Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.058 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Modified dose descriptor starting point:
NOAEC
DNEL value:
0.058 mg/m³
Explanation for the modification of the dose descriptor starting point:
Not applicable (inhalation OEL and inhalation route of exposure)
AF for dose response relationship:
1
Justification:
not applicable (OEL value is used)
AF for differences in duration of exposure:
1
Justification:
not applicable (OEL value is used)
AF for interspecies differences (allometric scaling):
1
Justification:
not applicable (OEL value is used)
AF for other interspecies differences:
1
Justification:
not applicable (OEL value is used)
AF for intraspecies differences:
1
Justification:
not applicable (OEL value is used)
AF for the quality of the whole database:
1
Justification:
not applicable (OEL value is used)
AF for remaining uncertainties:
1
Justification:
not applicable (OEL value is used)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.11 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):
150
Modified dose descriptor starting point:
NOAEC
DNEL value:
16.88 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:
3
Justification:
only two concentrations were tested
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling in case of inhalation
AF for other interspecies differences:
1
Justification:
AF for remaining interspecies differences is considered to be superfluous (it is largely covered by AF of 10 for severity of effects)
AF for intraspecies differences:
5
Justification:
default for workers
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
10
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:
DNEL (Derived No Effect Level)
Value:
0.058 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Dose descriptor:
NOAEC
AF for dose response relationship:
1
Justification:
not applicable (OEL value is used)
AF for differences in duration of exposure:
1
Justification:
not applicable (OEL value is used)
AF for interspecies differences (allometric scaling):
1
Justification:
not applicable (OEL value is used)
AF for other interspecies differences:
1
Justification:
not applicable (OEL value is used)
AF for intraspecies differences:
1
Justification:
not applicable (OEL value is used)
AF for the quality of the whole database:
1
Justification:
not applicable (OEL value is used)
AF for remaining uncertainties:
1
Justification:
not applicable (OEL value is used)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.046 mg/m³
Most sensitive endpoint:
sensitisation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
5
Dose descriptor starting point:
NOAEC
AF for dose response relationship:
1
Justification:
clear dose response
AF for interspecies differences (allometric scaling):
1
Justification:
default in case of local effects
AF for other interspecies differences:
1
Justification:
AF for remaining interspecies differences is considered to be superfluous in case of local effects (toxicokinetic and toxicodynamic are the same across mammalian species).
AF for intraspecies differences:
5
Justification:
default for workers
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are identified

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.08 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Modified dose descriptor starting point:
NOAEL
DNEL value:
0.008 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
OEL of 5 ppb for inhalation for aromatic diisocyanates is considered an appropriate surrogate value to be used as starting point for DNEL derivation.
AF for dose response relationship:
1
Justification:
not applicable (OEL value is used)
AF for differences in duration of exposure:
1
Justification:
not applicable (OEL value is used)
AF for interspecies differences (allometric scaling):
1
Justification:
not applicable (OEL value is used)
AF for other interspecies differences:
1
Justification:
not applicable (OEL value is used)
AF for intraspecies differences:
1
Justification:
not applicable (OEL value is used)
AF for the quality of the whole database:
1
Justification:
not applicable (OEL value is used)
AF for remaining uncertainties:
1
Justification:
not applicable (OEL value is used)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
133 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
150
Modified dose descriptor starting point:
LOAEL
DNEL value:
20 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Acute oral study is available.
AF for dose response relationship:
3
Justification:
extrapolation of LOAEL to NAEL
AF for interspecies differences (allometric scaling):
4
Justification:
default in case of oral-to-dermal extrapolation
AF for other interspecies differences:
2.5
Justification:
default for remaining interspecies differences in toxicokinetic and toxicodynamic
AF for intraspecies differences:
5
Justification:
default for workers
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
default

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
17.2 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
15
Dose descriptor starting point:
other: LOAEL
AF for dose response relationship:
3
Justification:
extrapolation of LOAEL to NAEL
AF for interspecies differences (allometric scaling):
1
Justification:
default in case of local effects
AF for other interspecies differences:
1
Justification:
AF for remaining interspecies differences is considered to be superfluous in case of local effects (toxicokinetic and toxicodynamic are the same across mammalian species)
AF for intraspecies differences:
5
Justification:
default for workers
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
default

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 (dermal DNEL):

There is neither for TRIDI nor for TDI an acute dermal study available. The data from an oral acute study were taken to derive dermal DNEL for short-term exposures. TRIDI is of low acute toxicity by oral route of exposure. A LD50 greater than 2000 mg/kg bw (OECD 401) is considered to be a LOAEL because only one animal died and no severe systemic signs of toxicity were observed in treated animals (Bomhard, 1990). DNEL for acute systemic effects by dermal route was derived for the comparison with peak exposures and/or for accidental cases.

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 NOEC of 10 mg/m³ was established in an acute inhalation study (Pauluhn, 1990) and will serve as the starting point for the derivation of DNEL. The derived DNEL should cover also local effects by inhalation. However, there is no data available on respiratory hypersensitivity of TRIDI and therefore data on its nearest analogue TDI will be taken to derive DNELInhalation sensitization.

