Isocyanic acid, polymethylenepolyphenylene ester, 2-ethyl-1-hexanol-blocked

Endpoint summary

Description of key information

Skin sensitisation: Desmodur MT (MDI MT) was investigated in the modified local lymph node assay (LLNA-IMDS) on female mice according to OECD TG 429 (Vohr, 2006). Concentrations of 0 (vehicle control), 1, 3 and 10 % formulated in acetone/olive oil (4:1) were tested. The results show that Desmodur MT has a sensitising potential in mice after dermal application. Compared to vehicle treated animals there was a significant increase regarding the weights of the draining lymph nodes and the cell counts in all dose groups. The corresponding cell count indices were 2.95, 4.41 and 4.58 exceeding the "positive level" of index 1.4. A significant increase compared to vehicle treated animals regarding ear swelling and ear weights was detected in the mid and high dose group. The results obtained would indicate a strong sensitizing potential in the LLNA. However a significant increase compared to vehicle treated animals regarding ear swelling and ear weights was detected in the mid and high dose group which is indicative for an acute irritant (inflammatory) response. Such an irritant property can also be combined with a strong skin sensitizing potential of a test compound. There are indications that irritation can contribute to a mild unspecific stimulation of  lymphocyte proliferation (McGarry 2007) which can lead to a bias in response indicating a strong sensitizing potential in  the LLNA. In addition, human observation with MDI indicated a  rather moderate skin sensitizing potential for MDI (Schlede et al., 2003). Assuming a bias response in the LLNA by irritation a classification as skin sensitizing category 1 (H317) with no sub-categorization is seen warranted for MDI MT, similar to the harmonised classification of 4,4’-MDI  skin sensitizing category 1 (H317) EU GHS 1272/2008 CLP. 

 

Respiratory sensitisation: There are no data available for the target substance MDI MT for the endpoint respiratory sensitisation. A read across to valid animal studies from the source substances 4,4’-MDI and pMDI is performed.

Rattray et al. (1994) evaluated the respiratory response in guinea pigs exposed to 4,4’-MDI. Guinea pigs were exposed to 4,4’-MDI by intradermal injection, topical application, or inhalation exposure for induction and by inhalation to 25-44 mg/m³ 4,4’-MDI for the challenge exposure. Attempts to sensitize guinea pigs by inhalation exposure to MDI were unsuccessful; no animals exhibited pulmonary responses following challenge with MDI. Intradermal injection or topical application of MDI induced specific antibody responses and pulmonary responses in 12-65 % of guinea pigs depending upon induction dose and route. The differences in immunogenicity observed clearly reflect variation in exposure route rather than the concentration of 4,4’-MDI used for sensitisation (Rattray et al., 1994).

In a guinea pig study using intradermal induction, 12.5 % of the 4,4’-MDI sensitized guinea pigs showed a marked non-specific pulmonary reaction after an inhalation challenge of 35 mg/m³ 4,4’-MDI which was not observed in sham or vehicle controls. An association between increased airway responsiveness, increased airway eosinophilia, and increased levels of IgG1 anti-MDI antibody titres could not be established (Pauluhn, 1994). Pauluhn and Mohr (1994) observed in another guinea pig study that respiratory responses were only provoked in animals challenged with overtly irritant 4,4’-MDI-concentrations (Pauluhn and Mohr, 1994). Guinea pigs sensitized to high concentrations of aerosolized 4,4’-MDI showed a mild airway hypersensitivity without concomitant influx of inflammatory cells (Pauluhn, 1995). An inter-laboratory study for the evaluation and validation of an animal model for low molecular weight chemicals to exhibit respiratory allergy in guinea pigs used intradermal induction of 0.0003 to 1 % and an inhalation challenge on day 22 to 18-55 mg/m³ 4,4-MDI. The results demonstrated that the intradermal injection of MDI was able to induce high titer antigen-specific antibodies in guinea-pigs. Inhalation exposure to 4,4’-MDI, approximately three weeks after sensitisation with 4,4’-MDI, induced a pulmonary response characterized by changes in respiratory rate (Blaikie et al., 1995).

