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EC number: 218-485-4 | CAS number: 2162-73-4
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
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- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
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- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
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- Nanomaterial pour density
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- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
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- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data

Toxicological Summary
- Administrative data
- Workers - Hazard via inhalation route
- Workers - Hazard via dermal route
- Workers - Hazard for the eyes
- Additional information - workers
- General Population - Hazard via inhalation route
- General Population - Hazard via dermal route
- General Population - Hazard via oral route
- General Population - Hazard for the eyes
- Additional information - General Population
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.67 mg/m³
- Most sensitive endpoint:
- acute toxicity
- Route of original study:
- By inhalation
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 50
- Dose descriptor starting point:
- NOAEC
- Value:
- 20 mg/m³
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 33.73 mg/m³
- Explanation for the modification of the dose descriptor starting point:
Not applicable (Inhalation study and inhalation route of exposure). Dose descriptor starting point is obtained using Haber's law (please refer to Discussion below)
- AF for dose response relationship:
- 1
- Justification:
- default (seven concentrations were tested; spacing range 2-3 fold for the first three concentrations with apparent clear dose-response)
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- default (no allometric scaling in case of inhalation should be applied)
- AF for other interspecies differences:
- 2.5
- Justification:
- default (no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans)
- AF for intraspecies differences:
- 5
- Justification:
- default (for workers)
- AF for the quality of the whole database:
- 1
- Justification:
- default (GLP guideline study of high quality)
- AF for remaining uncertainties:
- 4
- Justification:
- Severity of effects (2,4,6-triisopropyl-m-phenylene-diisocyanate is considered to be of high pulmonary toxicity)
Local effects
Long term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
Acute/short term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
DNEL related information
Workers - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
Acute/short term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
Workers - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- no hazard identified
Additional information - workers
The calculation of the DNELs is performed in accordance with the principles given in ECHA (2008) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health
Available dose descriptors:
For 2,4,6-triisopropyl-m-phenylene diisocyanate DNELs are needed for:
Acute/short-term exposure – systemic effects (inhalation DNEL):
Since the substance is classified as acute toxic Cat 1, Inhalation, H330, a DNEL for acute systemic effects by inhalation needs to be derived. A NOAEC of 20 mg/m³ can be established in an acute inhalation study (Pauluhn, 1990) and will serve as the starting point for the derivation of DNEL. The derived DNEL does not cover local effects by inhalation as the substance is classified as Resp. Sens. 1.
Modification of the starting point:
The inhalation rat NOAEC of 20 mg/m³ was adjusted for exposure duration because the animals were exposed to TRIDI by inhalation during 4 hours. Therefore, the NOEC is corrected to a dose descriptor representing 15 minutes exposure using the modified Haber's law (Gaylor, 2000): in case of extrapolation from longer to shorter durations of exposure (C³ x t) = (C') ³ x t', giving C' = C x (t/t') E0.333. C' is sought concentration. C' = 20 x (4h/0.25h) ^0.333 = 50.35 mg/m³. The concentration of 50.35 mg/m³ was adjusted for the differences in the respiratory rates by normal conditions and by light activity: 50.35 mg/m³ x (6.7/10) = 33.73 mg/m³.
DNEL = 33.73/(1x1x2.5x5x1x4) = 0.67 mg/m³. Assessment factors are: 1 – dose-response, 1 – interspecies differences (allometric scaling), 2.5 – intraspecies differences, 5 – intraspecies differences, 1 – quality of data base, 4 – severity of effects
Applying of assessment factors and calculation of DNELs:
The assessment factors have been applied to the correct starting point to obtain the endpoint specific DNELs. Assessment factors (AFs) correct uncertainties and variability within and between species in the effect data.
- Interspecies differences: No allometric scaling factor was applied when NOAEC from an inhalation study was used for the derivation of inhalation DNEL;
- Assessment factors of 2.5 was applied for remaining interspecies differences in toxicodynamics between rat and human.
Intraspecies differences: Assessment factor of 5 was applied for workers.
- Extrapolation of duration: Haber’s Law was used to derive 15-min effect concentration for inhalation (see calculation of endpoint specific DNELs).
- Quality of whole data base: The assessment factors for uncertainties to the quality of the data base were used: 1 because of good quality data base.
- Issues related to severity of effects: Diisocyanates are known to be of high concern for pulmonary toxicity at low exposure levels. Therefore an AF of 4 was considered for severity of effects by the derivation of acute DNEL for systemic effects by inhalation because no data is available on respiratory sensitization hazard of the substance. .