Acute/short-term exposure – local effects (dermal DNEL):

A DNEL for local effects should be calculated because TRIDI is assessed as skin sensitizer.

The general approach for assessing and controlling risks and setting DNELs for skin sensitizers is outlined in the ECHA Guidance Chapter R.8. The first step should always be a qualitative approach by using potency categorization to define risk management measures (RMMs) and operational conditions (OCs). Data derived from the LLNA can serve for the potency categorization and is based on EC3 value. The second step is setting a DNEL to judge the remaining/residual likelihood of risks after the appropriate RMMs and OCs are implemented.

The DNEL is derived from the LOAEL for induction which was obtained by conversion of EC3 value of 1 wt % for TDI (read-across substance) into dose per skin area (in µg/cm²). The substance induced a stimulation index of 13.8 in CBA mice, as a standard strain used in LLNA (Woolhiser et al., 2000). No linear interpolation can be made to a concentration which would induce a stimulation index of 3 because only one concentration of TDI was tested in the study. On the other hand, the topical application of 1% TDI did not induced antibody production in a Guinea Pig Maximisation Test (Karol et al., 1981). Therefore, 1% of TDI is considered to be a LOAEL for TRIDI.

Acute/short-term exposure – local effects (inhalation DNEL):

TDI, the nearest analogue to TRIDI, induced symptoms of respiratory hypersensitivity in guinea pigs if inhaled (Aoyama et al., 1984) or applied dermally (Karol et al., 1981). An induction level of 0.02 ppm failed to stimulate TDI-specific antibody production in animals, but elicited a pulmonary response in animals sensitized with higher dose levels than 0.02 ppm (Aoyama et al., 1984). Respiratory hypersensitivity was also demonstrated in guinea pigs sensitized dermally by inhalation challenge of 0.005 ppm (Karol et al., 1981). However, the elicitation thresholds correlate poorly with induction potency and the concentration which does not induce antibody production will ensure that no allergic response will occur if substance is inhaled. Therefore the level of 0.02 ppm is considered to be a threshold concentration which can serve as starting point for the DNEL derivation. The derived DNEL based on the data of TDI is inconsistent with the acute DNEL for systemic effects by inhalation.

Long-term exposure – systemic effects (dermal DNEL)

NOAEC of 0.15 ppm (corresponds to 1.75 mg/m³ for TRIDI) established for the read-across substance TDI in an inhalation carcinogenicity study in rats (OECD 451) (Loeser et al., 1983) can be used for the derivation of DNEL. NOAEL of 30 mg/kg bw established in an oral subchronic study in rats can also be used for the derivation of dermal DNEL and can serve for comparison to establish a definitive DNEL. Carcinogenicity was considered to be the most sensitive endpoint for long-term exposure since TRIDI (as other diisocyanates) was predicted carcinogenic. These DNELs will ensure sufficient that neoplastic and tumorigenic effects in humans will not occur after prolonged exposures.

Long-term exposure – systemic effects (inhalation DNEL)

The highest tested concentration of 0.15 ppm TDI in rats (Loeser, 1983), which did not produce clinical and histopathological signs and no significant carcinogenic effects can serve as the starting point for the DNEL derivation for TRIDI. This dose level was considered to be a NOAEC and was used to assess a definitive DNEL for TRIDI.

Long-term exposure – local effects (dermal DNEL)

No long-term dermal DNEL for local effects can be derived because there is no data available on effect levels for the target substance. Since sensitization response is developed after a single exposure, local effects should be covered by the long-term DNEL for systemic effects and by the DNELdermal sensitization.

Long-term exposure – local effects (inhalation DNEL)

Since the substance is classified as respiratory sensitizer (based on the available data for the nearest neighbour TDI), the long-term – inhalation DNEL for systemic effects should cover also local effects and ensure that no respiratory hypersensitivity in humans will occur. On the other hand, the short-term DNEL for sensitization by inhalation must not exceed the long-term – inhalation DNEL for systemic effects.

For the other non-threshold endpoints (mutagenicity, eye and skin irritation/corrosion) no DNELs can be derived because a No Observed Effect Level could not be established from the relevant studies. The controlling of risk of any hazard relevant for these endpoints should be covered by long-term DNELs and by DNELs derived for local effects.

Modification of the starting point:

From all available data for the different human health endpoints it is clear that 2,4,6-triisopropyl-m-phenylene diisocyanate exerts its effects by a threshold mode of action. Thus, DNELs can be calculated for the different threshold endpoints based on the most relevant dose descriptors per endpoint. DNELs are derived based on the available toxicity data for the target substance and for related substances, reflecting the routes, duration and frequency of exposure.

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).

Route-to-route extrapolation:

Oral-to-dermal extrapolation is performed to assess short-term dose for systemic effects by dermal route.

Inhalation-to-dermal extrapolation is performed to assess long-term dermal dose for systemic effects by dermal route.

