and SDS referenced from this site is with users. * Codes assigned to each of the hazard statements and codes for each of the precautionary statement are based on the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) in United Nations. |