Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.024 mg/m³
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
75
Dose descriptor starting point:
NOAEL
Value:
1 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
1.763 mg/m³
Explanation for the modification of the dose descriptor starting point:
Due to the low vapour pressure of the test substance acute exposure hazard via inhalation is unlikely for humans. Therefore a route-to -route extrapolation from an oral OECD 421 study, as a worst case is justified.
AF for dose response relationship:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for differences in duration of exposure:
6
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for interspecies differences (allometric scaling):
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for other interspecies differences:
2.5
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for intraspecies differences:
5
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for the quality of the whole database:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for remaining uncertainties:
1
Justification:
no uncertainties remaining
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.003 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
300
Dose descriptor starting point:
NOAEL
Value:
1 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Long-term systemic DNEL for dermal route has been derived from the NOAEL of 1 mg/kg bw established in the OECD 421 study in rats. The substance is well systemically available by the oral route. As seen in the acute dermal study in rats, the substance was not systemically toxic by the dermal route and is also expected to be of lower systemic toxicity after prolonged exposure with the skin. The starting point for the DNEL derivation can be obtained by conversion of oral NOAEL into dermal NOAEL (route-to-route extrapolation).
AF for dose response relationship:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for differences in duration of exposure:
6
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for interspecies differences (allometric scaling):
4
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for other interspecies differences:
2.5
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for intraspecies differences:
5
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for the quality of the whole database:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for remaining uncertainties:
1
Justification:
no other uncertainties remaining
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

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 (2010) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health.”

For bis(2,6-diisopropylphenyl)carbodiimide (CDI), the following dose descriptors are available:

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

 

There are two acute studies available: oral and dermal. The established LD50 of 300 -2000 mg/kg bw in the oral study (Gillissen, 2009) leads to classification of substance in the Cat 4. However, oral route of exposure is not relevant for workers and risk arising from an accidental intake of the substance orally should be controlled qualitatively (inclusion of appropriate RMMs and OCs as well as personal training). CDI was not acutely toxic after dermal administration to rats (Driscoll, 2001). A LD50 greater than 2000 mg/kg bw (OECD 401) is considered to be a NOAEL because no deaths and no clinical signs of systemic toxicity were noted in treated animals. The animals gained body weight, and no abnormalities were observed at necropsy. Therefore, DNEL for acute systemic effects by the dermal route is unnecessary since the long-term DNEL covers sufficiently the risk of short-term exposure. The calculated DNEL can serve only for peak exposures and/or for accidental cases.

 

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

 

No acute DNEL for systemic effects by inhalation can be established since there is no dose descriptor available. The substance has a very low vapour pressure ( ≤ 5.8*10E-3 Pa at 20°C) and is not expected to bear a significant airborne hazard.

 

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

 

The substance is not irritating to the skin (Kaufmann, 1993) and does not possess sensitisation potential (Driscoll, 2001). The long-term dermal DNEL for systemic effects covers sufficiently for local effects.

 

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

 

The substance does not bear a significant airborne hazard (and is not irritating or sensitizing to respiratory system). The long-term inhalation DNEL for systemic effects covers sufficiently for local effects.

 

Long-term exposure – systemic effects (dermal DNEL)

 

Long-term systemic DNEL for dermal route has been derived from the NOAEL of 1 mg/kg bw established in the oral OECD 421 screening study in rats, as it was identified to be the most sensitive endpoint. The available data indicates a clear dose-response-relationship, which allows a quantitative approach. The starting point for the DNEL derivation can be obtained by conversion of oral NOAEL into dermal NOAEL (route-to-route extrapolation).

 

Long-term exposure – systemic effects (inhalation DNEL)

 

There are no long-term inhalation studies with the target substance available. The inhalation DNEL can be derived from the oral NOAEL of 1 mg/kg bw established in the OECD 421 screening study in rats by route-to-route extrapolation.

 

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. Local effects are covered sufficiently by the long-term DNEL for systemic effects.

 

Long-term exposure – local effects (inhalation DNEL)

 

No long-term inhalation DNEL for local effects can be derived because there is no data available on effect levels for the target substance. Local effects are covered sufficiently by the long-term DNEL for systemic effects.

