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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
17.63 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Value:
440.79 mg/m³
Explanation for the modification of the dose descriptor starting point:
A NOAEL of 500 mg/kg bw /day from the one-generation oral repeated dose toxicity study with the calcium sulfonate read across substance, CAS 115733-09-0, is available for rats (Bjorn, 2004). This value was converted into the corrected inhalatory NOAEC taking into account the standard respiratory factor of 1/0.38 m3/kg/d and the absorption rates for absorption (oral 50 %, inhalation 100 %) and the standard respiratory volume in humans/ worker respiratory volume (6.7 m3 (8 h) / 10 m3 (8 h)).
AF for dose response relationship:
1
Justification:
default (three doses were tested, using a spacing range of 2-4 fold)
AF for differences in duration of exposure:
2
Justification:
since it is a subchronic study
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scalling should be applied in case of oral-to-inhalation extrapolation
AF for other interspecies differences:
2.5
Justification:
default; no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans
AF for intraspecies differences:
5
Justification:
default for workers
AF for the quality of the whole database:
1
Justification:
default
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

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
25 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):
100
Modified dose descriptor starting point:
NOAEL
Value:
2 500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
A NOAEL of 500 mg/kg bw /day from the one-generation oral repeated dose toxicity study with the calcium sulfonate read across substance, (CAS 115733-09-0), is available for rats (Bjorn, 2004). This value was converted into the corrected dermal NOAEL taking into account the rates for absorption (oral 50 %, dermal 10 %).
AF for dose response relationship:
1
Justification:
default (three doses were tested, using a spacing range of 2-4 fold)
AF for differences in duration of exposure:
2
Justification:
since it is a subchronic study
AF for interspecies differences (allometric scaling):
4
Justification:
default factor for rats
AF for other interspecies differences:
2.5
Justification:
default; no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans
AF for intraspecies differences:
5
Justification:
default for workers
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.04 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
5
Dose descriptor:
other: NOAEL
AF for dose response relationship:
1
Justification:
not applicable for sensitisation
AF for interspecies differences (allometric scaling):
1
Justification:
as it comes from human data
AF for intraspecies differences:
5
Justification:
default for workers
AF for the quality of the whole database:
1
Justification:
multiple reliable studies with Klimisch code 1 and 2
AF for remaining uncertainties:
1
Justification:
LOAEL to NOAEL
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:

For the calcium sulfonate target substance (C15 -C36), the following dose descriptors are available:

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

No DNEL for acute toxicity is needed, because the systemic toxicity of the calcium sulfonate read across substances are very low; the substances being non-toxic by ingestion (Swan, 1972 - LD50: > 10,000 - < 20,000 mg/kg bw; Sanitised, F., 1989 - LD50 < 5,000 mg/kg bw; Sanitised, A., 1981 - LD50 < 5,000 mg/kg bw, Sanitised, CA., 1984 - LD50 >5.000 mg/kg bw; Sanitised, C., 1985 - LD50 >5.000 mg/kg bw; Ohees, P. 1968a - LD50 > 20,000 mg/kg bw; Regel, L., 1970 - LD50 > 10,000 mg/kg bw; Ohees, P., 1968b - LD50 > 20,000 mg/kg bw, Gabriel, K. L:, 1981a - LD50 > 16,000 mg/kg bw). In addition no toxicity was found after percutaneous absorption (Sanitised, G., 1989, LD50 < 2,000 mg/kg bw; Sanitised, B., 1981 - LD50 > 5,000 mg/kg bw, Sanitised, J., 1993 - LD50 > 2000 mg/kg bw, Costello, B. A:, 1986a - LD50 > 4000 mg/kg bw). Therefore no DNEL for acute / short term exposure via the dermal route should be derived. The long-term DNEL for long-term dermal systemic exposure (skin sensitization) is sufficient to ensure that acute effects do not occur, provided high-peak acute exposure can be avoided.

