Methylenediphenyl diisocyanate, oligomers, reaction products with 2-ethylhexan-l-ol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.05 mg/m³

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.1 mg/m³

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.05 mg/m³

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.1 mg/m³

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

50 mg/kg bw/day

DNEL related information

Local effects

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

28.7 mg/cm²

Additional information - workers

For the risk assessment of MDI MT (CAS No. 147993-65-5) the DNELs derived for MDI (CAS No. 101-68-8) and polymeric MDI (pMDI; CAS No. 9016-87-9) were used. This read-across approach is justified in the attached document "Statement on MDI category" below.

According to the ECHA Guidance on information requirements and chemical safety assessment - chapter R.8 (May 2008) a national occupational exposure limit (OEL) was used as a surrogate for a DNEL. For MDI and pMDI the German MAK Commission established an OEL (MAK value) of 0.05 mg/m3 for inhalable aerosol referring to an 8-hour exposure period. This OEL is used as a surrogate DNEL for long-term exposure. A ceiling limit value of 0.1 mg/m3 was settled. This ceiling limit is used as a surrogate DNEL for short-term exposure. The justification of these OELs is given in the published MDI/pMDI evaluation of the German MAK Commission (MAK, 2008) with the following statements:

For MDI, no significantly increased rate of respiratory symptoms in workers were observed at concentrations of 0.1 mg/m3. For the new development of a specific hypersensitivity of the airways exposures above 0.2 mg/m3 or intensive contact with the skin are of importance. 0.05 mg/m3 were without effect (MAK,1992).

In several, and very detailed studies also it was shown with the repeated inhalation exposure that the toxicity is determined by MDI and pMDI by the local irritation effect on the lower respiratory tract. The first effects were observed at daily 6-hour exposure from approximately 1 mg pMDI/m3, with an extension of the exposure does not lead to a lowering of the concentration effect. The NOAEC for pMDI was obtained in an inhalation study of 24 months, with daily 6-hour exposure of 0.2 mg/m3. In an inhalation study with MDI over a period of 24 months with a daily 17-hour exposure, effects on the lungs were still observed at 0.2 mg MDI/m3. This concentration corresponds to the equivalent of a daily 6-hour exposure to a concentration of approximately 1 mg MDI/m3. Due to the similarity of the effects induced by MDI and pMDI, the pMDI NOAEC of 0.2 mg/m3 can be used for MDI.

Since both MDI and pMDI have equal amount of reactive NCO groups and have only minor differences between the biological effects of both substances, the MAK value of 0.05 mg/m3 now also applies to pMDI. The effect of MDI and pMDI to the respiratory tract is mostly determined by the level of concentration. For the induction of a specific hypersensitivity of the airways exposures above 0.2 mg/m3 or intensive skin contact are of importance. The peak limitation category with the excursion factor 1 and the momentary value of 0.1 mg/m3 will therefore be maintained for MDI and now also applies to pMDI.

Acute toxicity

Assessment of the available acute toxicity data indicates that inhalation exposure to aerosols of the MDI analogues included in the category results in toxicity confined predominantly to the respiratory tract. In terms of hazard characterization, the MDI analogues included in the category are harmful by inhalation according to EU (R20) and CLP (Cat. 4) classification and therefore an acute DNEL for inhalation exposure has to be derived.

The key acute oral study was performed in rats at only one concentration level of 4,4-MDI: 2,000 mg/kg, and no clinical symptoms were noted. LD50 >2,000 mg/kg (Bomhard, 1990). With pMDI the acute oral study in rats demonstrated an LD50 > 10,000 mg pMDI/kg, and 2,150 mg pMDI/kg was without any clinical symptoms (Wazeter, 1964a). An acute oral toxicity study in rats with MDI MT (Desmodur MT) confirmed the MDI/pMDI results with an LD50 cut-off value of ≥ 5,000 mg/kg (Schuengel, 2006).

There is no reliable acute dermal study with 4,4 -MDI. In the read across key acute dermal study with pMDI in rabbits, the LD50 was > 9400 mg pMDI/kg and 2500 mg pMDI/kg did not produce any clinical symptoms (Wazeter, 1964b).