In more recent studies the Brown Norway (BN) rat model for respiratory sensitization was used to evaluate MDI substances. Both inhalation and dermal routes of induction were investigated, whereas the elicitation phase was typically four inhalation exposures, spaced at approximately 15-day intervals. After the last challenge, the measurements made included: respiratory responses using whole body plethysmography, analysis of inflammatory endpoints using lung lavage fluid and IgE levels in lung lavage fluid or serum. Lung and lymph node weights were measured post mortem and the respiratory tract was used for histopathological investigations. Controls did not receive the induction treatment but were challenged by inhalation as for the test groups, to control for short term irritation effects. On occasion respiratory methacholine challenge was performed the day following MDI challenge to test for non-specific respiratory hyperreactivity. The test material in these studies was pMDI.

Both inhalation and dermal routes of induction were investigated in a study using BN rats.  One group of animals was induced by dermal exposure (150μl neat pMDI on the flanks Day 0 and 75 µl neat pMDI on both ears Day 7) followed by inhalation challenge (4 x 30 min exposures to 15.7 mg/m3 pMDI on Days 21, 35, 50, and 64.) A second group of animals received an inhalation induction of 25-30 mg/m³ (5 x 3 hours/day) and the same subsequent challenge.  The dermally-induced animals demonstrated mild but consistent time-related increased BAL neutrophils and slightly increased lung and lymph-node weights. Lung histopathology revealed activated lymphatic tissue and an increased recruitment of airway eosinophils.  However, the inhalation-induced animals demonstrated a respiratory response on the initial challenge which was not seen subsequently and was assessed as reflex rather than an immune response. The determination of total IgE in serum did not reveal statistically significant differences between the groups. Conclusive route-of-induction related were not observed.  It was concluded that an allergic respiratory response was seen with topical induction and respiratory challenge (Pauluhn, 2005b).

The dose-response for inhalation induction by pMDI was investigated using inhalation induction at 3 different concentration x exposure time (C x t) values in BN rats, either at higher-concentration-shorter-duration or lower-concentration-longer-duration (Pauluhn and Poole, 2011). This study used a modified sensitization protocol of 5-day inhalation exposure (days 0-4) of Brown Norway (BN) rats to two C x t) relationships of 1000, 5000, and 10,000 mg pMDl/m3 x min at exposure durations of either 10 or 360-min.  This was followed by four 30-min inhalation challenges to 40 mg pMDl/m3 on target days 20, 25, 50, and 65. After the last challenge, changes in breathing patterns delayed in onset were recorded and allergic lung inflammation was probed by bronchoalveolar lavage (BAL). The high-concentration short-exposure duration sensitization protocol produced a significant and more vigorous elicitation response. In phase 2 of the study, groups of rats were sensitized using the 10-min C x t protocol and challenged 3-times at 40 mg pMDl/m³. At the fourth challenge a dose-escalation regimen of 5.1 or 14.5 or 39.8 mg pMDI/m³ was used to determine the elicitation threshold on 'asthmatic' rats. The lowest challenge concentration did not elicit a response, thus a no-effect level for the elicitation of 5 mg/m³ was demonstrated.

In summary, several researchers have shown respiratory changes in animals after induction exposure and subsequent challenge with both 4,4’-MDI and pMDI. The available study data are consistent with the hypothesized MoA in which the NCO group on the monomeric MDI reacts with biological nucleophiles i.e. protein and drives the molecular initiating event (MIE) and subsequent sequence of key events (KEs) leading to the acquisition of MDI-mediated sensitization. As the source substances 4,4’-MDI, pMDI and the target substance contain sufficient monomeric MDI, the driver of toxicity, similarities in reactions leading to respiratory sensitization are assumed. In addition, as the higher molecular weight non-monomeric content of the UVCB substance MDI MT do not contains reactive centers and is consequently inert and thus do not contribute to the expected toxicity, it is reasonable to assume that using read across to the source substances 4,4’-MDI and pMDI is warranted. Accordingly, the CLP classification (Cat. 1, H334) for 4,4’-MDI is adopted to the target substance MDI MT.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation: in vivo (LLNA)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)

Deviations:

yes

Remarks:

- modification: in addition, measurements of ear swelling and ear weight were done to discriminate the irritating potential from the sensitizing potential of the test substance (Integrated Model for the Differentiation of Skin reactions (IMDS))

Principles of method if other than guideline:

Modified LLNA (IMDS; Integrated Model for the Differentiation of Skin Reactions). Modifications are authorised in the OECD TG 429 and in the Note for Guidance SWP/2145/00 of the CPMP (2001). Information on validation of IMDS and scientific justification is given in: Vohr HW et al., Arch. Toxicol., 73, 501-509 (2000); Ehling G et al., Toxicology 212, 60-68 and 69-79 (2005).

