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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.76 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):
75
Modified dose descriptor starting point:
NOAEC
Value:
132.2 mg/m³
Explanation for the modification of the dose descriptor starting point:
A systemic NOAEL of 150 mg/kg bw /day from the Oral-Reproduction/Developmental Toxicity Screening Study in Rats (Thorsrud, 2013) was converted into the corrected inhalatory NOAEC taking into account the standard daily respiratory volume of 0.38 m3 for rats, the standard respiratory volume in workers during 8 hours: 6.7 m3 under normal conditions and 10 m3 by light activity as well as 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:
6
Justification:
since it is a subacute 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 (GLP, guideline study)
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:
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):
300
Modified dose descriptor starting point:
NOAEL
Value:
750 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
A systemic NOAEL of 150 mg/kg bw /day from the Oral-Reproduction/Developmental Toxicity Screening Study in Rats (Thorsrud, 2013) was converted into the corrected dermal NOAEL taking into account the rates for absorpion (oral 50 %, dermal 10 %).Thereby the corrected dermal NOAEL is: oral NOAEL * (ABS oral-rat/ABS dermal-rat) * (ABS dermal-rat/ABS dermal-human) = 750 mg/kg bw.
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:
6
Justification:
since it is a sub-acute 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 (GLP, guideline study)
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

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:

Reaction Products of alcohols, C14-18, C18 unsat., esterified with phosphorus pentoxide and salted with amines, C12-14,-tert-alkyl is not acutely toxic by oral and dermal routes of exposure if administered to rats (for both routes: LD50 > 2000 mg/kg bw; Sanders, 2012a,b). Inhalation is not relevant route of exposure due to the low vapour pressure of the substance (0.0029 Pa at 25°C ) (Tremain, 2012). The substance is non-volatile and thefeore no risk of irritation or sensitisation of respiratory tract exists. The substance is not irritating or sensitising to skin (Sanders, 2012c; Smedley, 2012). 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 NOAEL of 150 mg/kg bw established in the Oral-Reproduction/Developmental Toxicity Screening Study in Rats (Thorsrud, 2013) was used as the starting point. This is the lowest NOAEL known for the target substance after repeated exposures to rats. 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 no No-Observed-Effect-Level could be established from the relevant studies.

Modification of the starting point:

From all available data on the Reaction Products of alcohols, C14-18, C18 unsat., esterified with phosphorus pentoxide and salted with amines, C12-14,-tert-alkyl it is clear that the 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:

Due to the molecular weight of 533.82 and 784.29 g/mol (for two repesentative stuctures: mono-, and dialkyl phosphate amino salt), a logPow of 8.0 together with the non-irritating properties of the substance and the effects found at the mid and the highest dose level in the Oral-Reproduction/Developmental Toxicity Screening Study in Rats (Throsrud, 2012) and the subacute study in rats (Dunster and Watson, 2012),absorption by oral route is considered to be slight to moderate for the 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). 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 Reaction Products of alcohols, C14-18, C18 unsat., esterified with phosphorus pentoxide and salted with amines, C12-14,-tert-alkyl. The log Pow of 8.0, the water solubility of 1.64 mg/L and the molecular weight of 533.82 and 784.29 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). Dermal absorption in rats, rabbits and in humans is assumed to be the same since no information for dermal absorption of the target susbtance in humans is available.

Inhalation absorption

Absorption by inhalation is considered to be negligible (low vapour pressure of 0.0029 Pa at 25°C) and not to be higher than absorption by oral route. However, 100% absorption is assumed for inhalation route (in case of the route-to-route extrapolation) and 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 (ABSoral-rat/ABSinh-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):

Corrected dermal NOAEL = oral NOAEL x (ABSoral-rat/ABSderm-rat) x (ABSderm-rat/ABSderm-human) = oral NOAEL x (ABSoral-rat/ABSderm-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 (0.38m³).

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 Oral-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 6 was applied for duration of exposure (Screening study = sub-acute).