The key acute inhalation study was performed in rats at only one concentration level: 2.24 mg/L/1h (International Isocyanate Institute (2004). Clinical symptoms noted. One female died. No NOAEL. However, the aerosols were generated using sophisticated techniques in the laboratory and were of extremely small particle size only in order to meet international guidelines for testing of aerosols (International Isocyanate Institute 1982a, 1982b). This type and concentration of aerosol is not generated in the workplace. According to the German TRGS 900, the effect on the respiratory tract of MDI and pMDI depends mainly on the concentration. For MDI, no breathing difficulties occurred in workers exposed to concentrations of 0.1 mg/m³. Therefore the ceiling level for MDI and pMDI is set at 0.1 mg/m3, based on human experience (MAK, 1992).

NOAELrat, oral = 2000 mg/kg

NOAELrabbit, dermal = 2500 mg/kg

NOAEChuman, inhal = 0.1 mg/m3

DNELacute oral, worker = NOAELrat, oral * ¼ * 2/5 * 1/5 = 40 mg/kg

DNELacute dermal, worker = NOAELdermal, rabbit * ¼ * 2/5 * 1/5 = 50 mg/kg

(systemic effects)

DNELacute dermal, worker = 28.7 mg/cm2 (local effects) (see below “skin irritation” for calculations)

DNELacute inhal, worker = NOAEChuman = 0.1 mg/m3

DNELacute oral, gen. pop. = NOAELrat, oral * ¼ * 2/5 * 1/10 = 20 mg/kg

DNELacute dermal, gen. pop. = NOAELdermal, rabbit * ¼ * 2/5 * 1/10 = 25 mg/kg (systemic effects)

DNELacute dermal, gen. pop. = 17.2 mg/cm2 (local effects) (see under General population, “skin irritation” for calculations)

DNELacute inhal, gen. pop. = DNELacute inhal, worker * ½ = 0.05 mg/m3

1/4: allometric scaling

2/5: remaining interspecies differences

1/5: worker

1/10: general population

Skin irritation

The MDI is classified as irritant to skin. In a dermal irritation/corrosion study in rabbits MDI MT (Desmodur MT) was only slightly irritating to the skin (Gmelin, 2007). Nevertheless, on a worst-case basis a read-across to MDI is considered for this endpoint.

The available data do not allow a quantitative approach. According to the REACH guidance on information requirements and chemical safety assessment, Part E: Risk Characterisation, a qualitative risk characterisation should be performed for this endpoint. In order to guarantee ‘adequately control of risks’, it is necessary to stipulate risk management measures that prevent skin irritation.

In the acute dermal study with pMDI in rabbits, the LD50 was > 9400 mg pMDI/kg and NOAEL was 2500 mg/kg. The study entry of the acute dermal toxicity study mentions that 19.35 cm2 skin surface was exposed. This results in a local level of: 2500 mg/kg bw * 2 kg (body weight rabbits)/19.35. Furthermore, local effects were observed at this concentration. Therefore the following assessment factors are needed for workers (using ECETOC recommendation): factor 1 for interspecies differences (local effect, allometric scaling is not needed in case of local effects), factor of 3 for intraspecies differences and an assessment factor for extrapolation from LOAEL to NAEL (usually 3).

DNELacute dermal, worker = NOAELdermal, rabbit * 2 / 19.35 / 1 / 3 / 3 = 28.7 mg/cm2

Eye irritation

The MDI analogues are classified for eye irritation (Xi, R36). In an eye irritation study MDI MT (Desmodur MT) was only slightly irritating to the eyes (Gmelin, 2007). Nevertheless, on a worst-case basis a read-across to MDI is considered for this endpoint. The available data do not allow a quantitative approach. According to the REACH guidance on information requirements and chemical safety assessment, Part E: Risk Characterisation, a qualitative risk characterisation should be performed for this endpoint. In order to guarantee ‘adequately control of risks’, it is necessary to stipulate risk management measures that prevent eye irritation.

Respiratory tract irritation

The MDI analogues are classified for respiratory tract irritation (Xi, R37). The acute inhalation DNEL for the MDI analogues (0.1 mg/m3) is also considered sufficient to prevent respiratory tract irritation.

Dermal sensitization

No DNEL for skin sensitization is calculated as the relationship between skin dose and response is not clear. There is no validated method of DNEL calculation for skin sensitization. Human experience shows this is not a concern with current workplace practices.

Respiratory sensitization

No DNEL for respiratory sensitization is calculated as there is no validated method. Human experience shows clearly that if the exposure concentrations of MDI are kept below 0.05 mg/m3, generally no new cases of MDI asthma are observed.

Repeated dose toxicity (non-cancer)

In the chronic 2 year study LOAEC was determined: 1.0 mg/m3 air.