GLP compliance:

yes (incl. QA statement)

Type of study:

mouse local lymph node assay (LLNA)

Species:

mouse

Strain:

NMRI

Sex:

female

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Harlan-Winkelmann GmbH, Borchen, Germany
- Age at study initiation: 9 weeks
- Weight at study initiation: 26-32 g
- Housing: individual
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 40 - 70
- Air changes (per hr): about 10
- Photoperiod (hrs dark / hrs light): 12 / 12

Vehicle:

acetone/olive oil (4:1 v/v)

Concentration:

0, 1, 3, 10 %

No. of animals per dose:

6

Details on study design:

TREATMENT PREPARATION AND ADMINISTRATION:
The test item in the formulation or the vehicle were applied epicutaneously onto the dorsal part of both ears of the animals. This  treatment was repeated on three consecutive days (d1, d2 and d3). The volume administered was 25µl/ear. The used concentrations were based on the experiences with the test system and the toxic properties of the test substance.
The animals were anaesthetized by inhalation of carbon dioxide and sacrificed one day after the last application (d4). The appropriate organs were then removed. Lymphatic organs (the auricular lymph nodes) were transferred into physiological saline (PBS).
Investigations:
- weight of draining lymph nodes (given as weight index compared to vehicle controls)
- cell counts in draining lymph nodes (given as cell count index compared to vehicle controls)
Stimulation indices were calculated by dividing the absolute weight or number of cell counts of the substance treated lymph nodes by the vehicle treated ones.
- ear swelling (given in 0.01 mm and as index)
- ear weight (given in mg/8 mm diameter punch and as index)
- body weights

Positive control substance(s):

hexyl cinnamic aldehyde (CAS No 101-86-0)

Statistics:

When it was statistically reasonable, the values from treated groups were compared with those from the control group by a one-way analysis of variance (ANOVA) when the variances are considered homogeneous according to a homogeneity testing like Cochran's test. Alternatively, if the variances are considered to be heterogenous (p<=0.05), a non-parametric Kruskal-Wallis test has been used (Kruskal-Wallis ANOVA) at significance levels of 5 % . Two sided multiple test procedures were done according to Dunnett or Bonferroni-Holm, respectively. Outlying values in the LN weights were eliminated at a probability level of 99% by Nalimov's method. In addition, for the LLNA/IMDS the smallest significant differentes in the means were calculated by Scheffels method, which according to Sachs can be used for both equal and unequal sample sizes.

Positive control results:

Alpha hexyl cinnamic aldehyde, checked in regular intervals, showed a clear sensitizing potential in the local lymph node assay (IMDS).

Key result

Parameter:

SI

Remarks:

Stimulation index: Cell count index 10 % dose

Value:

4.58

Variability:

± 13.51 (mean ± SD in %)

Test group / Remarks:

10 % dose

Key result

Parameter:

SI

Remarks:

Stimulation index: Cell count index 3 % dose

Value:

4.41

Variability:

± 32.30 (mean ± SD in %)

Test group / Remarks:

3 % dose

Key result

Parameter:

SI

Remarks:

Stimulation index: Cell count index 1 % dose

Value:

2.95

Variability:

± 30.21 (mean ± SD in %)

Test group / Remarks:

1 % dose

Key result

Parameter:

SI

Remarks:

Stimulation index: Cell count index vehicle control

Value:

1

Variability:

± 32.79 (mean ± SD in %)

Test group / Remarks:

vehicle control

Parameter:

SI

Remarks:

Stimulation index: weight draining lymph nodes

Value:

3.59

Variability:

± 12.45 (mean ± SD in %)

Test group / Remarks:

10 % dose

Parameter:

SI

Remarks:

Stimulation index: weight draining lymph nodes

Value:

3.03

Variability:

± 19.09 (mean ± SD in %)

Test group / Remarks:

3 % dose

Parameter:

SI

Remarks:

Stimulation index: weight draining lyymp nodes

Value:

2.08

Variability:

± 21.73 (mean ± SD in %)

Test group / Remarks:

1 % dose

Parameter:

SI

Remarks:

Stimulation index: weight of draining lymp nodes

Value:

1

Variability:

± 22.90 (mean ± SD in %)

Test group / Remarks:

Vehicle control

Table 1: Summary of the LLNA/IMDS results (means of 6 animals per group)

 