Exposure conditions:

Exposure time differed in workers and in experimental animals in the carcinogenicity study. Rats were exposed to the test substance 6h daily (5 days/week), while workers are exposed 8h daily (5days/week). Therefore the factor of (6/8 = 0.75) was used to adjust the starting point for the derivation of long-term DNEL for inhalation (systemic effects). This factor was also used if inhalation long-term NOAEC was converted into dermal NOAEL.

Respiratory volumes:

Standard respiratory volume of 0.38 m³/kg bw/day for rats during 8 hours was used when converting long-term inhalation NOAEC of 0.15 ppm (corresponds to 1.75 mg/m³ for TRIDI) into long-term dermal NOAEL.

6.7 and 10 m³ are standard respiratory volumes for workers under normal conditions and by light activity, respectively. They were used by adjusting the starting point (inhalation short-term and long-term NOAECs).

Conversion of EC3 value to LOAEL

The substance TDI induced a dermal sensitization response with a calculated EC3 of 1 wt% and meets the criteria as a strong dermal sensitizer (ECETOC Technical Report 87, “Contact Sensitisation: Classification According to Potency”). It is suggested that the LLNA EC3 value correlates relatively well with the NOEL from human sensitization tests designed to confirm lack of induction (Gerberick et al., 2001; Griem et al., 2003; Basketter et al., 2005, cited in ECHA guidance R.8). Therefore, a threshold for skin sensitization can be defined as EC3 concentration (%), which is converted into dose per skin area (in µg/cm2):

EC3 [%] x¿x 250 [µg/cm²/%] = EC3[µg/cm²] = LOAEL

where¿is density of the liquid, 250 factor is calculated by converting 25 µL (applied to the mouse ear in a standard LLNA protocol) into µg/cm².

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:

The species-specific default assessment factor of 4 for allometric scaling for rats was applied in case of usage of oral NOAEL to derive dermal short-term and long-term DNEL and when inhalation long-term NOAEC was used for the derivation of dermal long-term DNEL;

Interspecies differences factor of 1 was applied in case of derivation of acute dermal DNEL for local effects using EC3 value from sensitization study since skin sensitization is considered as local immunological effect. Mechanistically, the biological sequelae that take place for the immune system to mount a response are the same across mammalian species, so, toxicokinetic and toxicodynamic (Api, 2006; Basketter, 2000, cited in ECHA guidance R.8);

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:

Assessment factor of 1 was applied for duration of exposure (chronic and carcinogenicity studies were used). 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 (there is a good quality data base available for the related substance TDI).

Issues related to severity of effects:

Diisocyanates are known to be of high concern for pulmonary toxicity at low exposure levels. Therefore:

An assessment factor of 10 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.

Issues related to dose response:

An assessment factor of 3 was applied when LOAEL was extrapolated to NAEL and when only two doses were tested.

Calculation of endpoint specific DNELs:

Acute/short-term exposure – systemic effects (dermal DNEL):

The oral acute LOAEL of 2000 mg/kg bw was converted into the dermal LOAEL:

Corrected dermal LOAEL = oral rat LOAEL x (ABS oral-rat/ABS dermal-human) = 2000 mg/kg bw x (100%/10%) = 20000 mg/kg bw.

DNEL = 20000/(4 x 2.5 x 5 x 3 x 1) =133 mg/kg bw. Assessment factors are: 4-interspecies, 2.5-remaining interspecies differences, 5-intraspecies, 3 – extrapolation of LOAEL to NAEL, 1 – quality of data base.

Acute/short-term exposure – systemic effects (inhalation DNEL):

a) The inhalation rat NOEC of 10 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' = 10 x (4h/0.25h) ^0.333 = 25.2 mg/m³;

b) The concentration of 25.2 mg/m³ was adjusted for the differences in the respiratory rates by normal conditions and by light activity: 25.2 mg/m³ x (6.7/10) = 16.88 mg/m³.

DNEL = 16.88/(5 x 10 x 3 x 1) = 0.11 mg/m³(0.009 ppm). Assessment factors are: 5 – intraspecies differences, 10 – severity of effects, 3 – dose-response (only two dose levels were tested), 1 – quality of data base.

Acute/short-term exposure – local effects (dermal DNEL):

EC3 value of 1 wt% (=LOAEL) was converted to dose per skin area (µg/cm²) as follows:

EC3 [%] x¿x 250 [µg/cm²/%] = 1 x 1.03 x 250 = 257.5 [µg/cm²]

DNELdermal sensitization= 257.5 µg/cm²/(1 x 1 x 5 x 3 x 1) = 17.2 µg/cm²where AFs are: 1 -interspecies, 1 –remaining interspecies differences, 5 - intraspecies, 3 – dose response, 1 – quality of data base.

The dose of 17.2 µg/cm² corresponds to 0.2 mg/kg bw (assuming contact area of 840 cm² (palm of two hands) in 70 kg adult worker)

Acute/short-term exposure – local effects (inhalation DNEL):

The threshold concentration of 0.02 ppm is considered to be a NOAEC for induction of antibody production against TDI. The dose descriptor is not modified because: bioavailability of the substance in experimental animals and in humans is considered to be the same via inhalation (no differences are known); differences in human and experimental exposure conditions are not relevant because the effects of respiratory hypersensitivity triggered by a concentration and not by dose level; no differences in respiratory volumes between experimental animals and humans are taken into account (local effects).