 

For the other non-threshold endpoints (mutagenicity, eye and skin irritation/corrosion) no DNELs can be derived because no No Observed Effect Level could be established from the relevant studies. The controlling of risk of any hazard relevant for these endpoints should be covered by the long-term DNELs and by the DNELs derived for local effects.

 

Modification of the starting point:

From all available data for the different human health endpoints it is clear that bis-(2,6-diisopropylphenyl)carbodiimide 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, reflecting the routes, the duration and the frequency of exposure.

 

Bioavailability (absorption)

There is no substance-specific information on absorption by the oral, dermal and inhalation routes available. The absorption rates are assessed based on the physico-chemical properties and on the effects observed in the studies. Due to the effects seen in the OECD 421 screening study in rats, 100% absorption by oral route is considered for the target substance (for the detailed information on absorption please refer to section "Toxicokinetics, metabolism and distribution" of this CSR or section 7.1 of IUCLID file). No significant dermal absorption is expected for the substance (log Pow of 6.2 and water solubility of 0.05 mg/L point to a very poor absorption through the skin). However, dermal absorption cannot be completely ruled out since the molecular weight of 362.5 is under 500 and according to the TGD, Part I, Appendix VI, 100% of dermal absorption should be considered in this case. Dermal absorption in rats and in humans is assumed to be the same since no information for dermal absorption of the 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 110, 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 obtain long-term dermal NOAEL for systemic effects.

The following formula was used: corrected dermal NOAEL = oral NOAEL x (ABSoral-rat/ABS derm-human) where ABS is absorption.

Oral-to-inhalation extrapolation is performed to obtain long-term inhalation NOAEC for systemic effects. The following formula was used: corrected inhalatory NOAEC = oral NOAEL x (1/sRVrat) x (ABSoral-rat/ABSinh-human) x (6.7 m³/10 m³) where sRV is standard respiratory volume of rats during 8 hours (= 0.38 m³/kg/day); ABS-absorption and 6.7 m³ and 10 m³ are standard respiratory volumes for workers under normal conditions and by light activity.

 

Exposure conditions:

No modification of the starting points for exposure conditions was necessary since the systemic dose after oral administration of the test material was already assessed in respiratory volume taken for rats during 8 h (0.38m³).

 

Applying of assessment factors and calculation of DNELs:

The assessment factors have been applied to the corrected 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 the case of employment of the dermal LD50(=NOAEL) to derive dermal short-term DNEL, in case of the oral NOAEL from 28 -day study, which was used to derive the dermal long-term DNEL and when the inhalation long-term NOAEC was used for the derivation of dermal long-term DNEL;

No allometric scaling factor was applied when the oral NOAEL from the OECD 421 screening study in rats was used for the derivation of inhalation long-term DNEL;

An assessment factor of 2.5 was applied for remaining interspecies differences in toxicodynamics between rat and human in all cases.

 

Intraspecies differences:

An assessment factor of 5 was applied for workers in all cases.

 

Extrapolation of duration:

An assessment factor of 1 was applied for duration of exposure when acute study was used for the derivation of the acute dermal DNEL.

An assessment factor of 6 was applied for duration of exposure (subacute-to-chronic).

 

Quality of whole data base:

The assessment factors for uncertainties to the quality of the data base were used: 1 in all cases (GLP studies were used).

 

Issues related to dose response:

A default assessment factor of 1 was applied when NOAEL was used.

 

Calculation of DNELs:

 

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

The dermal acute NOAEL of 2000 mg/kg bw is not modified for differences in dermal absorptions between rats and humans: Corrected dermal NOAEL = dermal rat NOAEL x (ABS dermal-rat/ABS dermal-human) = 2000 mg/kg bw x (100%/100%) = 2000 mg/kg bw.

DNEL = 2000/(4 x 2.5 x 5 x 1 x 1) = 40 mg/kg bw. Assessment factors are: 4-interspecies, 2.5-remaining interspecies differences, 5-intraspecies, 1 -study duration (setting of acute DNEL based on acute study), 1 – quality of data base.

Long-term exposure – systemic effects (dermal DNEL)

The oral NOAEL of 1 mg/kg bw was converted into the dermal NOAEL: Dermal NOAEL = oral NOAEL x (ABS oral-rat/ABS dermal-human) = 1 mg/kg bw x (100%/100%) = 1 mg/kg bw.

