Hazardous substance assessment – 4,4’-Methylenediphenyl diisocyanate

Identification

Chemical name:

4,4'-Methylenediphenyl diisocyanate (4,4'-MDI)

CAS #:

101-68-8

Chemical composition:

C₁₅H₁₀N₂O₂

Synonyms:

1,1'-Methylenebis(4-isocyanatobenzene); 4,4'-Diphenylmethane diisocyanate; Methylenebis(phenylisocyanate); Benzene, 1,1'-methylenebis[4-isocyanato-; Methylene diphenyl diisocyanate (MDI); Bis(1,4-isocyanatophenyl)methane; Di-(4-isocyanatophenyl)methane.

UN #:

Not available

Pictogram(s):

Figure 1 - Text description

The symbol within the pictogram is a human skull with two crossed bones behind it. The symbol indicates that hazardous products with this pictogram can cause death or poisoning.

Figure 2- Text description

The symbol within the pictogram is an exclamation mark. This symbol indicates that hazardous products with this pictogram can cause certain health effects for example:

• skin irritation
• eye irritation
• skin sensitization

Figure 3 - Text description

The symbol within the pictogram is a black silhouette of a person's head and chest with a white star shape spreading out from the center of the chest. This symbol indicates that hazardous products with this pictogram can cause certain health effects for example:

• carcinogenicity
• specific target organ effects following single or repeated exposure
• reproductive toxicity

WHMIS classification

Health hazards:

Acute Toxicity (Inhalation) – Category 2

Eye Irritation – Category 2

Respiratory Sensitizer – Category 1

Skin Sensitizer – Category 1A

Specific Target Organ Toxicity – Repeated Exposure – Category 2

Physical hazards:

4,4'-MDI does not meet the criteria for classification.

Health hazards

Acute Toxicity (Oral):

Does not meet criteria

Median lethal dose (LD₅₀): 9,200 mg/kg (rat) ^{Footnote 1}.

In an acute oral toxicity study, 4,4'-MDI in dimethyl sulfoxide (DMSO) was administered by gavage to fasted rats (6 per dose; sex not specified) at doses of 2,000, 4,000, 8,000 or 16,000 mg/kg. The animals were then observed for 14 days. Signs of toxicity were noted at doses of 4,000 mg/kg and higher and included arching, hyporeflexia, lethargy and hypothermy ^{Footnote 1}.

The available data do not meet the classification criteria for Acute Toxicity (Oral).

Acute Toxicity (Dermal):

Does not meet criteria

LD₅₀: >2,000 mg/kg (rabbit)^{Footnote 1}.

There were no deaths or signs of intoxication after the occlusive administration of 2,000 mg/kg 4,4'-MDI to the shaved skin of 3 rabbits (sex not specified). After 24 hours, the occlusive wrap was removed and the excess material wiped off ^{Footnote 1}.

The available data do not meet the classification criteria for Acute Toxicity (Dermal).

Acute Toxicity (Inhalation – Gases):

Not applicable

4,4'-MDI is not a gas. The classification criteria for Acute Toxicity (Inhalation – Gases) do not apply to this substance.

Acute Toxicity (Inhalation – Vapours):

Does not meet criteria

No mortality occurred at the saturated vapour concentration of 4,4'-MDI; 5 of 6 rats showed respiratory distress in the form of rales which disappeared by 12 hours post exposure. All rats were alive and healthy at the end of the observation period of 14 days. No microscopic changes were observed at necropsy ^{Footnote 1}.

The available data do not meet the classification criteria for Acute Toxicity (Inhalation-Vapours).

Acute Toxicity (Inhalation – Dusts and Mists):

Category 2

Median lethal concentration (LC₅₀): 0.368 mg/L (male rat, 4 hours) ^{Footnote 2}.