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

No acute inhalation study is available for the calcium sulfonate target substance (C15 -C36). However, no vapour hazard exists based on results of animal studies with the calcium sulfonate read across substances and the low vapour pressure (0.01 Pa at 25 °C) (Tremain, 2013). Moreover, the acute toxicity results by the dermal route showed the calcium sulfonate read across substances not to be toxic via this route of exposure. Therefore an acute exposure hazard via this route this route is not relevant and no DNEL is derived. The long-term DNEL for long-term systemic inhalation exposure is sufficient to ensure that acute effects do not occur.

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

The calcium sulfonate read across substances are not irritating to the skin. In addition, systemic toxicity is low; the read across substances being non-toxic by ingestion (Swan, 1972 - LD50: > 10,000 - < 20,000 mg/kg bw; Sanitised, F., 1989 - LD50 < 5,000 mg/kg bw; Sanitised, A., 1981 - LD50 < 5,000 mg/kg bw, Sanitised, CA., 1984 - LD50 >5.000 mg/kg bw; Sanitised, C., 1985 - LD50 >5.000 mg/kg bw; Ohees, P. 1968a - LD50 > 20,000 mg/kg bw; Regel, L., 1970 - LD50 > 10,000 mg/kg bw; Ohees, P., 1968b - LD50 > 20,000 mg/kg bw, Gabriel, K. L:, 1981a - LD50 > 16,000 mg/kg bw). In addition no toxicity was found after percutaneous absorption (Sanitised, G., 1989, LD50 < 2,000 mg/kg bw; Sanitised, B., 1981 - LD50 > 5,000 mg/kg bw, Sanitised, J., 1993 - LD50 > 2000 mg/kg bw, Costello, B. A:, 1986a - LD50 > 4000 mg/kg bw). Therefore no DNEL for acute / short term exposure via the dermal route should be derived. The long-term DNEL for local dermal effects is sufficient to ensure that acute effects do not occur, provided high-peak acute exposure can be avoided.

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

No vapour hazard exists based on results of animal studies, no irritating effects on the respiratory system are expected and the substance has a low vapour pressure (0.01 Pa at 25 °C ) (Tremain, 2012). Local effects are covered sufficiently by the long-term DNEL for systemic effects.

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

No repeated dose data is available for the calcium sulfonate target substance (C15 -C36). However the long-term systemic DNEL for the dermal route has been derived from the NOAEL of an oral one-generation reproductive toxicity study in rats with the calcium sulfonate read across substance, (CAS 115733-09-0-47-5, Bjorn, 2004). A NOAEL of 500 mg/kg bw/day was established. The starting point for the DNEL derivation is the oral NOAEL (route-to-route extrapolation necessary).

The dose descriptor starting point is the oral NOAEL of 500 mg/kg bw. The dose descriptor starting point is obtained by conversion of the oral NOAEL of 500 mg/kg bw from the oral one-generation toxicity study in rats with the calcium sulfonate read across substance, (CAS 115733-09-0), to a dermal NOAEL taking into account a oral absorption of 50% and dermal absorption of 10%. Thereby the corrected dermal NOAEL is: oral NOAEL * (ABSoral-rat/ABSdermal-rat) * (ABSdermal-rat/ABSdermal-human) = 2500 mg/kg bw

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

There are no dose-response and route-specific information on repeated dose toxicity via inhalation. The substance does not pose a hazard for humans by the inhalation route of exposure. The inhalation DNEL can be derived from the oral NOAEL of 500 mg/kg bw established in the oral one-generation study in rats (Bjorn, 2004) by route-to-route extrapolation.

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

The NOAEL as well as the acute local dermal DNEL are calculated as follows: The amount applied to skin is described by 0.2 mL (applied volume) x 0.9423 g/mL (density) x 10 % (NOAEL/SCL concentration) which results in 18.8 mg. The amount applied per unit surface area is described by 18.8 mg (amount applied to skin) / 3.63 cm² skin (based on 3/4" x 3/4" patch noted in a number of studies) resulting in a NOAEL of 5.18 mg/cm². By applying the overall assessment factor of 5, the acute local dermal DNEL amounts to 1.04 mg/cm².