DNELinhalation sensitization= 0.02 ppm/(1 x 1 x 5 x 1 x 1) = 0.004 ppm (0.046 mg/m³), where 1 – interspecies (local effect), 1 – remaining interspecies differences (respiratory sensitization is a local effect: toxicokinetic and toxicodynamic are the same across mammalian species), 5 – intraspecies, 1 – dose response: (a clear dose response was detected in the study), 1 – quality of data base.

The concentration of 0.046 mg/m³ corresponds to 0.0067 mg/kg bw (taken 10 m³ as respiratory volume during 8-h working day and 70 kg body weigh in adult worker: (0.046 mg/m³ x 10 m³) /70 kg = 0.0067 mg/kg bw).

Long-term exposure – systemic effects (dermal DNEL)

1. The oral NOAEL of 30 mg/kg bw (males) was converted into dermal NOAEL according to the formula:

Corrected dermal NOAEL = oral rat NOAEL x (ABS oral-rat/ABS dermal-human) = 30 x (100%/10%) = 300 mg/kg bw.

DNEL = 300 mg/kg bw/(4 x 2.5 x 5 x 2 x 1) = 3.0 mg/kg bw.

Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 5 – intraspecies, 2 – study duration (sub-chronic study), 1 – quality of data base.

This DNEL is highly uncertain since it is higher than the DNEL of 0.2 mg/kg bw established for skin sensitization.

2. The inhalation NOAEC of 0.15 ppm (corresponds to 1.75 mg/m³ for TRIDI) was converted into the dermal NOAEL: Dermal NOAEL = inhalation NOAEC x sRVratx (ABS inhal-rat/ABS dermal-human) x (6/8) = 1.75 mg/m³ x 0.38 m³/kg/day x (100%/10%) x (6/8) = 5 mg/kg bw.

DNEL = 5 mg/kg bw/(4 x 2.5 x 5 x 1 x 3 x 1) = 0.033 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 5 – intraspecies, 1 – study duration (chronic study), 3 – dose response (only two concentrations were tested), 1 – quality of data base.

This DNEL must not be higher than the systemic dose which is protective against respiratory sensitization after long-term exposure by inhalation.

Long-term exposure – systemic effects (inhalation DNEL):

Using the LOAEC of 0.15 ppm established in a chronic study with rats and mice exposed to the structurally similar analogue TDI (Loeser, 1983), the corrected LOAEC would be: 1.75 mg/m³ x (6/8) x (6.7/10) = 0.88 mg/m³, where 1.75 mg/m³ is the concentration of TRIDI corresponding to 0.15 ppm.

DNEL = 0.88 mg/m³/(2.5 x 5 x 1 x 3 x 1) = 0.024 mg/m³. Assessment factors are: 2.5 – remaining interspecies differences, 5 – intraspecies, 1 – study duration (chronic study), 3 – dose response (only two concentrations were tested), 1 – quality of data base.

The DNEL of 0.024 mg/m³ is uncertain due to the deficiencies of the chronic study discussed in "Screening Assessment for TDIs, 2008", NIOSH, 1989 and in NTP, 1986. The concentration of 0.024 mg/m³ corresponds to 0.0034 mg/kg bw (taken 10 m³ as respiratory volume during 8-h working day under light activity and 70 kg body weigh in adult worker: (0.024 mg/m³ x 10 m³) /70 kg = 0.0034 mg/kg bw)

Long-term exposure – local effects (dermal DNEL):

Covered by the long-term – dermal DNEL (systemic effects) and by the DNELdermal sensitization

Long-term exposure – local effects (inhalation DNEL):

Covered by the long-term –inhalation DNEL and by the DNELinhalation sensitization.

Selection of the leading health effects and the corresponding DNELs

The critical DNELs should be the lowest DNELs obtained for each exposure pattern. Systemic effects should be assessed using the corresponding long-term DNELs. Local effects should be covered by DNELs for systemic effects.

TRIDI belong 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. Therefore DNELs are set for systemic and for local effects. The 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.

Comparison of DNELs

Acute/short-term exposures:

Dermal DNEL of 133 mg/kg bw for acute systemic effects is protective against systemic toxicity but it exceeds significantly dermal DNEL of 17.2 µg/cm² (0.2 mg/kg bw) for sensitization. In the same way, inhalation DNEL of 0.11 mg/m³ (0.009 ppm) for acute systemic effects is higher than the inhalation DNEL of 0.046 mg/m³ (0.004 ppm) for respiratory hypersensitivity. It can be explained by the fact that acute studies were conducted with TRIDI while the sensitization data belong to TDI. However, the risk of possible sensitization by dermal contact to TRIDI and by its inhalation cannot be ruled out therefore the lowest acute DNELs (in this case for local effects) should be more appropriate to cover risks of acute exposures. On the other hand, the DNELs for local effects can serve only as judgment that the remaining/residual likelihood of risks after the implementation of appropriate RMMs and OCs are excluded while primarily the qualitative approach of controlling of risk is proposed.