DNEL = 1 mg/kg bw/(4 x 2.5 x 5 x 6 x 1 x 1) = 0.0033 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 5 – intraspecies, 6 – study duration (sub-acute study), 1 – dose response (clear dose response), 1 – quality of data base (default).

 

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

The oral NOAEL of 1 mg/kg bw was converted into the inhalation NOAEC:

Inhalation NOAEC = oral NOAEL x (1/sRVrat) x (ABS oral-rat/ABS inhal-human) x (6.7 m³/10 m³) = 1 mg/kg bw x (1/0.38 m³/kg/day) x (100%/100%) x (6.7/10) = 1.763 mg/m³

DNEL = 1.763 mg/m³/(2.5 x 5 x 6 x 1 x 1) = 0.024 mg/m³. Assessment factors are: 2.5 – remaining interspecies differences, 5 – intraspecies, 6 – study duration (sub-acute study), 1 – dose response (clear dose response), 1 – quality of data base (default).

 

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. As seen from all available studies for the target chemical, toxicity of various organs can occur by prolonged exposure to the chemical.

The risk of dermal short-term exposure should be controlled qualitatively. Dermal short-term DNEL of 40 mg/kg bw for acute systemic effects is appropriate for remaining risks (after RMMs and OCs are implemented) and for accidental cases. Long-term dermal DNEL protects sufficiently against short-term exposures. The long-term DNELs for systemic effects are the lowest DNELs and they cover any hazard arising from short-term exposures as well as local effects. They ensure that organ toxicity will not occur in humans.

Selected DNELs

Long-term – dermal DNEL (systemic and local effects) = 0.0033 mg/kg bw

 

Long-term – inhalation DNEL (systemic and local effects) = 0.024 mg/m³

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.006 mg/m³
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
150
Dose descriptor starting point:
NOAEL
Value:
1 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
0.87 mg/m³
Explanation for the modification of the dose descriptor starting point:
Due to the low vapour pressure of the test substance acute exposure hazard via inhalation is unlikely for humans. Therefore a route-to -route extrapolation from an oral OECD 421 study, as a worst case is justified.
AF for dose response relationship:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for differences in duration of exposure:
6
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for interspecies differences (allometric scaling):
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for other interspecies differences:
2.5
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for intraspecies differences:
10
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for the quality of the whole database:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.002 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
600
Dose descriptor starting point:
NOAEL
Value:
1 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Long-term systemic DNEL for dermal route has been derived from the NOAEL of 1 mg/kg bw established in the oral OECD 421 study in rats. The substance is well systemically available by the oral route. As seen in the acute dermal study in rats, the substance was not systemically toxic by the dermal route and is also expected to be of lower systemic toxicity after prolonged exposure with the skin. The starting point for the DNEL derivation can be obtained by conversion of oral NOAEL into dermal NOAEL (route-to-route extrapolation).
AF for dose response relationship:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for differences in duration of exposure:
6
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for interspecies differences (allometric scaling):
4
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for other interspecies differences:
2.5
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for intraspecies differences:
10
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for the quality of the whole database:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
20 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Value:
2 000 mg/kg bw/day
AF for dose response relationship:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for interspecies differences (allometric scaling):
4
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for other interspecies differences:
2.5
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for intraspecies differences:
10
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for the quality of the whole database:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.002 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
600
Dose descriptor starting point:
NOAEL
Value:
1 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 mg/kg bw/day
AF for dose response relationship:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for differences in duration of exposure:
6
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for interspecies differences (allometric scaling):
4
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for other interspecies differences:
2.5
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for intraspecies differences:
10
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for the quality of the whole database:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.005 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
3
DNEL extrapolated from long term DNEL
Dose descriptor starting point:
NOAEL
Value:
1 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 mg/kg bw/day

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

A detailed risk assessment of bis(2,6 -diisopropylpheny)carbodiimide was conducted by the European Food Safety Authority (EFSA) for the substance’s use in food contact materials (EFSA, 2010). Due to the use in food-packaging materials, it is clear that the substance can not bear a high risk for human health. The respective SML was set as 0.05 mg/kg. Assuming a body weight of 60 kg and a daily intake of 1 kg food / day, the Tolerable Daily Intake (TDI) can be calculated via this relationship TDI (mg/kg bw/d) x 1 kg/d x 60 kg KG = SML (mg/kg) to TDI = 0.05 mg/kg / (1kg/d * 60 kg bw) = 8.3 µg/kg bw/d (Reference: EFSA (2010) Scientific Opinion on the safety evaluation of the substance bis(2,6-diisopropylphenyl)carbodiimide for use in food contact materials. EFSA Journal 2010;8(12):1928. / https://webgate.ec.europa.eu/foods_system/main/index.cfm?event=substance.view&identifier=438)

 

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.