Parameter investigated	Vehicle control	Dose 1 %	Dose 3 %	Dose 10 %
Stimulation index: weight of draining lymph nodes	1.00	2.08 *	3.03 *	3.59 *
Stimulation index: cell count in draining lymph nodes	1.00	2.95 *	4.41 *	4.58 *
Ear swelling in 0.01 mm on day 4 (index)	17.25 (1.00)	18.75 (1.09)	20.17 * (1.17)	21.92 * (1.27)
Ear weight in mg / 8 mm diameter punch on day 4 (index)	10.79 (1.00)	11.38 (1.05)	12.36 * (1.15)	13.58 * (1.26)

 

* statistically significant increase (p ≤ 0.05)

 

All dose groups (1, 3 and 10 %) of the NMRI mice showed a clear increase in the weights of the draining lymph nodes and in the stimulation indices for cell counts compared to control animals after application of the Desmodur MT. The "positive level" which is 1.4 for cell count indices has been exceeded in all dose groups. These increases are of statistical significance.

 

The "positive level" of ear swelling which is 2 x10-2 mm increase, i.e. about 10% of the control values, has been exceeded in the mid and high dose group. A statistical significant increase of the ear weights and ear swelling compared to control animals was also detected for the mid and high dose group. An increase in this parameter would point to an acute irritating (inflammatory) response. However, such an irritating property could also be combined with a strong skin sensitizing potential of a test compound.

 

The body weights of the animals were not affected by any treatment.

 

Taken together, a specific activation of the cells of the immune system via dermal route was determined after application of 1, 3 and 10 % Desmodur MT by the method used. Thus, Desmodur MT has to be classified as a skin sensitizer.

Interpretation of results:

Category 1 (skin sensitising) based on GHS criteria

Remarks:

The results obtained would indicate a strong sensitizing potential in the LLNA. However a significant increase compared to vehicle treated animals regarding ear swelling and ear weights was detected in the mid and high dose group which is indicative for an acute irritant (inflammatory) response. Such an irritant property can also be combined with a strong skin sensitizing potential of a test compound. There are indications that irritation can contribute to a mild unspecific stimulation of lymphocyte proliferation (McGarry 2007) which can lead to a bias in response indicating a strong sensitizing potential in the LLNA. In addition, human observation with MDI indicated a rather moderate skin sensitizing potential for MDI (Schlede et al., 2003). Assuming a bias response in the LLNA by irritation a classification with skin sensitizing category 1 (H317) with no sub-categorization is seen warranted for MDI MT.

Conclusions:

Desmodur MT was investigated in the modified local lymph node assay (LLNA-IMDS) on female mice according to OECD TG 429. Concentrations of 0 (vehicle control), 1, 3 and 10 % formulated in acetone/olive oil (4:1) were tested. The results show that Desmodur MT has a sensitizing potential in mice after dermal application. Compared to vehicle treated animals there was a significant increase regarding the weights of the draining lymph nodes and the cell counts in all dose groups. The corresponding cell count indices were 2.95, 4.41 and 4.58 exceeding the "positive level" of index 1.4. The results obtained would indicate a strong sensitizing potential in the LLNA. However a significant increase compared to vehicle treated animals regarding ear swelling and ear weights was detected in the mid and high dose group which is indicative for an acute irritant (inflammatory) response. Such an irritant property can also be combined with a strong skin sensitizing potential of a test compound. There are indications that irritation can contribute to a mild unspecific stimulation of lymphocyte proliferation (McGarry 2007*) which can lead to a bias in response indicating a strong sensitizing potential in the LLNA. In addition, human observation with MDI indicated a rather moderate skin sensitizing potential for MDI (Schlede et al., 2003). Assuming a bias response in the LLNA by irritation a classification with skin sensitizing category 1 (H317) with no sub-categorization is seen warranted for MDI MT.


*McGarry, H. F. (2007). The murine local lymph node assay: Regulatory and potency considerations under REACH. Toxicology 238:71-89.

Schlede, E., Aberer, W., Fuchs, T., Gerner, I., Lessmann, H., Maurer, T., Rossbacher, R., Stropp, G., Wagner, E., and Kayser, D. (2003). Chemical substances and contact allergy--244 substances ranked according to allergenic potency. Toxicology, 193, (3), 219-59.