Qualitative Assessment:
Acute/short-term and long-term exposure – local effects (dermal)
Acute/short-term and long-term exposure – local effects (inhalation)
Based on the following aspects, a qualitative risk assessment was conducted for the inhalative and dermal route regarding local effects:
TRIDI belongs to diisocyanates which are known to be of high concern for pulmonary toxicity at low exposure levels (US EPA, 2005). The substance is irritating to skin and predicted to be sensitizing to skin and respiratory system. Moreover, respiratory hypersensitivity can take place if the substance applied dermally. With regard to classification of Skin and Resp. Sens 1, sensitisation is considered the most sensitive endpoints for the inhalative and dermal route regarding local effects. According to ECHA Guidance on information requirements and chemical safety assessment (V2.1, 2012) “Skin sensitisation is generally regarded as a threshold effect, although in practise it may be very difficult to derive a threshold and to set a DNEL” further the Guidance states that “at present there are no validated or widely accepted animal or in vitro test protocols to detect respiratory sensitisation or to determine the induction or elicitation thresholds”.
This qualitative prediction of sensitisation property cannot be supported by a quantitative prediction of a hazard threshold for induction or elicitation of sensitisation responses for TRIDI. It is not possible to derive an approximate threshold for sensitisation based on available data for other diisocyanate members of the category, because a detailed evaluation of the data set by ECHA (2018, 2019) led to a conclusion that “it is not possible …to set any DNEL that will be meaningful for the risk characterization” for all diisocyanates in this category. This is because of various short-comings in the available studies as well as lack of knowledge on the quantitative a mechanistic interaction between the inhalation and dermal routes, which are both relevant for development of chronic bronchitis, chronic restrictive pulmonary disease and other hypersensitivity effects (ECHA, 2019)
Furthermore the established inhalative 5 ppb OEL values (8-hr Threshold Limit Value - time-weighted average (TLV-TWA)) for diisocyanatesfor lot of aliphatic, cyclic and aromatic isocyanates, is not considered further, as in the ECHA Scientific report (2019) it is stated that “ECHA has not proposed an OEL but proposes to further develop the approach to derive an exposure response and then establish an OEL”. In this report it is mentioned that “it is not possible to identify a threshold or to derive a dose-response for the induction of respiratory sensitisation” and with regard to elicitation, “ECHA considers that the data available do not allow identification of a threshold average exposure concentration below which no cases of asthma would occur among those workers where the induction of respiratory sensitisation to diisocyanates has already taken place.”
Since currently an exposure-response approach based on NCO groups is under development by RAC, it has no sense to derive an acceptable exposure level or a DNEL.
A "high hazard" is concluded for local effects (acute/short-term and long-term) for inhalation and dermal route for the substance TRIDI due to its classification as Resp. Sens. 1 (H334: May cause allergy of asthma symptoms or breathing difficulties if inhalted) and Skin. Sens. 1 (H315: Causes skin irritation), which corresponds to a high hazard according to ECHA's Guidance Part E (v3, May 2016). Appropriate risk management measures for the high hazard category given in Table E3 -1, Part E (Risk Characterisation) of the REACH Guidance on Information Requirements and Chemical Safety Assessment are applied.
Acute/short-term and long-term exposure – systemic effects (dermal)
Long-term exposure – systemic effects (inhalation)
"No hazard identified" is concluded for systemic effects after inhalation exposure for 2,4,6-triisopropyl-m-phenylene-diisocyanate (TRIDI), as local effects determine toxicity and prevail over systemic effect.
Based on the highly reactive isocyanate groups, TRIDI is considered to possess high local pulmonary toxicity that would also lead to certain dose-limiting local effects. This assumption is supported by the acute inhalation toxicity study of Pauluhn 1990, and the 2 year repeated-dose inhalation study (6 h/day, 5 days/week, ~2 years) of the read-across diisocyanate category substance toluene-diisocyanate (TDI) (Loeser, 1983). The results of both studies did not give indication for systemic availability of the test substance after inhalation.
Bioavailability (absorption)
Based on high logPow (7.56) and low water solubility (0.005 mg/L) of TRIDI only negligible dermal absorption is expected for the target substance (please refer to Annex III, attached to this CSR). Dermal absorption is considered to be 10%. The dermal absorption in rats and in humans is assumed to be the same since no information for dermal absorption of target chemical in humans is available. 100% absorption is assumed for oral and inhalation routes in rats and in humans (worst case; according to the ECETOC Report No 111, 100% absorption for inhalation can be used in case of absence of substance specific data for absorption).
Other leading health effect is carcinogenicity which is relevant only by oral route of exposure. Thus, a long-term DNEL for dermal and inhalation routes should be consistent with one another ensuring that no respiratory sensitization and no carcinogenic effects will occur. Further, DNELs for local effects by inhalation should be consistent with DNELs for systemic effects by inhalation, thereby controlling the risk of respiratory hypersensitivity.