In an Organisation for Economic Co-operation and Development Test Guideline (OECD TG) 403 study, rats (5 per sex per group) were exposed to a liquid aerosol of 4,4'-MDI at a concentration of 300.0, 354.2, 399.2, 500.0 or 553.8 mg/m³. Mortality occurred in a concentration-dependent manner at 354.2 mg/m³ and above. Male rats appeared to be more susceptible than female rats. The LC₅₀ was 0.368 mg/L (male rats) ^{Footnote 2}.

The available data for mists of 4,4'-MDI meet the classification criteria for Acute Toxicity (Inhalation) – Category 2 [HPR 8.1.1(1)].

Skin Corrosion / Irritation:

Does not meet criteria

In an OECD TG 404 study, 4,4'-MDI tested negative for skin irritation ^{Footnote 2}. The mean score (24, 48, 72 hours) was 0.61/4 for edema. The scoring for erythema could not be obtained due to colouration of the skin with the test substance. In a Draize study, 0.5 mL of 4,4'-MDI was applied to intact and abraded skin of 6 rabbits under semi-occlusive conditions for 24 hours. The combined primary irritation score was 0.47. Skin exposure did not result in skin irritation ^{Footnote 1}.

The available data do not meet the classification criteria for Skin Corrosion / Irritation.

Serious Eye Damage / Eye Irritation:

Category 2

In a well-conducted study equivalent in design to OECD TG 405, application of 100 mg of 4,4'-MDI to 6 rabbit eyes resulted in eye irritation ^{Footnote 1}. The mean scores (24, 48 and 72 hours) were 2.5/3 for conjunctival redness, 2.4/4 for chemosis, and 1/2 for iritis, meeting the classification criteria for Category 2. Since no observations were made after 72 hours, reversibility could not be determined for sub-categorization.

The available data meet the classification criteria for Eye Irritation – Category 2 [HPR 8.3.2(3)].

Respiratory Sensitization:

Category 1

Many human case studies are available demonstrating respiratory sensitization consistent with a high degree of proportionality amongst multiple responders ^{Footnote 3Footnote 4Footnote 5Footnote 6Footnote 7Footnote 8}. Specifically, an inhalation challenge test found that 21/59 of workers exposed to 4,4'-MDI experienced positive asthmatic and acute allergic alveolitis reactions ^{Footnote 4}. In another inhalation challenge test, 8 human subjects who were also workers at a plant using 4,4'-MDI were exposed to 4,4'-MDI resin for 4 - 120 minutes daily ^{Footnote 7}. A significant drop in the forced expiratory volume in the first second and in the forced vital capacity was seen in all 8 participants. Other studies in humans have demonstrated that 4,4'-MDI exposure can cause respiratory allergies in those who have been occupationally exposed to 4,4'-MDI ^{Footnote 6}. The study of the association between these allergic responses and Immunoglobulin E (IgE) production has seen mixed results. In some studies, there are people who experience an allergic response but see no changes in IgE levels. In others exposed to 4,4'-MDI but who do not experience any allergy symptoms, IgE production has been detected ^{Footnote 6}. Based on human data, 4,4'-MDI meets the classification criteria for Category 1 of HPR 8.4.1(1). Insufficient study details are available to sub-classify.

Animals: 4,4'-MDI failed to produce airway resistance in guinea pigs following challenge at lower concentrations; only a slight tracheobronchitis was observed ^{Footnote 9}.

The available data meet the classification criteria for Respiratory Sensitizer – Category 1 [HPR 8.4.1(1)].

Skin Sensitization:

Category 1A

There are several case reports of 4,4'-MDI-mediated contact dermatitis in humans ^{Footnote 10Footnote 11Footnote 12}. Positive results were also obtained in mouse local lymph node assays (LLNA), with stimulation indices (SI) of 16.88 and 27.04 reported when exposed to 1% 4,4'-MDI ^{Footnote 13Footnote 14}. The estimated concentration needed to produce an SI of 3 (EC3) was < 2% in these studies, meeting classification criteria for Category 1A.

The available data meet the classification criteria for Skin Sensitizer – Category 1A [HPR 8.4.1(4)].