Executive summary:

Desmodur MT was investigated in the modified local lymph node assay (LLNA-IMDS) on female mice according to OECD TG 429. Concentrations of 0 (vehicle control), 1, 3 and 10 % formulated in acetone/olive oil (4:1) were tested. The results show that Desmodur MT has a strong sensitizing potential in mice after dermal application. Compared to vehicle treated animals there was a significant increase regarding the weights of the draining lymph nodes and the cell counts in all dose groups. The corresponding cell count indices were 2.95, 4.41 and 4.58 exceeding the "positive level" of index 1.4. A significant increase compared to vehicle treated animals regarding ear swelling and ear weights was detected in the mid and high dose group. An increase in this parameter would point to an acute irritant (inflammatory) response. However, such an irritant property can also be combined with a strong skin sensitizing potential of a test compound. There are indications that irritation can contribute to a mild unspecific stimulation of  lymphocyte proliferation (McGarry 2007*) which can lead to a bias in response indicating a strong sensitizing potential in  the LLNA. In addition, human observation with MDI indicated a  rather moderate skin sensitizing potential for MDI (Schlede et al., 2003). Assuming a bias response in the LLNA by irritation a classification with skin sensitizing category 1 (H317) with no sub-categorization is seen warranted for MDI MT.

 

McGarry, H. F. (2007). The murine local lymph node assay: Regulatory and potency considerations under REACH. Toxicology 238:71-89.

Schlede, E., Aberer, W., Fuchs, T., Gerner, I., Lessmann, H., Maurer, T., Rossbacher, R., Stropp, G., Wagner, E., and Kayser, D. (2003). Chemical substances and contact allergy--244 substances ranked according to allergenic potency. Toxicology, 193, (3), 219-59.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Respiratory sensitisation

Link to relevant study records

Reference

Endpoint:

respiratory sensitisation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Fully reported study, No guideline available

Qualifier:

no guideline available

Principles of method if other than guideline:

No guideline for respiratory sensitisation is validated.

GLP compliance:

not specified

Species:

guinea pig

Strain:

Dunkin-Hartley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Porcellus Animal Breeding, Sussex, UK
- Weight at study initiation: 250-300g
- Housing: individually
- Diet (e.g. ad libitum): ad libitum except during inhalation exposure periods
- Water (e.g. ad libitum):ad libitum except during inhalation exposure periods
- Acclimation period: at least 10 days

Route of induction exposure:

other: groups were exposed by intradermal injection, topical application, or inhalation exposure

Route of challenge exposure:

inhalation

Vehicle:

other: corn oil only in i.d. and topical exposures

Concentration:

Topical induction: Concentration in vehicle: 0, 10, 30, 100 %
Intradermal induction: Concentration in vehicle: 0, 0.0003, 0.003, 0.03, 0.3% of MDI
Inhalation induction: Concentration: between 19.4 and 23.7 mg/m³

Inhalation challenge concentration:
topical sensitisation: 25.9 to 36.4 mg/m³;
intradermal sens.: 27.6 to 36.5 mg/m³;
inhalation sens.: 34.6 to 44.1 mg/m³

No. of animals per dose:

topical: 4 groups, n=8;
intradermal: 5 groups, n=8;
inhalation: n=16

Details on study design:

MAIN STUDY
A. INDUCTION EXPOSURE
1. Topical induction
- No. of exposures: 1
- Exposure period: 6 hours under occlusion
- Test groups: 3 Groups of 8 animals
- Control group: 8 animals untreated
- Site: shaved scapular region
- Concentrations: 400 μl of 0, 10, 30, 100 % MDI in corn oil

2. Intradermal induction
- No. of exposures: 1
- Test groups: 4 Groups of 8 animals
- Control group: 8 animals untreated
- Concentrations: 100 μl of 0, 0.0003, 0.003, 0.03, 0.3% of MDI in corn oil

3. Inhalation induction
- No. of exposures: 5
- Exposure period: 3 hours (nose only)
- Test groups: 3 Groups of 8 animals
- Control group: 8 animals exposed to dry air
- Frequency of applications: daily
- Duration: 5 days
- Concentrations: 19.4 and 23.7 mg/m³