General Population - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.5 mg/m³
- Most sensitive endpoint:
- acute toxicity
- Route of original study:
- By inhalation
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 100
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 50.4 mg/m³
- Explanation for the modification of the dose descriptor starting point:
- Not applicable (Inhalation study and inhalation route of exposure). Dose descriptor starting point is obtained using Haber's law (please refer to Discussion below)
- AF for dose response relationship:
- 1
- Justification:
- seven concentrations were tested
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- No allometric scaling in case of inhalation
- AF for other interspecies differences:
- 2.5
- Justification:
- Default value
- AF for intraspecies differences:
- 10
- Justification:
- default for general population
- AF for the quality of the whole database:
- 1
- Justification:
- default
- AF for remaining uncertainties:
- 4
- Justification:
- Severity of effects (2,4,6-triisopropyl-m-phenylene-diisocyanate is considered to be of high pulmonary toxicity)
Local effects
Long term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
Acute/short term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
DNEL related information
General Population - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
Acute/short term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
General Population - Hazard via oral route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- medium hazard (no threshold derived)
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
General Population - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- no hazard identified
Additional information - General Population
The calculation of the DNELs is performed in accordance with the principles given in ECHA (2008) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health
Available dose descriptors:
For 2,4,6-triisopropyl-m-phenylene diisocyanate DNELs are needed for:
Acute/short-term exposure – systemic effects (inhalation DNEL):
Since the substance is classified as acute toxic Cat 1, Inhalation, H330, a DNEL for acute systemic effects by inhalation needs to be derived. A NOAEC of 20 mg/m³ can be established in an acute inhalation study (Pauluhn, 1990) and will serve as the starting point for the derivation of DNEL. The derived DNEL does not cover local effects by inhalation as the substance is classified as Resp. Sens. 1.
Modification of the starting point:
The inhalation rat NOAEC of 20 mg/m³ was adjusted for exposure duration because the animals were exposed to TRIDI by inhalation during 4 hours. Therefore, the NOEC is corrected to a dose descriptor representing 15 minutes exposure using the modified Haber's law (Gaylor, 2000): in case of extrapolation from longer to shorter durations of exposure (C³ x t) = (C') ³ x t', giving C' = C x (t/t') E0.333. C' is sought concentration. C' = 20 x (4h/0.25h) ^0.333 = 50.35 mg/m³. The concentration of 50.35 mg/m³ was adjusted for the differences in the respiratory rates by normal conditions and by light activity: 50.35 mg/m³ x (6.7/10) = 33.73 mg/m³.
DNEL = 33.73/(1x1x2.5x5x1x4) = 0.67 mg/m³. Assessment factors are: 1 – dose-response, 1 – interspecies differences (allometric scaling), 2.5 – intraspecies differences, 5 – intraspecies differences, 1 – quality of data base, 4 – severity of effects
Applying of assessment factors and calculation of DNELs:
The assessment factors have been applied to the correct starting point to obtain the endpoint specific DNELs. Assessment factors (AFs) correct uncertainties and variability within and between species in the effect data.
- Interspecies differences: No allometric scaling factor was applied when NOAEC from an inhalation study was used for the derivation of inhalation DNEL;
- Assessment factors of 2.5 was applied for remaining interspecies differences in toxicodynamics between rat and human.
Intraspecies differences: Assessment factor of 5 was applied for workers.
- Extrapolation of duration: Haber’s Law was used to derive 15-min effect concentration for inhalation (see calculation of endpoint specific DNELs).
- Quality of whole data base: The assessment factors for uncertainties to the quality of the data base were used: 1 because of good quality data base.
- Issues related to severity of effects: Diisocyanates are known to be of high concern for pulmonary toxicity at low exposure levels. Therefore an AF of 4 was considered for severity of effects by the derivation of acute DNEL for systemic effects by inhalation because no data is available on respiratory sensitization hazard of the substance. .
Qualitative Assessment:
Acute/short-term and long-term exposure – local effects (dermal)
Acute/short-term and long-term exposure – local effects (inhalation)
Based on the following aspects, aqualitative risk assessment was conducted for the inhalative and dermal route regarding local effects:
TRIDI belongs to diisocyanates which are known to be of high concern for pulmonary toxicity at low exposure levels (US EPA, 2005). The substance is irritating to skin and predicted to be sensitizing to skin and respiratory system. Moreover, respiratory hypersensitivity can take place if the substance applied dermally. With regard to classification of Skin and Resp. Sens 1, sensitisation is considered the most sensitive endpoints for the inhalative and dermal route regarding local effects. According to ECHA Guidance on information requirements and chemical safety assessment (V2.1, 2012) “Skin sensitisation is generally regarded as a threshold effect, although in practise it may be very difficult to derive a threshold and to set a DNEL” further the Guidance states that “at present there are no validated or widely accepted animal or in vitro test protocols to detect respiratory sensitisation or to determine the induction or elicitation thresholds”.