Germ Cell Mutagenicity:

Does not meet criteria

In vivo: Negative results were obtained in mammalian erythrocyte micronucleus tests, in accordance with OECD TG 474, in rats ^{Footnote 2} and in mice ^{Footnote 15} when exposed to 4,4'-MDI aerosols.

In vitro: Negative results were obtained in bacterial cells, Salmonella (S.) typhimurium strains TA98, TA100, TA1535, TA1537 and TA97, in an Ames assay, with and without metabolic activation when an appropriate vehicle (ethyleneglycol dimethylether, EGDE) was used ^{Footnote 2}. 4,4'-MDI was found to be mutagenic in S. typhimurium strains TA100 and TA98 with metabolic activation when DMSO was used as a solvent ^{Footnote 16Footnote 17}, although it has been demonstrated that 4,4'-MDI is unstable in DMSO ^{Footnote 18}. Contrary to this, in another Ames study, 4,4'-MDI tested negative in S. typhimurium strains TA98, TA100, TA1535, TA1537 and TA97, in the presence and absence of metabolic activation, when DMSO was used as a solvent ^{Footnote 19}.

The available data do not meet the classification criteria for Germ Cell Mutagenicity.

Carcinogenicity:

Does not meet criteria

The International Agency for Research on Cancer (IARC) has classified 4,4'-MDI as Group 3 – not classifiable as to its carcinogenicity to humans ^{Footnote 20}. 4,4'-MDI has not been evaluated for carcinogenicity by the National Toxicology Program (NTP) nor the American Conference of Governmental Industrial Hygienists (ACGIH).

A 2-year chronic repeat-dose toxicity and carcinogenicity study by the inhalation route of exposure was conducted on 4,4'-MDI (study summary in ^{Footnote 21}). Groups of 80 female Wistar rats were exposed to 4,4'-MDI aerosols, whole-body, at 0.23, 0.70 or 2.05 mg/m³ for 17 hours per day, 5 days per week, for up to 24 months. A single treatment-related bronchio-alveolar adenoma was observed in one high-dose animal. However, the difference in incidence of adenomas between the high-dose and control group was not statistically significant (study summary in ^{Footnote 21}).

Although a carcinogenicity study is also available on the polymeric form of 4,4'-MDI (pMDI), where a statistically significant increase in lung adenomas was observed in males of the high-dose group (study summary in ^{Footnote 21}), this study is not considered for classification purposes. As adequate data of the type referred to in subparagraph 2.1(a)(ii) of the HPR is available on 4,4'-MDI to evaluate its carcinogenicity, data on a similar substance of the types referred to in subparagraphs 2.1(b)(i) to (iv) of the HPR are not considered.

Reproductive Toxicity:

Does not meet criteria

4,4'-MDI tested negative in a reproductive toxicity study combined with a chronic repeat-dose toxicity study ^{Footnote 2}. Female rats (20 per concentration) were exposed to 0.23, 0.70 or 2.05 mg/m³ of respirable aerosols of 4,4'-MDI for 17 hours per day, 5 days per week for up to 24 months. No treatment related findings were reported on assessed reproductive organs, which included adrenals, ovaries, uterus, vagina and mammary gland. In an embryo-toxicity study, rats (10 per sex per concentration) were exposed by whole-body inhalation to 1, 3 or 9 mg/m³ 4,4'-MDI for 6 hours per day from days 6-15 post-conception ^{Footnote 22}. A significant reduction in food consumption was observed in the mid- and high-concentration groups. Treatment did not influence any reproductive or fetal parameters (number of corpora lutea, implantation sites, pre- and post-implantation loss, fetal and placental weights, gross and visceral anomalies, and degree of ossification). A slight but significant increase in litters with fetuses displaying a skeletal anomaly (asymmetric sternebra(e)) was reported; however, this was only observed after exposure to the highest concentration (9 mg/m³).

The available data do not meet the classification criteria for Reproductive Toxicity.

