Reaction mass of disodium [2,2'-(imino-κN)dibutanedioato-κ2O1,O4(4-)]cuprum(2-) and sodium sulphate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.28 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

Explanation for the modification of the dose descriptor starting point:

Not applicable (DNEL is derived based on OEL of 0.03-0.04 for inhalable fraction for copper and its inorganic compounds)

AF for dose response relationship:

1

Justification:

OEL is used

AF for differences in duration of exposure:

1

Justification:

OEL is used

AF for interspecies differences (allometric scaling):

1

Justification:

OEL is used

AF for other interspecies differences:

1

Justification:

OEL is used

AF for intraspecies differences:

1

Justification:

OEL is used

AF for the quality of the whole database:

1

Justification:

OEL is used

AF for remaining uncertainties:

1

Justification:

OEL is used

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:

1.2 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1

Modified dose descriptor starting point:

other: equivalent RDA

Value:

0.072 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

DNEL was derived using RDA of 0.013 mg/kg bw, available for copper which was converted to an equivalent dose for Cu(2Na)IDHA.

AF for dose response relationship:

1

Justification:

RDA is used

AF for differences in duration of exposure:

1

Justification:

RDA is used

AF for interspecies differences (allometric scaling):

1

Justification:

RDA is used

AF for other interspecies differences:

1

Justification:

RDA is used

AF for intraspecies differences:

1

Justification:

RDA is used

AF for the quality of the whole database:

1

Justification:

RDA is used

AF for remaining uncertainties:

1

Justification:

RDA is used

Acute/short term exposure

Hazard assessment conclusion:

no DNEL required: short term exposure controlled by conditions for long-term

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 (2012) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health”.

Available dose descriptors:

The target substance Cu(Na)IDHA is acutely toxic by oral route of exposure because LD50 was between 300 – 2000 mg/kg bw (Gruszka, 2007). Therefore a short-term DNEL for systemic effects is needed for oral route for general public. The substance is not toxic by dermal route of exposure (LD50 > 2000 mg/kg bw; Kropidło, 2010) and inhalation is not relevant route of exposure due to the low vapour pressure of the substance (3.02 x E-7 Pa at 20 °C). The target substance is non-volatile (in microgranulated form) and therefore no risk of irritation or sensitisation of respiratory tract exists. Therefore, no DNELs for acute/short-term exposures (systemic and local effects) and for long-term exposures (local effects for both inhalation and dermal routes) need to be derived.

For the long-term exposure – systemic effects (inhalation and dermal DNEL), the LOAEL of 150 mg/kg bw established in the Combined repeated dose toxicity study with reproduction/ developmental toxicity screening test in rats (Lina, 2013) was used as the starting point. This is the lowest LOAEL known for the target substance after repeated exposures to rats. However, LOAEL of 150 mg/kg bw established for Cu(2Na)EDTA may underestimate the risk of Cu(2Na)IDHA due to the higher absorption of IDHA (37 %) comparing to the absorption of EDTA ligand (5 %) or its complexes (less than 1 -2 %).

The effects in animals treated by iminodisuccinic acid, sodium salt (28-day study, Stropp and Popp, 1997) were less pronounced than those in the Combined study with Cu(2Na)EDTA. The only findings were reduced motor activity in males in the highest dose group. NOAEL was 1000 mg/kg bw for females and 200 mg/kg bw for males. The lowest NOAEL of 200 mg/kg bw > 150 mg/kg bw for Cu(2Na)EDTA. On the other hand, the lowest NOAEL of 2 mg Cu/kg bw /day in male rats and 0.83 mg Cu/kg bw /day in female rats were established in a combined repeated dose and reproductive/ developmental study (ATSDR, 2004; please refer to the endpoint summary section “Repeated dose toxicity”). These data allow to speculate that systemic toxicity of Cu(2Na)IDHA will be driven by released copper ions and therefore DNEL derived from the LOAEL for Cu(2Na)EDTA will underestimate the risk of copper toxicity because Cu(2Na)EDTA is expected to be absorbed less extensively. Therefore, existed safety exposure limits for copper have been taken to derive an equivalent levels for Cu(2Na)IDHA and compare them with the derived DNELs by classic way by read-across and to make a decision for the most appropriate DNELs for Cu(2Na)IDHA.