This qualitative prediction of sensitisation property cannot be supported by a quantitative prediction of a hazard threshold for induction or elicitation of sensitisation responses for TRIDI. It is not possible to derive an approximate threshold for sensitisation based on available data for other diisocyanate members of the category, because a detailed evaluation of the data set by ECHA (2018, 2019) led to a conclusion that “itis not possible …to set any DNEL that will be meaningful for the risk characterization” for all diisocyanates in this category. This is because of various short-comings in the available studies as well as lack of knowledge on the quantitative a mechanistic interaction between the inhalation and dermal routes, which are both relevant for development of chronic bronchitis, chronic restrictive pulmonary disease and other hypersensitivity effects (ECHA, 2019)
Furthermore the established inhalative 5 ppb OEL values (8-hr Threshold Limit Value - time-weighted average (TLV-TWA)) for diisocyanatesfor lot of aliphatic, cyclic and aromatic isocyanates, is not considered further, as in the ECHA Scientific report (2019) it is stated that “ECHA has not proposed an OEL but proposes to further develop the approach to derive an exposure response and then establish an OEL”. In this report it is mentioned that “it is not possible to identify a threshold or to derive a dose-response forthe induction of respiratorysensitisation” and with regard to elicitation, “ECHA considers that the data available do not allow identification of a threshold average exposure concentration below which no cases of asthma would occur among those workers where the induction of respiratory sensitisation to diisocyanates has already taken place.”
Since currently an exposure-response approach based on NCO groups is under development by RAC, it has no sense to derive an acceptable exposure level or a DNEL.
A "high hazard" is concluded for local effects (acute/short-term and long-term) for inhalation and dermal route for the substance TRIDI due to its classification as Resp. Sens. 1 (H334: May cause allergy of asthma symptoms or breathing difficulties if inhalted) and Skin. Sens. 1 (H315: Causes skin irritation), which corresponds to a high hazard according to ECHA's Guidance Part E (v3, May 2016). Appropriate risk management measures for the high hazard category given in Table E3 -1, Part E (Risk Characterisation) of the REACH Guidance on Information Requirements and Chemical Safety Assessment are applied.
Long-term exposure – systemic effects (oral exposure)
TRIDI is proposed to be classified and labelled as possible carcinogen due to the evidence that TRIDI rapidly hydrolyses to its corresponding diamine TRIDA, which may possess carcinogenic activity in similarity to other diamines produced from isocyanates. Even though TRIDI was negative in thre ein vitro genotoxicity tests, and was predicted to be negative for non-genotoxic carcinogenicity by Toxtree modelling software, the aromatic amine TRIDA was identified as a structural alert leading to genotoxic carcinogenicity. Furthermore, the substance was predicted to possess carcinogenic activity by the OECD QSAR Toolbox v4.4.
Carcinogenicity was considered to be the most sensitive endpoint for long-term exposure since TRIDI (as other diisocyanates) was predicted carcinogenic. In an oral subchronic study in rats a NOAEL of 30 mg/kg bw was established. A worst-case approach, by a qualitative assessment with a hazard conclusion of "medium hazard" ensure sufficient that neoplastic and tumorigenic effects in humans will not occur after prolonged exposures. The evaluation of Loeser and colleagues revealed toluene diisocyanate not to be carcinogenic after exposure via inhalation.
Acute/short-term and long-term exposure – systemic effects (dermal)
Long-term exposure – systemic effects (inhalation)
"No hazard identified" is concluded for systemic effects after inhalation exposure for 2,4,6-triisopropyl-m-phenylene-diisocyanate (TRIDI), as local effects determine toxicity and prevail over systemic effect.
Based on the highly reactive isocyanate groups, TRIDI is considered to possess high local pulmonary toxicity that would also lead to certain dose-limiting local effects. This assumption is supported by the acute inhalation toxicity study of Pauluhn 1990, and the 2 year repeated-dose inhalation study (6 h/day, 5 days/week, ~2 years) of the read-across diisocyanate category substance toluene-diisocyanate (TDI) (Loeser, 1983). The results ob both studies did not give indication systemic availability of the test substance after inhalation.
Bioavailability (absorption)
Based on high logPow (7.56) and low water solubility (0.005 mg/L) of TRIDI only negligible dermal absorption is expected for the target substance (please refer to Annex III, attached to this CSR). Dermal absorption is considered to be 10%. The dermal absorption in rats and in humans is assumed to be the same since no information for dermal absorption of target chemical in humans is availab
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