 

Applying of assessment factors:

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

 

Calculation of endpoint-specific DNEL for general population

 

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

The dermal acute LD50 of 2000 mg/kg bw (= NOAEL since no mortalities, no signs of toxicity were observed) is not modified for differences in dermal absorptions between rats and humans:

Corrected dermal NOAEL = dermal rat NOAEL x (ABS dermal-rat/ABS dermal-human) = 2000 mg/kg bw x (100%/100%) = 2000 mg/kg bw.

DNEL = 2000/(4 x 2.5 x 10 x 1 x 1) = 20 mg/kg bw. Assessment factors are: 4-interspecies, 2.5-remaining interspecies differences, 10-intraspecies, 1 -study duration (setting of acute DNEL based on acute study), 1 – quality of data base.

 

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

The substance is acute toxic via the oral route (300<LD50<2000 mg/kg bw; Gilissen, 2009). 33% of mortalities occurred at 300 mg/kg bw. This dose served as the starting point for the oral DNEL acute. The starting point was not modified for differences in oral absorption between animals and humans.

DNEL = 300/(4 x 2.5 x 10 x 100) = 0.03 mg/kg bw. Assessment factors are: 4 -interspecies, 2.5 -remaining interspecies differences, 10 -intraspecies. Since only data on mortality is available, a default assessment factor of 100 was used for severity of effects.

The other approach was used for the derivation of DNEL acute for the oral route. The long-term oral DNEL of 0.0017 mg/kg bw for systemic effects was multiplied with a factor of 3 (due to the clear dose response in the OECD 421 study) (0.0017 x 3 = 0.0051 mg/kg bw). This DNEL is slightly lower than that calculated based on lethality data and is considered to be more appropriate.

 

Long-term exposure – systemic effects (dermal DNEL)

The oral NOAEL of 1 mg/kg bw was converted into the dermal NOAEL: Dermal NOAEL = oral NOAEL x (ABS oral-rat/ABS dermal-human) = 1 mg/kg bw x (100%/100%) = 1 mg/kg bw.

DNEL = 1 mg/kg bw/(4 x 2.5 x 10 x 6 x 1 x 1) = 0.0017 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 6 – study duration (sub-acute study), 1 – dose response (clear dose response), 1 – quality of data base (default).

 

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

The oral NOAEL of 1 mg/kg bw was converted into the inhalation NOAEC:

Corrected inhalation NOAEC = oral rat NOAEL x (1/1.15 m³/kg bw/day) x (ABS oral-rat/ABS inhal-human), where 1.15 is standard respiratory volume (m³/kg bw) of rats during 24 h exposure, ABS is absorption (values are the same as described for workers).

Corrected Inhalation NOAEC = 1 mg/kg bw x (1/1.15 m³/kg/day) x (100%/100%) = 0.87 mg/m³

DNEL = 0.87 mg/m³/(2.5 x 10 x 6 x 1 x 1) = 0.0058 mg/m³. Assessment factors are: 2.5 – remaining interspecies differences, 10 – intraspecies, 6 – study duration (sub-acute study), 1 – dose response (clear dose response), 1 – quality of data base (default).

 

Long-term exposure – systemic effects (oral DNEL)

The oral NOAEL of 1 mg/kg bw was not modified for differences in absorption by oral route since no substance- and route specific information is available: Oral NOAEL = dermal NOAEL = 1 mg/kg bw.

DNEL = 1 mg/kg bw/(4 x 2.5 x 10 x 6 x 1 x 1) = 0.0017 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 6 – study duration (sub-acute study), 1 – dose response (clear dose response), 1 – quality of data base (default).