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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
16.46 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:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
1 235 mg/m³
Explanation for the modification of the dose descriptor starting point:

Calculation was mainly performed via default assumptions given by the DNEL calculator except one additional factor. As indicated by ECHAs guideline R.8, “Default absorption values have been proposed for the different routes of exposure…, but substance-specific data on absorption via the different routes are to be preferred. Such information may for instance be generated based on considerations of the chemical structure“. This approach was followed in the section toxicokinetics. However, this approach is, without explicit testing data on toxicokinetics, tainted with some uncertainties, despite the fact that the deduction of absorption rates was performed scientifically reasonably. So out of precautionary reasons the approach as proposed under R.8.4.2 will be followed as if no route-specific information on the starting route was available, i.e. to include a default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route). So the present default assessment factor is overridden here out of precautionary reasons, and in consequence the resulting NOAEC (modified dose descriptor stating point) is half as high as it would be when calculated via DNEL calculator.

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
6
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
1
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
5
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
There are no remaining uncertainties. According to the Guidance on Assessment Factors to Derive a DNEL, Technical Report No. 110, Assessment factors for Quality of whole database, i.a. Completeness and consistency of available data, Reliability of alternative data (e.g. read-across) must be regarded, the value should be set as ≥ 1. Due to the high similarity of both substances, i.e. the registered substance and the substance tested in a OECD 422 study which serves as the basis for DNEL derivation, including the low hazard of both substances, there are no remaining uncertainties left and the value of the AF can be set as 1.
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:
46.7 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:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
14 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

No long-term study on dermal toxicity is available and required, so only oral toxicity data can be used. The oral route was chosen as it is better suited to assess overall systemic effects. Further, as outlined in detail in subchapter „Toxicokinetics“, dermal absorption is very low compared to the oral route, so testing may have not allowed an assessment of the actual hazard properly and was so omitted due to animal welfare, as testing by the oral route allowed a better assessment. Therefore a route-to-route extrapolation from an oral repeated dose study, as a worst case, is justified.

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
6
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
4
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
5
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
There are no remaining uncertainties. According to the Guidance on Assessment Factors to Derive a DNEL, Technical Report No. 110, Assessment factors for Quality of whole database, i.a. Completeness and consistency of available data, Reliability of alternative data (e.g. read-across) must be regarded, the value should be set as ≥ 1. Due to the high similarity of both substances, i.e. the registered substance and the substance tested in an OECD 422 study which serves as the basis for DNEL derivation, including the low hazard of both substances, there are no remaining uncertainties left and the value of the AF can be set as 1.
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 (2008) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health.” and performed when enabled with the tool, by using the IUCLID 6 DNEL calculator.

Available dose descriptors:

For PPSOH, DNELs are needed for chronic exposure by the oral (only for consumers), dermal (for workers and consumers) and inhalation routes of exposure (workers and consumers). Inhalation is not a relevant route of exposure due to the low vapour pressure and the physical state in combination with precautionary measures of the substance. Since PPSOH does not represent an acute hazard (not classified for acute toxicity), no DNELs for acute systemic toxicity need to be derived.

No DNEL is needed for acute local effects because there is no dose-response and route-specific information on these endpoints, and no skin or eye irritating effects were observed. Long-term systemic DNELs cover sufficiently local (long term) effects.

From all available data for the different human health endpoints it is clear that PPSOH exerts its effect 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 substance, reflecting the routes, duration and frequency of exposure. DNELs are derived for workers and the general population. The general population includes consumers and humans exposed via the environment. There are following annotations for each endpoint:

 

- Since the substance is not acutely toxic by the oral or dermal route of exposure, no DNEL needs to be derived. This is based on the following data:

LD50(oral) = 5000 mg/kg, no mortality or signs of toxicity occurred (PPSOH, OECD 423)

LD50(oral) > 5000 mg/kg, LD0≥5000 mg/kg, no mortality occurred (read-across from PPS, OECD 401)

LD50(dermal) > 2000 mg/kg, LD0≥2000 mg/kg, no mortality, signs of systemic toxicity or dermal irritation occurred (read-across from PPS, OECD 402)

- Acute DNELs for inhalation (systemic and local) are not necessary since there is no acute toxic hazard by inhalation, as concluded from data via the other exposure routes.

- A qualitative approach in hazard assessment for eye and skin irritation/corrosion and skin sensitization is used because no quantitative dose descriptors are available on these endpoints.

- There is no animal data on repeated dermal or inhalation exposure. To cover this endpoint, data from an oral OECD 422 study in rats on a suitable read-across substance as the only available endpoint has been used to calculate the long-term DNELs, covering both reproductive and repeated dose toxicity.

 

First of all, available dose descriptors were converted into a correct starting point to take into account differences in routes of exposure between experimental animals and humans and differences in human and animal exposure conditions. Consecutively, the assessment factors have been applied to the correct starting point to obtain the endpoint specific DNELs. Assessment factors (AFs) correct uncertainties and variability within and between species in the effect data. In addition, out of precautionary reasons the approach as proposed under R.8.4.2 will be followed as if no route-specific information on the starting route was available, i.e. to include a default factor of 2 (i.e. the absorption percentage for the starting route (oral) is half that of the end route (inhalation).