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

No long-term inhalation DNEL for local effects is needed since the substance is not expected to be irritating or sensitising to the respiratory system. A DNEL is not quantifiable and not relevant. 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. However there does not exist any hazard as the classification of the calcium sulfonate target substance (C15 -C36) as skin sensitising with a specific concentration of 10 % was necessary.

Modification of the starting point:

From all available data on the calcium sulfonate target substance (C15 -C36), and on the calcium sulfonate read across substances for the different human health endpoints, it is clear that the substances exert their 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 the read across substances, 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.

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:

Due to the molecular weight of≥ 817.3 and ≤ 1111.87g/mol, a logPow of 6.65 together with the non-irritating properties of the substance and the very slight effects found at the highest dose level in the subacute study in rats,absorption by oral route is considered to be slight to moderatefor the calcium sulfonate target substance (C15 -C36) (for the detailed information on absorption please refer to section "Toxicokinetics, metabolism and distribution" of this CSR or section 7.1 of IUCLID file).The oral absorption is set to 50% since physico-chemical properties of the substance are not in range suggestive of significant absorption from the gastro-intestinal tract. 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 calcium sulfonate target substance (C15 -C36). The log Pow of 6.65, the water solubility of 1.69 mg/L and the molecular weight of≥ 817.3 and ≤ 1111.87 g/mol point to a poor absorption through the skin. According to the TGD, Part I, Appendix IV, 10% of dermal absorption can be considered in this case, since the criteria for molecular weight and Log Pow are met (MW above 500 g/mol and log Pow > 4). Moreover, a critical assessment of all available data (toxicity effects in the available studies and physicochemical properties) should be taken into account before using default assumptions (ECETOC, TR No. 110). The absorption after dermal exposure is generally more gradual and slower than oral absorption and a lower bioavailability is expected due to the presence of the absorption hindering outer skin layer stratum corneum and a comparatively smaller surface area. Schuhmacher et al. recommended that a low dermal penetration (< 10%) can be assumed for substances with a logPow value >5 or for substances with a Kp value <0.0001 (cm/h). (Schumacher et al., 2003). A skin permeability constant (Kp) of 1.0E-7 cm/min (= 6.0E-6 cm/h) for human epidermis was obtained experimentally for the related substance dodecyl benzenesulfonate (CAS 25155-30-0, Howes, 1975). This substance is structurally similar to the caclcium sulfonate target substance (C15 -C36), but its alkyl chain consisting of 12 carbon atoms is shorter and therefore it is less lipophilic. The Kp value for the calcium sulfonate target substance (C15 -C36),which is even more lipophilic than dodecyl benzenesulfonate, is expected to be much lower. Thus, 10% absorption applies also in this case.

Dermal absorption in rats, rabbits and in humans is assumed to be the same since no information for dermal absorption of the calcium sulfonate target substance (C15 -C36) in humans is available.

Reference:

1.Schuhmacher-Wolz U., Kalberlach F., Oppl R., van Hemmen J. J. (2003). A toolkit for dermal risk assessment: toxicological approach for hazard characterization. Ann. Occup. Hyg., Vol 47 No.8, pp. 641 -652.

Inhalation absorption

Absorption by inhalation is considered to be negligible (low vapour pressure of 0.01 Pa at 25°C) and not to be higher than absorption by oral route. However, 100% absorption is assumed for inhalation route and considered to be equal in rats and in humans since no substance specific information is available (worst-case for the purposes of DNEL derivation).

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 (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).

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 subchronic one generation reproductive toxicity study, which was used to derive the dermal long-term DNEL.

No allometric scaling factor was applied when the oral NOAEL from the one-generation study 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.