For MDI, no repeated dose dermal toxicity studies are available. Dermal penetration of MDI is considered to be low. In the GLP-study of Leibold et al. (1998) the largest proportion of radioactivity was recovered from the application site. Only 0.9 % of the applied radioactivity was absorbed at the most. The exposure to MDI via the air does not lead to systemic toxicity, therefore taking into consideration the low dermal penetration, systemic toxicity is covered by the respective DNELs for inhalation exposure and a DNEL for systemic toxicity (short-term and long-term) after dermal contact is not required. Regarding local effects the irritation potential as well as the sensitization potential needs to be considered in the selection of the respective risk management tools at the workplaces.

The agreed MAK value of 0.05 mg/m³ for inhalable MDI-aerosol was derived from experience in humans. Since MDI and pMDI have a similar rate of reactive NCO-groups and because there is only a slight difference noticed between the biological effects of the 2 substances, the MAK value is also applicable of 0.05 mg/m3 for pMDI.

LOAEC rat, inhal = 1.0 mg/m3

Worker : general population* 1/2

DNELinhal, chronic, worker = MAK = 0.05 mg/m³

DNELinhal, chronic, gen pop = MAK * 1/2 = 0.025 mg/m³

Carcinogenicity

In a 2 year inhalation study the chronic toxicity and the carcinogenicity of monomeric 4,4’-MDI were investigated. Female Wistar rats in groups of 80 animals, were exposed in 6 m³ inhalation chambers for 17 hours/day, 5 days/week to 0.23, 0.70, and 2.03 mg/m3 MDI in aerosol form, a control group was exposed to clean air. There was no MDI-related increase in the organ-specific tumor rate. The number of tumor-bearing rats was identical and the total number did not significantly differ between in control and the high dosegroup. There was an untypical high mortality due to tumors of the pituitary gland in all groups including the control group. Therefore, on the basis of this study it is not possible to derive DNEL for monomeric 4,4’-MDI.

In rats, preneoplastic and neoplastic changes were observed in the lung after a chronic exposure of MDI and pMDI-aerosol, respectively. All available results support a mechanism induced by chronic cell proliferation. The tumor causing mechanism in rats is triggered only at exposures that cause clear local irritating effects. The irritation of the respiratory tract occurs after acute exposure at circa 10 times lower concentration than the tumor formation in the respiratory tract. If the irritation is avoided, no carcinogenicity is expected. MAK value of 0.05 mg/m3 for inhalable MDI-aerosol was derived from experience in humans (TRGS 900).

DNELcancer, worker = MAK = 0.05 mg/m³

Reproduction/Developmental

As evaluated by the German MAK Commission, studies on rats demonstrated slight embryotoxic effects in the range of maternal toxicity of 9 mg MDI/m³, and 12 mg pMDI/m³. The lung irritation caused increased lung weights triggering a disturbance of the lung function. The cause of the nonspecific growth defect was induced by maternal stress or hypoxaemy. The NOAEC for developmental toxicity is around 3 mg MDI/m³ and 4 mg pMDI/m³. By keeping the MAK value at 0.05 mg/m³, no embryotoxic effect is to expected.

DNELrepro/developmental, worker = MAK = 0.05 mg/m³

DNELrepro/developmental, gen pop = MAK * 1/2 = 0.025 mg/m³.

References:

Bomhard E (1990). Desmodur VP PU 1806: acute oral toxicity study in male and female Wistar rats. Testing laboratory: Bayer AG, Institute of Toxicology, Industrial Toxicology, Friedrich-Ebert-Str. 217-333, D-5600 Wuppertal 1, Germany. Report no.: Bayer report no. 19787. Owner company: Bayer AG. Study number: Bayer Study no. T8039501. Report date: 1990-12-11.

EU Rist Assessment Report on MDI, 2005, Belgium.

International Isocyanate Institute (2004) Monomeric MDI: lethality to rats following one hour inhalation of an inhalable aerosol.project 216-AM-.

International Isocyanate Institute (1982a) - Appelman LM and de Jong AWJ: Acute inhalation toxicity study of polymeric MDI in rats, CIVO Institutes Report No. V82.050/212478, August 1982.

International Isocyanate Institute (1982b) - Appelman LM and de Jong AWJ: Deposition of aerosol components on the hair of rats exposed to polymeric MDI aerosols, CIVO Institutes Report No. V82.049/212478, August 1982.

MAK (2008) - Deutsche Forschungsgemeinschaft, Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area. Occupational toxicants, critical data evaluation for MAK-values and classification of carcinogens.(Diphenylamethan- 4,4’-diisocyanat (MDI) und “polymeres MDI” (pMDI)). Nachtrag 2008. Weinheim: VCH Verlagsgesellschaft, 2008a.