The DNELs for inhalation and dermal routes can be derived by route-to-route extrapolation applying appropriate assessment factors.

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.

Modification of the starting point:

From all available data on the target and read-across substances it is clear that these substances exert their effects by a threshold mode of action. Thus, DNELs can be calculated for the 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 reflecting the routes, the duration and the frequency of exposure. DNELs are derived for workers and the general population. The general population includes consumers and humans exposed via the environment (please see below).

Bioavailability (absorption):

There is no substance-specific experimental 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 treated animals in the available studies.

Oral absorption:

The complex Cu(2Na)IDHA is expected to be in de-chelated form in the stomach due to its dissociation under high acidic conditions (for the detailed information on absorption please refer to section "Toxicokinetics, metabolism and distribution" of this CSR or section 7.1 of IULID file). Therefore oral absorption will result from released sodium and copper ions, and free IDHA. Metal ions will be extensively absorbed in the GI tract. The average absorption efficiencies of copper ranged from 24 to 60 % in presumably healthy adults (ATSDR, 2004). In the toxicokinetic study, the chelating agent IDHA was extensively absorbed and at least 37 % of the administered dose became systemically available in rats Koester, 2007; Report No. M81819180). Based on this information and taking into account molecular weight of 354.7g/mol and the negative logPow (-3.09), moderate absorption potential via oral route is expected for Cu(2Na)IDHA.For the purposes of hazard assessment (DNEL derivation), the oral absorption for Cu(2Na)IDHA is set to 60 %, the upper level known for copper (worst-case).The oral absorption is considered to be the same in animals and in humans (worst-case).

Dermal absorption:

No significant dermal absorption is expected for the target substance. The log Pow of -3.09 is below the optimal logPow range (0 - 4) values favourable for dermal absorption. High water solubility of 412 g/L points also to a low absorption potential through the skin. The molecular weight of 354.69 g/mol indicates that a certain potential to penetrate the skin (< 500) exists. However, in case of such a hydrophilic substance dermal penetration is rather unlikely. The target substance could dissociate in contact with skin and therefore breakdown products with a slightly deviating absorption pattern are expected. The available in vivo data do not provide information on the rate and extent of absorption through intact skin following dermal exposure of humans or animals to copper (ATSDR, 2004; SCOEL, 2013). In vitro studies suggest that copper is poorly absorbed through intact skin. Less than 6 % of copper deposited on ex vivo human skin samples were absorbed (ATSDR, 2004). Low absorption potential through the skin would also apply to free IDHA chelating agent due to its high hydrophilicity (water solubility of 564 g/L; data for Baypure CX 100 (Bayer)). Based on these data, 6 % (the highest value reported (= worst case)) dermal absorption is considered appropriate for Cu(2Na)IDHA.Dermal absorption in rats, and in humans is assumed to be the same since no information for dermal absorption of the target substance in humans is available.

Inhalation absorption

Absorption by inhalation is considered to be negligible due to the low vapour pressure of 3.02 x 10-7 Pa at 20 °C and that the substance is in microgranulated form with particles with aerodynamic diameter higher than 100 µm. It means that 100 % of inhaled substance (in case of dust forming) will be deposited in the upper respiratory tract, which will finally be taken up orally. Of this, 60 % will be absorbed in the GI tract and become systemic available: 1 x 0.6 = 0.6 will be the total absorption factor for inhalation (or 60 %). Absorption by inhalation is considered to be equal in rats and in humans since no substance specific information is available.

Route-to-route extrapolation:

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 (ABS oral-rat/ABS inh-human) x (6.7 m³/10 m³) where sRV is the 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.