Specific Target Organ Toxicity – Single Exposure:

Does not meet criteria

Oral Route of Exposure: Central nervous system (CNS) effects, including arching, hyporeflexia, lethargy and hypothermy, were observed at high exposure concentrations of 4,4'-MDI in rats (4,000 - 16,000 mg/kg) in a single-dose acute toxicity study ^{Footnote 1}. These doses exceed the concentration value ranges for classification.

Dermal Route of Exposure: No deaths or signs of intoxication were reported in rats in a well-conducted single-dose acute toxicity study up to a dose level of 4,4'-MDI of 2,000 mg/kg ^{Footnote 1}.

Inhalation Route of Exposure: In an OECD TG 403 study, rats were exposed to 4,4'-MDI aerosols at 300.0, 354.2, 399.2, 500.0 or 553.8 mg/m³ for 4 hours ^{Footnote 2}. The exposure caused irritation in the respiratory tract. Mortality was concentration dependent, beginning at 354.2 mg/m³, and was associated with acute lung edema. The authors of the study concluded that the lower respiratory tract effects are dependent on a highly respirable aerosol not usually encountered in the workplace. Autopsies revealed no abnormal findings in animals sacrificed at the end of the observation period. As a result, these data do not meet the criteria for classification.

In another study, 6 rats were exposed to the saturated vapor concentration of 4,4'-MDI for 4 hours ^{Footnote 1}. All animals survived until the end of the observation period of 14 days. Of the 6 animals exposed, 5 showed respiratory distress evidenced by rales, which disappeared by hour 12 and all the rats were alive and healthy at day 14. Autopsy showed no adverse effects in any of the tissues of the surviving rats. As a result, these data do not meet the criteria for classification.

The available data do not meet the classification criteria for Specific Target Organ Toxicity – Single Exposure.

Specific Target Organ Toxicity – Repeated Exposure:

Category 2

Oral Route of Exposure: No data available

Dermal Route of Exposure: In a repeat-dose skin exposure study, 0.5 g of 4,4'-MDI was applied daily to the skin of 6 rabbits for 20 days ^{Footnote 1}. Only edema and erythema were observed, with no mention of systemic toxicity.

Inhalation Route of Exposure: In a chronic inhalation toxicity study for 4,4'-MDI, female rats were exposed to 0.23, 0.70 or 2.05 mg/m³ 4,4'-MDI aerosols for 18 hours per day, 5 days per week for 24 months ^{Footnote 23}. A control group was exposed to the clean air. The study reported a dose-dependent impairment of lung function, increased lung weights, and an intermediately retarded lung clearance only in the high-dose group, as well as slight-to-moderate dose-dependent interstitial fibrosis and alveolar bronchiolization observed also only in the high-dose group.

The available data meet the classification criteria for Specific Target Organ Toxicity – Repeated Exposure – Category 2.

Aspiration Hazard:

No data available

No human data are available for 4,4'-MDI. This substance is not a liquid hydrocarbon.

Biohazardous Infectious Materials:

Not applicable

4,4'-MDI is not a microorganism, protein or nucleic acid.

Physical hazards

Explosives:

Not evaluated*

* Explosives are excluded from the HPAand its regulations. Explosives are regulated under the Explosives Act. For more information, visit Natural Resources Canada.

Flammable Gases:

Not applicable

4,4'-MDI is not a gas. The classification criteria for Flammable Gases do not apply to this substance.

(Flammable) Aerosols:

Not evaluated

Classification of a hazardous product in the Flammable Aerosols or Aerosols hazard class is product dependent.

Oxidizing Gases:

Not applicable

4,4'-MDI is not a gas. The classification criteria for Oxidizing Gases do not apply to this substance.

Gases Under Pressure:

Not applicable

4,4'-MDI is not a gas. The classification criteria for Gases Under Pressure do not apply to this substance.

Flammable Liquids:

Not applicable

4,4'-MDI is not a liquid. The classification criteria for Flammable Liquids do not apply to this substance.