MAK (1992) - Deutsche Forschungsgemeinschaft, Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area. Occupational toxicants, critical data evaluation for MAK-values and classification of carcinogens. (4,4’-Methylene diphenyl isocyanate (MDI) and “polymeric MDI” (pMDI)). Weinheim: VCH Verlagsgesellschaft, 1992.

TRGS 900, Occupational Exposure Limits (AGW), BArbBl.1/2006, p.41, Jan 2006, as amended through June 2008.

Wazeter FX (1964a) Director, International Research and Development Corporation, Acute Toxicity Studies (LD50) in Male Albino Rats, 12 March 1964.

Wazeter FX (1964b) Director, International Research and Development Corporation, Acute Dermal Toxicity Studies (LD50) in Male Albino Rats.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.025 mg/m³

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.05 mg/m³

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.025 mg/m³

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.05 mg/m³

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

25 mg/kg bw/day

DNEL related information

Local effects

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

17.2 mg/cm²

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

20 mg/kg bw/day

DNEL related information

Additional information - General Population

Acute toxicity

Assessment of the available acute toxicity data indicates that inhalation exposure to aerosols of the MDI analogues included in the category results in toxicity confined predominantly to the respiratory tract. In terms of hazard characterization, the MDI analogues included in the category are harmful by inhalation according to EU (R20) and CLP (Cat. 4) classification and therefore an acute DNEL for inhalation exposure has to be derived. For MDI, no breathing difficulties occurred in workers exposed to concentrations of 0.1 mg/m3. Therefore the acute inhalation DNEL for the MDI analogues is set at 0.1 mg/m3 for workers, based on human experience (comparable to the MAK ceiling). A correction for interspecies differences between workers (5) and the general population (10) results in an acute inhalation DNEL of 0.05 mg/m3 for the general population.

DNELacute oral, gen. pop. = NOAELrat, oral * ¼ * 2/5 * 1/10 = 20 mg/kg

DNELacute inhal, gen. pop. =DNELacute inhal, worker* ½ = 0.05 mg/m3

DNELacute dermal, gen. pop. = NOAELdermal, ratbbit* ¼ * 2/5 * 1/10 = 25 mg/kg

(systemic effects)

DNELacute dermal, gen. pop. = 17.2 mg/cm2 (local effects) (see below “skin irritation” for calculations)

1/4: allometric scaling

2/5: remaining interspecies differences

1/10: general population

Skin irritation

The MDI is classified as irritant to skin. In a dermal irritation/corrosion study in rabbits MDI MT (Desmodur MT) was only slightly irritating to the skin (Gmelin, 2007). Nevertheless, on a worst-case basis a read-across to MDI is considered for this endpoint. The available data do not allow a quantitative approach. According to the REACH guidance on information requirements and chemical safety assessment, Part E: Risk Characterisation, a qualitative risk characterisation should be performed for this endpoint. In order to guarantee ‘adequately control of risks’, it is necessary to stipulate risk management measures that prevent skin irritation.

In the acute dermal study with pMDI in rabbits, the LD50 was > 9400 mg pMDI/kg and NOAEL was 2500 mg/kg. The study entry of the acute dermal toxicity study mentions that 19.35 cm2 skin surface was exposed. This results in a local level of: 2500 mg/kg bw * 2 kg (body weight rabbits)/19.35. Furthermore, local effects were observed at this concentration. Using ECETOC recommendation: factor 1 for interspecies differences (local effect, allometric scaling is not needed in case of local effects), factor of 5 for intraspecies differences and an assessment factor for extrapolation from LOAEL to NAEL (usually 3).

DNELacute dermal, gen. pop. = NOAELdermal, rabbit * 2 / 19.35 / 1 / 5 / 3 = 17.2 mg/cm2

Eye irritation

The MDI analogues are classified for eye irritation (Xi, R36). In an eye irritation study MDI MT (Desmodur MT) was only slightly irritating to the eyes (Gmelin, 2007). Nevertheless, on a worst-case basis a read-across to MDI is considered for this endpoint.

The available data do not allow a quantitative approach. According to the REACH guidance on information requirements and chemical safety assessment, Part E: Risk Characterisation, a qualitative risk characterisation should be performed for this endpoint. In order to guarantee ‘adequately control of risks’, it is necessary to stipulate risk management measures that prevent eye irritation.