Long-term exposures:

Respiratory hypersensitivity can arise after dermal contact (TDI induced respiratory hypersensitivity in animals after dermal contact, Karol et al., 1981). Therefore, DNELs for systemic effects after prolonged contact must not be higher than those which are safe for dermal and respiratory sensitization.

The long-term DNELs for systemic effects by dermal route are very different: 3.0 mg/kg bw (originated from the oral study) and of 0.033 mg/kg bw (originated from the inhalation study). The DNEL of 3.0 mg/kg bw cannot be protective since it is higher than the DNELs for local effects (dermal =0.2 mg/kg bw (0.17 µg/cm²); inhalation = 0.0067 mg/kg bw (0.046 mg/m³). The long-term DNEL of 0.024 mg/m³ (corresponds to 0.0034 mg/kg bw) for systemic effects by inhalation is the lowest DNEL and is by a factor of 10 lower than the dermal DNEL of 0.033 mg/kg bw.

Evaluation of read-across data available for TRIDI and justification of an appropriate "safe level" for long-term exposures

Comparing DNELs, which have been derived from NOAELs available for TRIDI and TDI, it is evident that an appropriate safe exposure level of TRIDI for humans is highly uncertain. There is no data available for TRIDI on skin sensitization and respiratory hypersensitivity. Based on the read-across approach, these effects cannot be ruled out and therefore should be assessed using the data of its structural analogue TDI. However, a lot of inconsistences arise when the TRIDI data are used for systemic effects and TDI data for local effects. It can lead to over- or underestimation of hazard levels. Further, the reliability of experimental results of long-term inhalation study available for TDI (Loeser, 1983) is doubtful due to the high mortality in control and in treatment groups. Besides, the exposure levels used by Loeser have been criticized since they did not achieve a maximum tolerated dose and therefore they may not have been sufficient to detect a response” (Screening Assessment for TDIs (2008); NTP Report No. 251 (1986)). The long-term DNEL for systemic effects by inhalation derived from the NOAEC of this study is therefore overestimated for TRIDI. On the other hand, there are MAK values available for other aromatic and aliphatic diisocyanates, which lie in the range of 0.005 and 0.010 ppm (Wolf and Stirn, 2000). For 2,4-TDI and 2,6-TDI there are no MAK value available but Occupational Exposure Limit of 0.005 ppm is mentioned in the German TRGS 430 (March, 2009) and in CAREX Canada (http: //www. carexcanada. ca/en/toluene_diisocyanates/). According to the REACH Guidance R8., scientific justification is required as prerequisite to use such a value for the DNEL. The scientific background for setting of the German OEL is well documented and available via numerous public available literature sources. It is established from the most recent scientific animal studies and based on experience in humans taking into account measurements at the work place (Screening Assessment for TDIs, 2008; Woolrich, 1982). Comparing the derived DNELs for local and systemic effects with the surrogate value of 0.005 ppm which is proposed as DNEL, it is apparent that the values are of similar order of magnitude: 0.005 ppm (the lowest known OEL for aromatic diisocyanates) corresponds to 0.058 mg/m³ for TRIDI and is near the same as the calculated DNELinhalation sensitizationof 0.046 mg/m³. The calculated short-term DNEL of 0.11 mg/m³ (0.009 ppm) for systemic effects by inhalation is two times higher than the proposed 0.005 ppm and is in well expected correlation. For long-term dermal exposures, the concentration of 0.058 mg/m³ corresponds to 0.08 mg/kg bw (taken 10 m³ as respiratory volume during 8-h working day under light activity and 70 kg body weigh in adult worker: (0.058 mg/m³ x 10 m³) /70 kg = 0.008 mg/kg bw; moreover, taken into account dermal absorption rate of 10%: 0.008mg/kg bw x 10 = 0.08 mg/kg bw). The dose of 0.08 mg/kg bw is more appropriate as DNEL since it will protect against skin sensitization (it is lower than the calculated DNEL for skin sensitization (17.2 µg/cm² (=0.2 mg/kg bw)).

In conclusion, it is proposed to use a surrogate value of 0.005 ppm as the lowest known OEL value for aromatic diisocyanates (corresponding to 0.058 mg/m³ for TRIDI) * as DNEL for long-term exposure by inhalation. Since respiratory hypersensitivity can be developed after skin contact, the concentration of 0.058 mg/m³ (corresponding to 0.08 mg/kg bw) is proposed to be used as DNEL for long-term exposures by dermal route. These DNELs will protect against possible systemic effects, skin sensitization and respiratory hypersensitivity in workers.