Flammable Solids:

Does not meet criteria

The flammability of 4,4'-MDI was assessed according to EU Method A.10 and it was found to be not flammable (based on study summary ^{Footnote 2}).

The available data do not meet the classification criteria for Flammable Solids.

Self-reactive Substances and Mixtures:

No data available

4,4'-MDI decomposes at a temperature of approximately 400°C ^{Footnote 2}. Self-reactive substances and mixtures must have a self-accelerating decomposition temperature (SADT) of ≤75°C to meet the minimum classification in this hazard class.

The available data do not meet the classification criteria for Self-reactive Substances and Mixtures.

Pyrophoric Liquids:

Not applicable

4,4'-MDI is not a liquid. The classification criteria for Pyrophoric Liquids do not apply to this substance.

Pyrophoric Solids:

Does not meet criteria

The pyrophoric properties of 4,4'-MDI were assessed according to EU method A.13 (based on study summary ^{Footnote 2}). According to the test result, there was no ignition on contact with air, therefore the test substance has no pyrophoric properties.

The available data do not meet the classification criteria for Pyrophoric Solids.

Self-heating Substances and Mixtures:

Does not meet criteria

4,4'-MDI has an auto-ignition temperature of 601°C (based on a study summary ^{Footnote 2}), which is well above the temperature at which spontaneous ignition would need to occur for classification.

The available data do not meet the classification criteria for Self-heating Substances and Mixtures.

Substances and Mixtures which, in Contact with Water, Emit Flammable Gases:

Not applicable

4,4'-MDI has a chemical structure that does not contain metals or metalloids and is, therefore, excluded from classification [HPR 7.12.1(1)].

Oxidizing Liquids:

Not applicable

4,4'-MDI is not a liquid. The classification criteria for Oxidizing Liquids do not apply to this substance.

Oxidizing Solids:

Does not meet criteria

Paragraph 7.14.1(1)(b) of the HPR excludes any organic solid from classification that contains oxygen, fluorine or chlorine if those elements are chemically bonded only to carbon or hydrogen. 4,4'-MDI contains oxygen that is chemically bonded only to carbon.

The available data do not meet the classification criteria for Oxidizing Solids.

Organic Peroxides:

Not applicable

4,4'-MDI is not an organic peroxide. The classification criteria for Organic Peroxides do not apply to this substance.

Corrosive to Metals:

No data available

No data are available to determine if this substance is corrosive to metals; however, the spray-on polyurethane/polyurea products containing isocyanates such as 4,4'-MDI have been used routinely to protect steel and aluminum surfaces such as truck beds, trailers and boats ^{Footnote 24}.

Combustible Dusts:

No data available

No data are available to determine whether 4,4'-MDI meets the classification criteria for Combustible Dusts.

Simple Asphyxiants:

Not applicable

4,4'-MDI is not a gas. The classification criteria for Simple Asphyxiants do not apply to this substance.

Pyrophoric Gases:

Not applicable

4,4'-MDI is not a gas. The classification criteria for Pyrophoric Gases do not apply to this substance.

Chemicals Under Pressure:

Not evaluated

Classification of a hazardous product in the Chemicals Under Pressure hazard class is product dependent.

Regulatory and other information

Regulatory information:

Hazardous substance assessments are prepared by Health Canada as educational and information resources. Under the HPA, suppliers of hazardous products must, upon the sale or importation of a hazardous product, provide a safety data sheet and label that meet the requirements set out in the HPR.

Other information:

The information and classifications contained in these hazardous substance assessments are based on publicly available sources, such as peer-reviewed literature or reports by international bodies. New information, including proprietary information, could have an impact on the classification of substances or hazardous products containing them. It is the responsibility of the supplier to ensure the accuracy, sufficiency and reliability of their hazardous product classifications.

Last updated:

2022

Prepared by:

Workplace Hazardous Materials Bureau, Health Canada