Oral-to-dermal extrapolation is performed to obtain dermal NOAEL for systemic effects. The following formula was used (as described in the Example B.5 of the Appendix R.8 -2, ECHA REACH Guidance R8):

Corrected dermal NOAEL = oral NOAEL x (ABS oral-rat/ABS derm-rat) x (ABS derm-rat/ABS derm-human) = oral NOAEL x (ABS oral-rat/ABS derm-human).

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 (0.38 m³).

Differences in the respiratory volumes between experimental animals and humans were used when an oral rat NOAEL from the oral one-generation reproductive toxicity study in rats was used to assess inhalation exposure in humans. 0.38 m³/kg/day is the standard respiratory volumes in rats during 8h exposure. 6.7 and 10 m³ are standard respiratory volumes for workers under normal conditions and by light activity, respectively.

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 oral NOAEL from the Combined oral repeated dose toxicity study with reproduction/ developmental toxicity screening study in rats, which was used to derive the dermal long-term DNEL.

No allometric scaling factor was applied when the oral NOAEL 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 for all endpoints and for all exposure routes.

Extrapolation of duration:

An assessment factor of 2 was applied for duration of exposure (Combined screening study = sub-chronic).

Quality of whole data base:

A default assessment factor of 1 was used.

Issues related to dose response:

An assessment factor of 3 was applied when the LOAEL from the Combined study was extrapolated to NOAEL (the NOAEL was < 150 mg/kg bw due to limited liver and kidney effects at this level. It is expected that the NOAEL is close to 150 mg/kg bw).

Calculation of DNELs:

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

Initially, DNEL has been derived using LOAEL available for the read-across substance Cu(2Na)EDTA. Then, the existing OEL value for copper and its compounds was compared with the derived DNEL in order to establish the most realistic DNEL for Cu(Na)IDHA.

The oral rat LOAEL of 150 mg/kg bw (established for the read-across substance Cu(2Na)EDTA) was converted into the inhalation NOAEC:

Inhalation LOAEC = oral LOAEL x (1/sRVrat) x (ABS oral-rat/ABS inhal-human) x (6.7 m³/10 m³) = 150 mg/kg bw x (1/0.38 m³/kg/day) x (60 %/60 %) x (6.7/10) = 264.5 mg/m³

DNEL = 264.5 mg/m³/(2.5 x 5 x 2 x 3 x 1) = 3.5 mg/m³.

Assessment factors are: 2.5 – remaining interspecies differences, 5 – intraspecies, 2 – study duration (sub-chronic study), 3 – dose response due to LOAEL, 1 – quality of data base. The total AF amounts to 75.

There is OEL of 0.01 mg/m³ for respirable fraction for copper and its inorganic compounds available (SCOEL, 2013). Since no respirable fraction is expected for Cu(2Na)IDHA (particles of Cu(2Na)IDHA are > 100 µm), an OEL of 0.03-0.04 mg/m³ for inhalable fraction would be more appropriate. This limit would correspond to 0.17 mg/m³ of Cu(2Na)IDHA: ((MW of Cu(2Na)IDHA 354.7/ MW of copper 64) x 0.03 mg/m³).

Taking into account 60 %absorption by inhalation (equal to oral absorption), the estimated NOAEC (=DNEL for inhalation, systemic effects) would result in 0.28 mg/m³: 0.17 x (100 %/60 %).

This equivalent concentration of 0.28 mg/m³ calculated for Cu(2Na)IDHA is lower than the derived DNEL of 3.5 mg/m³ based on LOAEL for the read-across substance Cu(2Na)EDTA. Therefore, DNEL of 3.5 mg/m³ may underestimate the risk originating from the toxicity of copper originating from Cu(2Na)IDHA exposure. The equivalent concentration of 0.28 mg/m³ based on OEL for inorganic copper may overestimate the risk of inhalable Cu(2Na)IDHA but can serve directly as a DNEL for humans without applying of assessment factors.

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

For the oral rat LOAEL of 150 mg/kg bw the following conversion was necessary:

Dermal LOAEL =oral LOAEL x (ABS oral-rat/ABS derm-human) = 150 x (60 %/6 %) = 1500 mg/kg bw

DNEL = 1500 mg/kg bw/ (4 x 2.5 x 5 x 2 x 3 x 1) = 5 mg/kg bw.

Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 5 – intraspecies, 2 – study duration (sub-chronic study), 3 – dose response, 1 – quality of data base. The total AF amounts to 300.

Based on RDA of 0.013 mg/kg bw, available for copper an equivalent dose for Cu(2Na)IDHA for systemic effects for humans can be estimated (please refer to the endpoint summary section “Repeated dose toxicity”). It corresponds to 0.072 mg/kg bw for Cu(2Na)IDHA: ((MW of Cu(2Na)IDHA is 354.7 g/mol / MW of Cu is 64 g/mol) x 0.013 mg/kg bw). This dose level however may be overprotective but it can serve as an internal DNEL for systemic effects.

Taking into account absorption rate of 6 % for dermal route, when 0.072 mg/kg bw corresponds to 6 % absorbed through the skin, then 0.072 x 100/6 = 1.2 mg/kg bw corresponds to an external dermal dose. 1.2 mg/kg bw < 5 mg/kg bw derived using read-across LOAEL.

Selected DNELs

DNEL systemic inhalation =0.28 mg/m³

DNEL systemic dermal (long-term) =1.2 mg/kg bw

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.28 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

Explanation for the modification of the dose descriptor starting point:

Not applicable (DNEL is derived based on OEL of 0.03-0.04 for inhalable fraction for copper and its inorganic compounds)

AF for dose response relationship:

1

Justification:

OEL is used

AF for differences in duration of exposure:

1

Justification:

OEL is used

AF for interspecies differences (allometric scaling):

1

Justification:

OEL is used

AF for other interspecies differences:

1

Justification:

OEL is used

AF for intraspecies differences:

1

Justification:

OEL is used

AF for the quality of the whole database:

1

Justification:

OEL is used

AF for remaining uncertainties:

1

Justification:

OEL is used

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:

1.2 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1

Modified dose descriptor starting point:

other: equivalent RDA

Value:

0.072 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

DNEL was derived using RDA of 0.013 mg/kg bw, available for copper which was converted to an equivalent dose for Cu(2Na)IDHA.

AF for dose response relationship:

1

Justification:

RDA is used

AF for differences in duration of exposure:

1

Justification:

RDA is used

AF for interspecies differences (allometric scaling):

1

Justification:

RDA is used

AF for other interspecies differences:

1

Justification:

RDA is used

AF for intraspecies differences:

1

Justification:

RDA is used

AF for the quality of the whole database:

1

Justification:

RDA is used

AF for remaining uncertainties:

1

Justification:

RDA is used

Acute/short term exposure

Hazard assessment conclusion:

no DNEL required: short term exposure controlled by conditions for long-term

DNEL related information

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:

0.12 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1

Modified dose descriptor starting point:

other: equivalent RDA

Value:

0.072 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

DNEL was derived using RDA of 0.013 mg/kg bw, available for copper which was converted to an equivalent dose for Cu(2Na)IDHA.

AF for dose response relationship:

1

Justification:

RDA is used

AF for differences in duration of exposure:

1

Justification:

RDA is used

AF for interspecies differences (allometric scaling):

1

Justification:

RDA is used

AF for other interspecies differences:

1

Justification:

RDA is used

AF for intraspecies differences:

1

Justification:

RDA is used

AF for the quality of the whole database:

1

Justification:

RDA is used

AF for remaining uncertainties:

1

Justification:

RDA is used

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.6 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Explanation for the modification of the dose descriptor starting point:

Not applicable (DNEL is derived by extrapolation from the long-term DNEL, multiplying with factor of 5)

AF for dose response relationship:

1

Justification:

RDA is used

AF for interspecies differences (allometric scaling):

1

Justification:

RDA is used

AF for other interspecies differences:

1

Justification:

RDA is used

AF for intraspecies differences:

1

Justification:

RDA is used

AF for the quality of the whole database:

1

Justification:

RDA is used

AF for remaining uncertainties:

1

Justification:

RDA is used

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.