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-Reproduction/Developmental Toxicity Screening Study in Rats was used (there was a clear dose response).

Calculation of DNELs:

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

The oral rat NOAEL of 150 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) = 150 mg/kg bw x (1/0.38 m³/kg/day) x (50%/100%) x (6.7/10) = 132.2 mg/m³

DNEL = 132.2 mg/m³/(2.5 x 5 x 6 x 1 x 1) = 1.76 mg/m³.

Assessment factors are: 2.5 – remaining interspecies differences, 5 – intraspecies, 6 – study duration (sub-acute study), 1 – dose response, 1 – quality of data base. The total AF amounts to 75.

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

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

Dermal NOAEL = oral NOAEL x (ABSoral-rat/ABSderm-human) = 150 x (50%/10%) = 750 mg/kg bw

DNEL = 750 mg/kg bw/(4 x 2.5 x 5 x 6 x 1 x 1) = 2.5 mg/kg bw.

Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 5 – intraspecies, 6 – study duration (sub-acute study), 1 – dose response, 1 – quality of data base. The total AF amounts to 300.

Selected DNELs

DNEL systemic inhalation = 1.76 mg/m³

DNEL systemic dermal (long-term) = 2.5 mg/kg bw

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.434 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):
150
Modified dose descriptor starting point:
NOAEC
Value:
65.2 mg/m³
Explanation for the modification of the dose descriptor starting point:
A systemic NOAEL of 150 mg/kg bw /day from the Oral-Reproduction/Developmental Toxicity Screening Study in Rats (Thorsrud, 2013) was converted into the corrected inhalatory NOAEC taking into account the standard daily respiratory volume of 1.15 m3 for rats 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:
6
Justification:
since it is a sub-acute 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:
1.25 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):
600
Modified dose descriptor starting point:
NOAEL
Value:
750 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
A systemic NOAEL of 150 mg/kg bw /day from the Oral-Reproduction/Developmental Toxicity Screening Study in Rats (Thorsrud, 2013) was converted into the corrected dermal NOAEL taking into account the rates for absorpion (oral 50 %, dermal 10 %). Thereby the corrected dermal NOAEL is: oral NOAEL * (ABS oral-rat/ABS dermal-rat) * (ABS dermal-rat/ABS dermal-human) = 750 mg/kg bw.
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:
6
Justification:
since it is a sub-acute 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:
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:
0.25 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):
600
Modified dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
not relevant (oral exposure and oral study in rats)
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:
6
Justification:
since it is a sub-acute 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 target substance 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 - systemic effects (inhalation):

The oral NOAEL of 150 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 = 150 mg/kg bw x (1/1.15 m³/kg/day) x (50%/100%) = 65.2 mg/m³

DNEL = 65.2 mg/m³/(2.5 x 10 x 2 x 1 x 1) = 0.434 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). The total AF amounts to 150.

Long-term exposure - systemic effects (dermal):

For the oral rat NOAEL of 150 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) = 150 x (50%/10%) = 750 mg/kg bw

DNEL = 750 mg/kg bw/(4 x 2.5 x 10 x 6 x 1 x 1) = 1.25 mg/kg bw.

Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 6 – study duration (sub-acute study), 1 – dose response, 1 – quality of data base. The total AF amounts to 600.

Long-term exposure - systemic effects (oral):

The oral NOAEL of 150 mg/kg bw had not to be converted.

The oral NOAEL of 150 mg/kg bw was not modified for differences in absorption by oral route in rats and in humans since no substance- and route specific information is available: oral absorptionrat= oral absorptionhuman.

DNEL = 150 mg/kg bw/(4 x 2.5 x 10 x 6 x 1 x 1) = 0.25 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). The total AF amounts to 600.

Selected DNELs

DNEL systemic inhalation =0.434 mg/m³

DNEL systemic dermal (long term) = 1.25 mg/kg bw

DNEL systemic oral (long-term) = 0.25 mg/kg bw