Selected DNELs

The most critical health effects are dermal sensitization, pulmonary hypersensitivity and carcinogenicity. The following DNELs are relevant to ensure that these effects will not occur:

Long-term – dermal DNEL (systemic and local effects) =0.08 mg/kg bw

Long-term – inhalation DNEL (systemic and local effects) =0.058 mg/m³

*Formula used according to ECHA Guidance R.7a: mg/m3= (molecular weight * ppm) / 24.5

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.058 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Modified dose descriptor starting point:
NOAEC
DNEL value:
0.058 mg/m³
Explanation for the modification of the dose descriptor starting point:
Not applicable (Inhalation OEL and inhalation route of exposure)
AF for dose response relationship:
1
Justification:
not applicable (OEL value is used)
AF for differences in duration of exposure:
1
Justification:
not applicable (OEL value is used)
AF for interspecies differences (allometric scaling):
1
Justification:
not applicable (OEL value is used)
AF for other interspecies differences:
1
Justification:
not applicable (OEL value is used)
AF for intraspecies differences:
1
Justification:
not applicable (OEL value is used)
AF for the quality of the whole database:
1
Justification:
not applicable (OEL value is used)
AF for remaining uncertainties:
1
Justification:
not applicable (OEL value is used)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.084 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):
300
Modified dose descriptor starting point:
NOAEC
DNEL value:
25.2 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:
3
Justification:
only two concentrations were tested
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling in case of inhalation
AF for other interspecies differences:
1
Justification:
AF for remaining interspecies differences is considered to be superfluous (it is largely covered by AF of 10 for severity of effects)
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:
10
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:
DNEL (Derived No Effect Level)
Value:
0.058 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Dose descriptor:
NOAEC
AF for dose response relationship:
1
Justification:
not applicable (OEL value is used)
AF for differences in duration of exposure:
1
Justification:
not applicable (OEL value is used)
AF for interspecies differences (allometric scaling):
1
Justification:
not applicable (OEL value is used)
AF for other interspecies differences:
1
Justification:
not applicable (OEL value is used)
AF for intraspecies differences:
1
Justification:
not applicable (OEL value is used)
AF for the quality of the whole database:
1
Justification:
not applicable (OEL value is used)
AF for remaining uncertainties:
1
Justification:
not applicable (OEL value is used)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.023 mg/m³
Most sensitive endpoint:
sensitisation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Dose descriptor starting point:
NOAEC
AF for dose response relationship:
1
Justification:
clear dose response
AF for interspecies differences (allometric scaling):
1
Justification:
default in case of local effects
AF for other interspecies differences:
1
Justification:
AF for remaining interspecies differences is considered to be superfluous in case of local effects (toxicokinetic and toxicodynamic are the same across mammalian species)
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:
1
Justification:
No remaining uncertainties are identified

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.19 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Modified dose descriptor starting point:
NOAEL
DNEL value:
0.019 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
OEL of 5 ppb for inhalation for aromatic diisocyanates is considered an appropriate surrogate value to be used as starting point for DNEL derivation.
AF for dose response relationship:
1
Justification:
not applicable (OEL value is used)
AF for differences in duration of exposure:
1
Justification:
not applicable (OEL value is used)
AF for interspecies differences (allometric scaling):
1
Justification:
not applicable (OEL value is used)
AF for other interspecies differences:
1
Justification:
not applicable (OEL value is used)
AF for intraspecies differences:
1
Justification:
not applicable (OEL value is used)
AF for the quality of the whole database:
1
Justification:
not applicable (OEL value is used)
AF for remaining uncertainties:
1
Justification:
not applicable (OEL value is used)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
66.7 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
300
Modified dose descriptor starting point:
LOAEL
DNEL value:
20 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Acute oral study is available.
AF for dose response relationship:
3
Justification:
extrapolation of LOAEL to NAEL
AF for interspecies differences (allometric scaling):
4
Justification:
default in case of oral-to-dermal extrapolation
AF for other interspecies differences:
2.5
Justification:
default for remaining interspecies differences in toxicokinetic and toxicodynamic
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:
1
Justification:
default

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.6 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
30
Dose descriptor starting point:
other: LOAEL
AF for dose response relationship:
3
Justification:
extrapolation of LOAEL to NAEL
AF for interspecies differences (allometric scaling):
1
Justification:
default in case of local effects
AF for other interspecies differences:
1
Justification:
AF for remaining interspecies differences is considered to be superfluous in case of local effects (toxicokinetic and toxicodynamic are the same across mammalian species)
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:
1
Justification:
default

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.019 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Modified dose descriptor starting point:
NOAEL
DNEL value:
0.019 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
OEL of 5 ppb for inhalation for aromatic diisocyanates is considered an appropriate surrogate value to be used as starting point for DNEL derivation.
AF for dose response relationship:
1
Justification:
not applicable (OEL value is used)
AF for differences in duration of exposure:
1
Justification:
not applicable (OEL value is used)
AF for interspecies differences (allometric scaling):
1
Justification:
not applicable (OEL value is used)
AF for other interspecies differences:
1
Justification:
not applicable (OEL value is used)
AF for intraspecies differences:
1
Justification:
not applicable (OEL value is used)
AF for the quality of the whole database:
1
Justification:
not applicable (OEL value is used)
AF for remaining uncertainties:
1
Justification:
not applicable (OEL value is used)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.7 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
300
Modified dose descriptor starting point:
NOAEL
DNEL value:
2 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Not applicable (Oral study and oral route of exposure in humans)
AF for dose response relationship:
3
Justification:
extrapolation of LOAEL to NAEL
AF for interspecies differences (allometric scaling):
4
Justification:
default
AF for other interspecies differences:
2.5
Justification:
default for remaining interspecies differences in toxicokinetic and toxicodynamic
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:
1
Justification:
No other uncertainties are identified

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

The principles of the DNEL calculation for the general population are the same as already described for workers. However, there are additional considerations or deviations for:

Modification of the starting point:

Bioavailability (absorption by oral route)

The oral absorption in rats and in humans is assumed to be the same since no information for oral absorption for target chemical in rats and in humans is available.