 

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

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

The oral rat LOAEL of 150 mg/kg bw was converted into the inhalation NOAEC:

Inhalation LOAEC = oral LOAEL x (1/sRVrat) x (ABS oral-rat/ABS inhal-human) = 150 mg/kg bw x (1/1.15 m³/kg/day) x (60 %/60 %) = 130.4 mg/m³

DNEL = 130.4 mg/m³/(2.5 x 10 x 2 x 3 x 1) = 0.87 mg/m³. Assessment factors are: 2.5 – remaining interspecies differences, 10 – intraspecies, 2 – study duration (sub-chronic study), 3 – dose response (LOAEL is used), 1 – quality of data base. The total AF amounts to 150.

As in case of workers, the equivalent concentration of 0.28 mg Cu(2Na)IDHA /m³ calculated from the OEL for copper (see above) is lower than 0.87 mg/m³ (DNEL, based on NOAEL from the read-across substance Cu(2Na)EDTA ) is more appropriate for general public.

 

Long-term exposure – systemic effects (dermal DNEL)

Dermal LOAEL =oral LOAEL x (ABS oral-rat/ ABS derm-human) = 150 x (60 %/6 %) = 1500 mg/kg bw

DNEL = 1500 mg/kg bw/(4 x 2.5 x 10 x 2 x 3 x 1) = 2.5 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 2 – study duration (sub-chronic study), 3 – dose response (LOAEL is used), 1 – quality of data base. The total AF amounts to 600.

As in case with workers, the dose of 1.2 mg Cu(2Na)IDHA /kg bw) equivalent to RDA of 0.013 mg/kg bw available for copper (see above) is lower than 2.5 mg/kg bw (based on LOAEL from the read-across substance Cu(2Na)EDTA) and therefore is more appropriate as DNEL.

 

Long-term exposure – systemic effects (oral DNEL)

The oral LOAEL of 150 mg/kg bw does not need to be modified into a corrected LOAEL since no difference in oral absorption between animals and humans are considered (example A.1 in ECHA Guidance R.8):

Corrected oral LOAEL = oral LOAEL x (ABS oral-rat/ ABS oral-human) = 150 mg/kg bw x (60 %/60 %) = 150 mg/kg bw.

DNEL = 150 mg/kg bw/(4 x 2.5 x 10 x 2 x 3 x 1) = 0.25 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 2 – study duration (sub-chronic study), 3 – dose response (LOAEL is used), 1 – quality of data base (default). The total AF amounts to 600.

RDA of 0.013 mg/kg bw, available for copper is equivalent to 0.12 mg/kg bw for Cu(2Na)IDHA: ((MW of Cu(2Na)IDHA is 354.7 g/mol / MW of Cu is 64 g/mol) x 0.013 mg/kg bw) x (100 %/ 60 %) (please refer to the endpoint summary section “Repeated dose toxicity”). Surprisingly, this dose is close to 0.25 mg/kg bw calculated from the LOAEL of 150 mg/kg bw for the read-across substance Cu(2Na)EDTA.

 

Short-term exposure – systemic effects (oral DNEL)

As mentioned in the ECHA guidance R8. (Appendix R.8-8, Box 6.) short-term DNEL can be derived using “the long-term DNEL that shall then be modified by multiplying with a factor of 1-5, where the size of this factor depends on the potency and the dose-response curve of the substance”. Since the equivalent dose of 0.12 mg/kg bw based on RDA for copper may be overprotective for Cu(2Na)IDHA the highest factor of 5 is used to convert long-term DNEL in a short.-term DNEL: 0.12 x 5 = 0.60 mg/kg bw

Selected DNELs

DNEL systemic inhalation = 0.28 mg/m³

DNEL systemic dermal (long-term) = 1.2 mg/kg bw

DNEL systemic oral (long-term) = 0.12 mg/kg bw

DNEL systemic oral (short-term) = 0.60 mg/kg bw