Respiratory tract irritation

The MDI analogues are classified for respiratory tract irritation (Xi, R37). The acute inhalation DNEL for the MDI analogues (0.1 mg/m3) is also considered sufficient to prevent respiratory tract irritation.

Dermal sensitization

No DNEL for skin sensitization is calculated as the relationship between skin dose and response is not clear. There is no validated method of DNEL calculation for skin sensitization. Human experience shows this is not a concern with current workplace practices, and consumer exposures will be considerably less.

Respiratory sensitization

No DNEL for respiratory sensitization is calculated as there is no validated method. Human experience shows clearly that if the exposure concentrations of MDI are kept below 0.05 mg/m3, generally no new cases of MDI asthma are observed. Public exposures at this level are not forseen.

Repeated dose toxicity (non-cancer)

No repeated dose oral toxicity studies are available for MDI. Therefore, it is not possible to derive a DNEL for long-term exposure.

For MDI, no repeated dose dermal toxicity studies are available. Dermal penetration of MDI is considered to be low. In the GLP-study of Leibold et al. (1998) the largest proportion of radioactivity was recovered from the application site. Only 0.9 % of the applied radioactivity was absorbed at the most. The exposure to MDI via the air does not lead to systemic toxicity, therefore taking into consideration the low dermal penetration, systemic toxicity is covered by the respective DNELs for inhalation exposure and a DNEL for systemic toxicity (short-term and long-term) after dermal contact is not required.

Worker : general population* 1/2

DNELinhal, chronic, gen pop = MAK * 1/2 = 0.025 mg/m³.

DNEL cancer

DNELcancer, gen pop = MAK * 1/2 = 0.025 mg/m³

Carcinogenicity

In a 2 year inhalation study the chronic toxicity and the carcinogenicity of monomeric 4,4’-MDI were investigated. Female Wistar rats in groups of 80 animals, were exposed in 6 m³ inhalation chambers for 17 hours/day, 5 days/week to 0.23, 0.70, and 2.03 mg/m3 MDI in aerosol form, a control group was exposed to clean air. There was no MDI-related increase in the organ-specific tumor rate. The number of tumor-bearing rats was identical and the total number did not significantly differ between in control and the high dosegroup. There was an untypical high mortality due to tumors of the pituitary gland in all groups including the control group. Therefore, on the basis of this study it is not possible to derive DNEL for monomeric 4,4’-MDI.

In rats, preneoplastic and neoplastic changes were observed in the lung after a chronic exposure of MDI and pMDI-aerosol, respectively. All available results support a mechanism induced by chronic cell proliferation. The tumor causing mechanism in rats is triggered only at exposures that cause clear local irritating effects. The irritation of the respiratory tract occurs after acute exposure at circa 10 times lower concentration than the tumor formation in the respiratory tract. If the irritation is avoided, no carcinogenicity is expected. MAK value of 0.05 mg/m3 for inhalable MDI-aerosol was derived from experience in humans (TRGS 900).

Reproduction/Developmental

As evaluated by the German MAK Commission (2008), studies on rats demonstrated slight embryotoxic effects in the range of maternal toxicity of 9 mg MDI/m3, and 12 mg pMDI/m3. The lung irritation caused increased lung weights triggering a disturbance of the lung function. The cause of the nonspecific growth defect was induced by maternal stress or hypoxaemy. The NOAEC for developmental toxicity is around 3 mg MDI/m3 and 4mg pMDI/m3. By keeping the DNEL value at 0.025 mg/m3, no reproduction/developmental toxicity effect is to be expected.

DNELrepro/developmental, gen pop = MAK * 1/2 = 0.025 mg/m³.

References:

EU Rist Assessment Report on MDI, 2005, Belgium

MAK (2008) - Deutsche Forschungsgemeinschaft, Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area. Occupational toxicants, critical data evaluation for MAK-values and classification of carcinogens.(Diphenylamethan- 4,4’-diisocyanat (MDI) und “polymeres MDI” (pMDI)). Nachtrag 2008. Weinheim: VCH Verlagsgesellschaft, 2008a.

MAK (1992) - Deutsche Forschungsgemeinschaft, Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area. Occupational toxicants, critical data evaluation for MAK-values and classification of carcinogens. (4,4’-Methylene diphenyl isocyanate (MDI) and “polymeric MDI” (PMDI)). Weinheim: VCH Verlagsgesellschaft, 1992.

TRGS 900, Occupational Exposure Limits (AGW), BArbBl.1/2006, p.41, Jan 2006, as amended through June 2008.