Respiratory volumes:

No differences in the respiratory volumes under normal conditions and by light activity in humans were taken into account.

Exposure conditions:

Exposure duration of 24 hours was assumed for general population. Therefore a factor of (6/24 = 0.25) was used to adjust the starting point for the derivation of long-term DNEL for inhalation (systemic effects). This factor was also used if inhalation long-term NOAEC was converted into dermal NOAEL.

Body weight

Body weight of 60 kg for consumers was used.

Applying of assessment factors:

A higher assessment factor of 10 (in place of 5 for workers) for intraspecies variation/differences of human population was used.

Calculation of endpoint-specific DNEL for general population based on the available studies

Acute/short-term exposure – systemic effects (dermal DNEL):

The oral acute LOAEL of 2000 mg/kg bw was converted into the dermal LOAEL:

Corrected dermal LOAEL = oral rat LOAEL x (ABS oral-rat/ABS dermal-human) = 2000 mg/kg bw x (100%/10%) = 20000 mg/kg bw.

DNEL = 20000/(4 x 2.5 x 10 x 3 x 1)= 66.6 mg/kg bw. Assessment factors are: 4-interspecies, 2.5-remaining interspecies differences, 10 - intraspecies, 3 – extrapolation of LOAEL to NAEL, 1 – quality of data base (GLP study conducted with TRIDI).

Acute/short-term exposure – systemic effects (inhalation DNEL):

a) The inhalation rat NOEC of 10 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' = 10 x (4h/0.25h) ^0.333 = 25.2 mg/m³ b) The concentration of 25.2 mg/m³ was not adjusted for the differences in the respiratory rates by normal conditions and by light activity as in case with workers.

DNEL = 25.2/(10 x 10 x 3 x 1) = 0.084 mg/m³ (0.007 ppm). Assessment factors are: 10 – intraspecies differences, 10 – severity of effects, 3 – dose-response (only two dose levels were tested), 1 – quality of data base.

Acute/short-term exposure – local effects (dermal DNEL):

EC3 value of 1 wt% (=LOAEL) was converted to dose per skin area (µg/cm²) as follows:

EC3 [%] x¿x 250 [µg/cm²/%] = 1 x 1.03 x 250 = 257.5 [µg/cm²]

DNELdermal sensitization= 257.5 µg/cm²/(1 x 1 x 10 x 3 x 1) = 8.6 µg/cm²where AFs are: 1 -interspecies, 1 –remaining interspecies differences, 10 - intraspecies, 3 – dose response, 1 – quality of data base.

The dose of 8.6 µg/cm² corresponds to 0.12 mg/kg bw (assuming contact area of 840 cm² (palm of two hands) in 60 kg adult consumer: (8.6 µg/cm² x 840 cm²)/60 kg = 120.4 µg/kg bw = 0.12 mg/kg bw . Taken into account dermal absorption of 10%, 0.12 mg/kg bw x 10 =1.2 mg/kg bw

Acute/short-term exposure – local effects (inhalation DNEL):

The threshold concentration of 0.02 ppm is considered to be a NOAEC for induction of antibody production against TDI. The dose descriptor is not modified because: bioavailability of the substance in experimental animals and in humans is considered to be the same via inhalation (no differences are known); differences in human and experimental exposure conditions are not relevant because the effects of respiratory hypersensitivity triggered by a concentration and not by dose level; no differences in respiratory volumes between experimental animals and humans are taken into account (local effects).

DNELinhalation sensitization= 0.02 ppm/(1 x 1 x 10 x 1 x 1) = 0.002 ppm (0.023 mg/m³), where 1 – interspecies (local effect), 1 – remaining interspecies differences (respiratory sensitization is a local effect: toxicokinetic and toxicodynamic are the same across mammalian species), 10 – intraspecies, 1 – dose response: (a clear dose response was detected in the study), 1 – quality of data base.

The concentration of 0.023 mg/m³ corresponds to 0.008 mg/kg bw(taken 20 m³ as respiratory volume during 24 h and 60 kg body weigh in adult consumer: (0.023 mg/m³ x 20 m³) /60 kg = 0.008 mg/kg bw).

Acute/short-term exposure – systemic effects (oral DNEL):

The oral acute LOAEL of 2000 mg/kg bw has been taken as the starting point. The starting point was not modified for absorption rate. 100% absorption by oral route is assumed for rats and humans.

DNEL = 2000/(4 x 2.5 x 10 x 3 x 1)= 6.7 mg/kg bw. Assessment factors are: 4-interspecies, 2.5-remaining interspecies differences, 10 - intraspecies, 3 – extrapolation of LOAEL to NAEL, 1 – quality of data base.