The assessment factors are applied in accordance with R.8 ECHA guidance document.

 

Modification of the relevant dose descriptors to the correct starting point:

 

Bioavailability (absorption)

A dermal absorption rate of 10% is considered for the target substance as outlined in the subchapter “Basic Toxicokinetics”, based on the available physico-chemical and toxicological properties of the substance. The dermal absorption in rats and in humans is assumed to be the same since no experimentally determined values are available for dermal absorption of the target chemical in rats and in humans. In case of oral to inhalation extrapolation, 100% absorption is assumed for oral absorption in rats and 100% absorption for inhalation is assumed in humans.

 

Route-to-route extrapolation:

Oral-to-inhalation extrapolations are performed to assess long-term inhalation effects in humans, as well as oral-to-dermal extrapolations are conducted to assess long-term dermal effects in humans. This is due to the fact that only oral studies are available, because oral exposure in general is the most suitable administration route to assess systemic toxicity.

 

Exposure conditions:

Exposure time differs in workers and in the ca. 6 week (subacute) oral OECD 422 study in rats. Rats were exposed to the test substance once a day via gavage, while workers are exposed 8h daily (5 days/week). However, the dose descriptor (the NOAEL of 1000 mg/kg bw/d) was not adjusted to 8h exposure because exposure time is not really relevant for the systemic dose resulting from only dermal exposure. However, assuming a dose- and not concentration-dependent NOAEL, as further described in the Manual for the SECO-DNEL Tool 1.0 issued by the Swiss EAER, Differences experimental and human exposure conditions are taken into account as follows: Animals are dosed with the test item in repeated dose toxicity studies daily 7 days a week, whereas workers are only exposed 5 days a week on working days. Hence, the starting NOAEL is corrected with the factor 7 days / 5 days = 1.4.

 

 

Respiratory volumes:

Differences in the respiratory volumes between experimental animals and humans were used when an oral rat NOAEL from the oral 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:

 

Interspecies differences:

No allometric scaling factor is applied in case of oral-to-inhalation extrapolation.

An additional assessment factor of 2.5 is applied for remaining interspecies differences in toxicodynamics between rats and humans.

 

Intraspecies differences:

An assessment factor of 5 is applied for workers for all endpoints and for all exposure routes. The factor of 10 is used in the process of DNEL-calculation for general population due to the greater intra-species variations.

 

Extrapolation of duration:

An assessment factor of 6 was applied in case of the subacute toxicity study. This is a default assessment factor for subacute to chronic extrapolation according to ECHA’s guidance R.8 and no reason for deviation was identified.

 

Quality of whole data base:

An assessment factor for uncertainties in the quality of the data base is regarded to be 1, because no concern was indicated upon the quality of the provided data.

 

Issues related to dose response:

An assessment factor of 1 was used because there were no indications for deviation from the default value.

 

Remaining uncertainties:

An assessment factor of 1 was applied here because no remaining uncertainties were identified.

 

 

Calculation of endpoint-specific DNELs for workers

Long-term exposure - systemic effects (dermal)

The oral NOAEL of 1000 mg/kg bw was converted into the dermal NOAEL: Dermal NOAEL = oral NOAEL x (ABS oral-rat/ABS dermal-human) = 1000 mg/kg bw x (100%/10%) x 1.4 = 14000 mg/kg bw.

DNEL = 14000 mg/kg bw/(1 x 6 x 4 x 2.5 x 5 x 1 x 1) = 46.67 mg/kg bw.

Assessment factors are: 1 – dose response (clear dose response), 6 – study duration (subacute to chronic), 4 – interspecies, allometric scaling, 2.5 – remaining interspecies differences, 5 – intraspecies (workers), 1 – quality of data base, 1 – remaining uncertainties (none remaining).

 

Long-term exposure - systemic effects (inhalation)

The oral NOAEL of 1000 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) = 50 mg/kg bw x (1/0.38 m³/kg/day) x (100%/100%) x (6.7/10) x 1.4 x 0.5 = 1234.21 mg/m³

DNEL = 1234.21 mg/m³/(1 x 6 x 1 x 2.5 x 5 x 1 x 1) = 16.46 mg/m³.

Assessment factors are: 1 – dose response (clear dose response), 6 – study duration (subacute to chronic), 1 – interspecies, no allometric scaling required for oral to inhalation exposure, 2.5 – remaining interspecies differences, 5 – intraspecies (workers), 1 – quality of data base, 1 – remaining uncertainties (none remaining).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.9 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:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
434.8 mg/m³
Explanation for the modification of the dose descriptor starting point:

Calculation was mainly performed via default assumptions given by the DNEL calculator except one additional factor. As indicated by ECHAs guideline R.8, “Default absorption values have been proposed for the different routes of exposure…, but substance-specific data on absorption via the different routes are to be preferred. Such information may for instance be generated based on considerations of the chemical structure“. This approach was followed in the section toxicokinetics. However, this approach is, without explicit testing data on toxicokinetics, tainted with some uncertainties, despite the fact that the deduction of absorption rates was performed scientifically reasonably. So out of precautionary reasons the approach as proposed under R.8.4.2 will be followed as if no route-specific information on the starting route was available, i.e. to include a default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route). So the present default assessment factor is overridden here out of precautionary reasons, and in consequence the resulting NOAEC (modified dose descriptor stating point) is half as high as it would be when calculated via DNEL calculator.