An assessment factor of 1 was applied, if human data were available.

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 (subchronic study). However, this is not applicable for sensitisation and therefore an assessment factor of 1 was applied.

Quality of whole data base:

A default assessment factor of 1 was used.

Issues related to dose response:

A default assessment factor of 1 was applied when the NOAEL from the oral one generation reproductive toxicity study was used.

Calculation of DNELs:

Long-term exposure - local effects (dermal DNEL)

For the long-term local dermal DNEL, a dermal NOAEL of 5.18 mg/cm² was calculated.

DNEL = 5.18 mg/cm² / (1 x 5 x 1 x 1 x 1) = 1.04 mg/cm².

Assessment factors are: 1 – interspecies, 5 – intraspecies, 1 – study duration (not applicable for sensitisation), 1 – dose response, 1 – quality of data base, 1 - LOAEL = NOAEL. The total AF amounts to 5.

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

For the oral rat NOAEL of 500 mg/kg bw the following conversion was necessary:

dermal NOAEL = oral NOAEL x (ABS oral-rat/ABS dermal-rat) x (ABS dermal-rat/ABS dermal-human) = 2500 mg/kg bw

DNEL = 2500 mg/kg bw/(4 x 2.5 x 5 x 2 x 1 x 1) = 25 mg/kg bw.

Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 5 – intraspecies, 2 – study duration (subchronic study), 1 – dose response, 1 – quality of data base. The total AF amounts to 100.

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

The oral rat NOAEL of 500 mg/kg bw was converted into the inhalation NOAEC:

Inhalation NOAEC = oral NOAEL x (1/sRVrat) x (ABSoral-rat/ABSinhal-human) x (6.7 m³/10 m³) = 500 mg/kg bw x (1/0.38 m³/kg/day) x (50%/100%) x (6.7/10) = 440.79 mg/m³

DNEL = 440.79 mg/m³/(2.5 x 5 x 2 x 1 x 1) = 17.63 mg/m³.

Assessment factors are: 2.5 – remaining interspecies differences, 5 – intraspecies, 2 – study duration (subchronic study), 1 – dose response, 1 – quality of data base. The total AF amounts to 25.

Selected DNELs

DNEL local dermal (long-term) =1.04 mg/cm²

DNEL systemic dermal (long-term) =25 mg/kg bw

DNEL systemic inhalation =17.63 mg/m³

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.35 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEC
Value:
217.39 mg/m³
Explanation for the modification of the dose descriptor starting point:
A NOAEL of 500 mg/kg bw /day from a oral one-generation toxicity study with the calcium sulfonate read across substance, (CAS 115733-09-0) is available (Bjorn, 2004). This value was converted into the corrected inhalatory NOAEC taking into account the standard respiratory factor of 1/1.15 m3/kg/d for a 24-hour exposure and the absorption rates (oral 50 %, inhalation 100 %).
AF for dose response relationship:
1
Justification:
default (three doses were tested, using a spacing range of 2-4 fold)
AF for differences in duration of exposure:
2
Justification:
since it is a subchronic study
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scalling should be applied in case of oral-to-inhalation extrapolation
AF for other interspecies differences:
2.5
Justification:
default; no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans
AF for intraspecies differences:
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
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:
12.5 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):
200
Modified dose descriptor starting point:
NOAEL
Value:
2 500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
A NOAEL of 500 mg/kg bw /day from the one-generation oral repeated dose toxicity study with the calcium sulfonate read across substance, (CAS 115733-09-0), is available for rats (Bjorn, 2004). This value was converted into the corrected dermal NOAEL taking into account the rates for absorption (oral 50 %, dermal 10 %).
AF for dose response relationship:
1
Justification:
default (three doses were tested, using a spacing range of 2-4 fold)
AF for differences in duration of exposure:
2
Justification:
since it is a subchronic study
AF for interspecies differences (allometric scaling):
4
Justification:
default factor for rats
AF for other interspecies differences:
2.5
Justification:
default; no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans
AF for intraspecies differences:
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
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.518 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Dose descriptor:
other: NOAEL
AF for dose response relationship:
1
Justification:
not applicable for sensitisation
AF for interspecies differences (allometric scaling):
1
Justification:
as it comes from human data
AF for intraspecies differences:
10
Justification:
default for general population
AF for the quality of the whole database:
1
Justification:
multiple reliable studies with Klimisch code 1 and 2
AF for remaining uncertainties:
1
Justification:
LOAEL to NOAEL
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:
2.5 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):
200
Modified dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
not relevant
AF for dose response relationship:
1
Justification:
default (three doses were tested, using a spacing range of 2-5 fold)
AF for differences in duration of exposure:
2
Justification:
since it is a subchronic study
AF for interspecies differences (allometric scaling):
4
Justification:
default for rats
AF for other interspecies differences:
2.5
Justification:
default; no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans
AF for intraspecies differences:
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
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