B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: day 21
- Exposure period: 15 minutes
- Test groups: all induction groups
- Control group:
- Concentrations: topically induced: 25.9 to 36.4 mg/m³; intradermally induced.: 27.6 to 36.5 mg/m³; inhalation induction: 34.6 to 44.1 mg/m³
- Evaluation : 10 minute baseline monitoring after 15 minute settling period; Monitoring 15 minutes during exposure and 15 minutes after removal from the challenge atmosphere
EXPOSURE ATMOSPHERE:
pre-warmed air was passed over the surface of MDI maintained at 65°C to create a saturated vapour. The MDI vapour was condensed by cooling to form an aerosol, adjusted with air to provide the appropriate atmospheric concentration. Particle size: MMAD ± 1.5 μm
PARAMETERS ASSESSED DURING THE STUDY:
- pulmonary hypersensitivity: measured as changes in respiratory rate following inhalation challenge;
- contact hypersensitivity: measured by topical challenge (modified Magnusson and Kligman; 100 μl of 3% MDI on shaved flanks) and antibody responses: ELISA and Passive Cutaneous Anaphylaxis (PCA). Blood was drawn by cardiac puncture 18 days following the initiation of exposure

Challenge controls:

control group n=7 received induction exposure to dry air and challenge expposure as treated animals

Results:

Attempts to sensitize guinea pigs by inhalation exposure to MDI were unsuccessful. No animals exhibited pulmonary responses following challenge with atmospheric MDI. In contrast, a proportion of animals exhibited pulmonary responses following inhalation challenge after induction by intradermal injection or topical application

GROUP	% MDI	PULMONARY RESPONSES	PCA
Topical 1	0	0/8	0/8
Topical 2	10	2/8	0/8
Topical 3	30	2/8	2/8
Topical 4	100	3/7	2/8
Intradermal 1	0	0/8	0/8
Intradermal 2	0.0003	0/6	0/8
Intradermal 3	0.003	1/8	0/8
Intradermal 4	0.03	5/8	1/8
Intradermal 5	0.3	5/8	3/8
Inhalation 1	0 mg/m^3	1/7	0/8
Inhalation 2	19.4-23.7 mg/m^3	0/16	0/16

Interpretation of results:

sensitising

Conclusions:

The current study is a source key study used (Rattray et al. 1994) for read-across to MDI MT and indicates a potential of respiratory sensitization. Also no generally accepted and validated test system is available to investigate the sensitizing effects of substances on the respiratory tract, numerous animal studies are available to demonstrate the respiratory sensitizing potential. Groups of guinea pigs were exposed to 4,4’-MDI by intradermal injection, topical application, or inhalation exposure for induction and by inhalation to 25-44 mg/m3 MDI for the challenge exposure (Rattray et al. 1994). Attempts to sensitize guinea pigs by inhalation exposure to MDI were unsuccessful; no animals exhibited pulmonary responses following challenge with MDI. Intradermal injection or topical application of MDI induced specific antibody responses and pulmonary responses in 12-65 % of guinea pigs depending upon induction dose and route. The findings from the guinea pig study, indicating a potential for respiratory sensitization and are in line with findings from other animals studies and observations in humans. 4,4’-MDI is officially classified as respiratory sensitizer (Cat.1) EU GHS 1272/2008 CLP.

Executive summary:

Numerous animal studies are available to demonstrate the respiratory sensitizing potential of MDI, which is supported by clinical observations in humans. For the endpoint respiratory sensitization all effects are consistent with the hypothesized MoA and direct electrophilic reactions of the NCO group on mMDI with biological nucleophiles. Reaction of NCO with a protein, marks antigen formation and the MIE of the sensitization process. Upon re-exposure via the respiratory route, protein-hapten complexes are recognized by the immune system, triggering an immunological response resulting in the induction of sensitization.

As the source substance 4,4’-MDI and the target substance MDI MT contain sufficient monomeric MDI, the driver of toxicity, similarities in reactions leading to respiratory sensitization are assumed. Accordingly, the CLP classification (Cat. 1, H334) for 4,4’-MDI is adopted to the target substance MDI MT.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

Human data: Data from clinical case reports (Ott et al., 2007) and epidemiological study data indicate respiratory sensitization in workers exposed to MDI substances (Bernstein et al., 1993, Bernstein et al. 2006, Bernstein & Jolly 1999).

Justification for classification or non-classification

According to CLP Regulation (EC) No.1272/2008 the classification of 4,4'-MDI (CAS No.101-68-8) is considered for the classification of MDI MT (CAS No.147993-65-5):

 GHS: Resp. Sens. 1 (H334: may cause allergy or asthma symptoms or breathing difficulties if inhaled); Skin Sens. 1 (H317: may cause an allergenic skin reaction)

MDI MT revealed a skin sensitizing potential in the mouse LLNA (classification: H317, Skin Sens. 1)