Long-term exposure – systemic effects (dermal DNEL)

1. The oral NOAEL of 30 mg/kg bw (males) was converted into dermal NOAEL.Corrected dermal NOAEL = oral rat NOAEL x (ABS oral-rat/ABS dermal-human) = 30 x (100%/10%) = 300 mg/kg bw

DNEL = 300 mg/kg bw/(4 x 2.5 x 10 x 2 x 1) = 1.5 mg/kg bw.

Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 2 – study duration (sub-chronic study), 1 – quality of data base.

This DNEL is of the same order of magnitude as DNEL of 1.1 mg/kg bw for skin sensitisation.

2. The inhalation NOAEC of 0.15 ppm (corresponds to 1.75 mg/m³ for TRIDI) was converted into the dermal NOAEL: Dermal NOAEL = inhalation NOAEC x sRVratx (ABS inhal-rat/ABS dermal-human) x (6/24) = 1.75 mg/m³ x 1.15 m³/kg/day x (100%/10%) x (6/24) = 5.0 mg/kg bw.

DNEL = 5.0 mg/kg bw/(4 x 2.5 x 10 x 1 x 3 x 1) = 0.017 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 1 – study duration (chronic study), 3 – dose response (only two concentrations were tested), 1 – quality of data base.

Long-term exposure – systemic effects (inhalation DNEL):

Using the LOAEC of 0.15 ppm established in a chronic study with rats and mice exposed to the structurally similar analogue TDI (Loeser, 1983), the corrected LOAEC would be: 1.75 mg/m³ x (6/24) = 0.44 mg/m³, where 1.75 mg/m³ is the concentration of TRIDI corresponding to 0.15 ppm.

DNEL = 0.44 mg/m³/(2.5 x 10 x 1 x 3 x 1)= 0.0058 mg/m³. Assessment factors are: 2.5 – remaining interspecies differences, 10 – intraspecies, 1 – study duration (chronic study), 3 – dose response (only two concentrations were tested), 1 – quality of data base.

The DNEL of 0.0058 mg/m³ is uncertain due to the deficiencies of the chronic study discussed in "Screening Assessment for TDIs, 2008", NIOSH, 1989 and in NTP, 1986. The concentration of 0.0058 mg/m³ corresponds to 0.0019 mg/kg bw (taken 20 m³ as respiratory volume during 24 h and 60 kg body weigh in adult consumer: (0.0058 mg/m³ x 20 m³) /60 kg =0.0019 mg/kg bw)

Long-term exposure – systemic effects (oral DNEL)

1. The oral NOAEL of 30 mg/kg bw (males) has been taken as the starting point. The starting point was not adjusted for differences in absorption rates in rats and in humans. 100% absorption by oral route is assumed.

DNEL = 30 mg/kg bw/(4 x 2.5 x 10 x 2 x 1) =0.15 mg/kg bw.

Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 2 – study duration (sub-chronic study), 1 – quality of data base.

2. The inhalation NOAEC of 0.15 ppm (corresponds to 1.75 mg/m³ for TRIDI) was converted into the dermal NOAEL: Dermal NOAEL = inhalation NOAEC x sRVratx (ABS inhal-rat/ABS oral-human) x (6/24) = 1.75 mg/m³ x 1.15 m³/kg/day x (100%/100%) x (6/24) = 0.5 mg/kg bw.

DNEL = 0.5 mg/kg bw/(4 x 2.5 x 10 x 1 x 3 x 1) =0.0017 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 1 – study duration (chronic study), 3 – dose response (only two concentrations were tested), 1 – quality of data base.

Long-term exposure – local effects (dermal DNEL)

Covered by the long-term – dermal DNEL (systemic effects) and by the DNELdermal sensitization

Long-term exposure – local effects (inhalation DNEL):

Covered by the long-term –inhalation DNEL and by the DNELinhalation sensitization.

Selected DNELs for consumers

For the same reasons as by workers, it is proposed to use a surrogate value of 0.005 ppm as the lowest known OEL value for aromatic diisocyanates (corresponding to 0.058 mg/m³ for TRIDI) * as DNEL for long-term exposure by inhalation. The concentration of 0.058 mg/m³ corresponding to 0.019 mg/kg bw (considering 20 m³ as respiratory volume during 24-h/day and 60 kg body weight: (0.058 mg/m³ x 20 m³) /60 kg = 0.019 mg/kg bw)) is proposed to be used as DNEL for long-term exposures by oral route. Taken into account dermal absorption of 10%, the DNEL is 0.019 mg/kg bw x 10 = 0.19 mg/kg bw is considered to be appropriate for dermal route.

Long-term – dermal DNEL (systemic and local effects)= 0.19 mg/kg bw

Long-term – inhalation DNEL (systemic and local effects) = 0.058 mg/m³

Long-term – oral DNEL (systemic and local effects) = 0.019 mg/kg bw

 

*Formula used according to ECHA Guidance R.7a: mg/m3 = (molecular weight * ppm) / 24.5