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
6
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
1
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
10
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
There are no remaining uncertainties. According to the Guidance on Assessment Factors to Derive a DNEL, Technical Report No. 110, Assessment factors for Quality of whole database, i.a. Completeness and consistency of available data, Reliability of alternative data (e.g. read-across) must be regarded, the value should be set as ≥ 1. Due to the high similarity of both substances, i.e. the registered substance and the substance tested in an OECD 422 study which serves as the basis for DNEL derivation, including the low hazard of both substances, there are no remaining uncertainties left and the value of the AF can be set as 1.
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:
16.7 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:
1 000 mg/kg bw/day
Value:
10 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

No long-term study on dermal toxicity is available and required, so only oral toxicity data can be used. The oral route was chosen as it is better suited to assess overall systemic effects. Further, as outlined in detail in subchapter „Toxicokinetics“, dermal absorption is very low compared to the oral route, so testing may have not allowed an assessment of the actual hazard properly and was so omitted due to animal welfare, as testing by the oral route allowed a better assessment. Therefore a route-to-route extrapolation from an oral repeated dose study, as a worst case, is justified.

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
6
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
4
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
10
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
There are no remaining uncertainties. According to the Guidance on Assessment Factors to Derive a DNEL, Technical Report No. 110, Assessment factors for Quality of whole database, i.a. Completeness and consistency of available data, Reliability of alternative data (e.g. read-across) must be regarded, the value should be set as ≥ 1. Due to the high similarity of both substances, i.e. the registered substance and the substance tested in an OECD 422 study which serves as the basis for DNEL derivation, including the low hazard of both substances, there are no remaining uncertainties left and the value of the AF can be set as 1.
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:
1.67 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:
1 000 mg/kg bw/day
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
6
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
4
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
10
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
There are no remaining uncertainties. According to the Guidance on Assessment Factors to Derive a DNEL, Technical Report No. 110, Assessment factors for Quality of whole database, i.a. Completeness and consistency of available data, Reliability of alternative data (e.g. read-across) must be regarded, the value should be set as ≥ 1. Due to the high similarity of both substances, i.e. the registered substance and the substance tested in an OECD 422 study which serves as the basis for DNEL derivation, including the low hazard of both substances, there are no remaining uncertainties left and the value of the AF can be set as 1.
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:

 

Bioavailability (absorption)

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. 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 (instead 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 (oral)

The oral NOAEL of 1000 mg/kg bw was not modified for differences in absorption by oral route since no substance- and route specific information is available: Oral NOAEL rat = oral NOAEL human = 1000 mg/kg bw.

DNEL = 1000 mg/kg bw/(1 x 6 x 4 x 2.5 x 10 x 1 x 1) = 1.667 mg/kg bw.

Assessment factors are:1 – dose response (clear dose response), 6 – study duration (subacute to chronic), 4 – interspecies, allometric scaling, 2.5 – remaining interspecies differences, 10 – intraspecies (general population), 1 – quality of data base, 1 – remaining uncertainties (none remaining).

 

Long-term exposure - systemic effects (dermal)

The oral NOAEL of 1000 mg/kg bw was converted into the dermal NOAEL: Dermal NOAEL = oral NOAEL x (ABS oral-rat/ABS dermal-human) = 1000 mg/kg bw x (100%/10%) = 10000 mg/kg bw.

DNEL = 10000 mg/kg bw/(1 x 6 x 4 x 2.5 x 10 x 1 x 1) = 16.667 mg/kg bw.

Assessment factors are: 1 – dose response (clear dose response), 6 – study duration (subacute to chronic), 4 – interspecies, allometric scaling, 2.5 – remaining interspecies differences, 10 – intraspecies (general population), 1 – quality of data base, 1 – remaining uncertainties (none remaining).

 

Long-term exposure - systemic effects (inhalation)

The oral NOAEL of 1000 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 m³/kg bw is standard respiratory volume of rats during 24 h, ABS is absorption (values are the same as described for workers).

Corrected Inhalation NOAEC = 1000 mg/kg bw x (1/1.15 m³/kg/day) x (100%/100%) x 0.5 = 434.78 mg/m³

DNEL = 434.78 mg/m³/(1 x 6 x 1 x 2.5 x 10 x 1 x 1) = 2.90 mg/m³.

Assessment factors are:1 – dose response (clear dose response), 6 – study duration (subacute to chronic), 1 – interspecies, no allometric scaling required for oral to inhalation exposure, 2.5 – remaining interspecies differences, 10 – intraspecies (general population), 1 – quality of data base, 1 – remaining uncertainties (none remaining).