The 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:

Bioavalability (absorption):

The oral absorption in rats and in humans is assumed to be the same since no information for oral absorption for the calcium sulfonate target substance (C15 -C36) 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. A default respiratory volume of 1.15 m³/kg bw for rats was used to convert oral NOAEL into inhalation NOAEC.

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 - local effects (dermal)

For the long-term local dermal DNEL, a dermal NOAEL of 5.18 mg/cm² was calculated.

DNEL = 5.18 mg/cm² / (1 x 10 x 1 x 1 x 1) = 0.518 mg/cm².

Assessment factors are: 1 – interspecies, 10 – intraspecies, 1 – study duration (not applicable for sensitisation), 1 – dose response, 1 – quality of data base, 1 - LOAEL = NOAEL. The total AF amounts to 10.

Long-term exposure - systemic effects (oral):

The oral NOAEL of 500 mg/kg bw had not to be converted.

The oral NOAEL of 500 mg/kg bw was not modified for differences in absorption by oral route since no substance- and route specific information is available: Oral NOAELrat= oral NOAELhuman= 500 mg/kg bw.

DNEL = 500 mg/kg bw/(4 x 2.5 x 10 x 2 x 1 x 1) = 2.5 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 2 – study duration, 1 – dose response (clear dose response), 1 – quality of data base (default). The total AF amounts to 200.

Long-term exposure - systemic effects (dermal):

For the oral rat NOAEL of 500 mg/kg bw the following conversion was necessary:

dermal NOAEL = oral NOAEL x (ABS oral-rat/ABS dermal-rat) x (ABS dermal-rat/ABS dermal-human) = 2500 mg/kg bw

DNEL = 2500 mg/kg bw/(4 x 2.5 x 10 x 2 x 1 x 1) = 12.5 mg/kg bw.

Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 2 – study duration (subchronic study), 1 – dose response, 1 – quality of data base. The total AF amounts to 200.

Long-term exposure - systemic effects (inhalation):

The oral NOAEL of 500 mg/kg bw was converted into the inhalation NOAEC:

Corrected inhalation NOAEC = oral rat NOAEL x (1/1.15 m³/kg bw/day) x (ABSoral-rat/ABSinhal-human), where 1.15 is the 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 = 500 mg/kg bw x (1/1.15 m³/kg/day) x (50%/100%) = 217.39 mg/m³

DNEL = 217.39 mg/m³/(2.5 x 10 x 2 x 1 x 1) = 4.35 mg/m³.

Assessment factors are: 2.5 – remaining interspecies differences, 10 – intraspecies, 2 – study duration, 1 – dose response (clear dose response), 1 – quality of data base (default). The total AF amounts to 50.

Selected DNELs

DNEL local dermal (long term) =0.518 mg/cm²

DNEL systemic oral =2.5 mg/kg bw

DNEL systemic dermal (long term) =12.5 mg/kg bw

DNEL systemic inhalation =4.35 mg/m³