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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.95 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
Dose descriptor starting point:
NOAEL
DNEL value:
24 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
296 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:
no uncertainties remaining
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

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

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.224 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
Dose descriptor starting point:
NOAEL
DNEL value:
24 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
67.2 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:
5
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

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 the registered substance, 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 precautionary measures of the substance. Since the substance does not represent an acute hazard for the dermal or inhalative route, no DNELs for acute systemic toxicity need to be derived.

No DNELs are needed for local effects because there is no dose-response and route-specific information on these endpoints, and no skin irritating effects were observed. Long-term systemic DNELs cover sufficiently local effects. From all available data for the different human health endpoints it is clear that the substance 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 dermal or inhalative route of exposure, no DNEL needs to be derived, as evident from the available studies incl. estimated absorption parameters).

- Acute DNELs for inhalation (systemic and local) are not necessary since there is no acute toxic hazard by inhalation as described above.

- 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 skin irritating or sensitizing potential, but the substance is classified as eye dam. Cat. 1.

- There is no animal data on repeated dermal or inhalation exposure. To cover this endpoint, data from an oral OECD 422 toxicity study in rats as most sensitive / only available repeated dose endpoint has been used to calculate the long-term DNELs.

- No DNELs for reprotoxic effects are derived because no evidence for toxicity to reproduction or development is available, the derived NOAEL of 500 mg/kg bw/d indicates no reproductive effect, whilst systemic toxicity is already evident.

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 50% is considered for the 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 10% absorption for inhalation is assumed in humans. In addition, an uncertainty factor of 2 for the estimated absorption rates is employed for NOAEC derivation.

 

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 6-7 week (subacute) oral 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 24 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 in 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 OECD 422 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, relevant for workers with an assumed body weight of 70 kg. 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 oral 6-7 week reproductive / repeated dose 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, a clear dose-response was seen in the OECD 422 study.

 

Remaining uncertainties:

An assessment factor of 1 was applied here because no remaining uncertainties were identified, as the chosen NOAEL was considered as a sufficiently safe approach, taking into account the slightly prolonged study duration (6-7 weeks compared to 4 weeks), the fact that the females were pregnant, and the fact that the OECD 422 study revealed a NOAEL = 24 mg/kg bw/d for repeated dose toxicity, while the dose of 500 mg/kg bw/d lead to no reproductive toxicity.

 

Calculation of endpoint-specific DNELs for workers

Long-term exposure - systemic effects (dermal)

The oral NOAEL of 24 mg/kg bw was converted into the dermal NOAEL: Dermal NOAEL = oral NOAEL x (ABS oral-rat/ABS dermal-human) x (exposure animals / exposure workers) = 24 mg/kg bw x (100%/50%) x 1.4 = 67.2 mg/kg bw.

DNEL = 67.2 mg/kg bw/(1 x 6 x 4 x 2.5 x 5 x 1 x 1) = 0.224 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 24 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) x (exposure animals / exposure workers) = 24 mg/kg bw x (1/0.38 m³/kg/day) x (100%/10%) x (6.7/10) x 1.4 x 0.5 = 296.2 mg/m³

DNEL = 296.2 mg/m³/(1 x 6 x 1 x 2.5 x 5 x 1 x 1) = 3.949 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:
0.696 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
Dose descriptor starting point:
NOAEL
DNEL value:
24 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
104.35 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:
no remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

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

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
80 µg/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
Dose descriptor starting point:
NOAEL
DNEL value:
24 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
48 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:
no uncertainties remaining
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
40 µg/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
Dose descriptor starting point:
NOAEL
DNEL value:
24 mg/kg bw/day
DNEL value:
24 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:
no uncertainties remaining
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

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, relevant for consumers with an assumed body weight of 70 kg, 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 24 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 = 24 mg/kg bw.

DNEL = 24 mg/kg bw/(1 x 6 x 4 x 2.5 x 10 x 1 x 1) = 0.04 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 24 mg/kg bw was converted into the dermal NOAEL: Dermal NOAEL = oral NOAEL x (ABS oral-rat/ABS dermal-human) = 24 mg/kg bw x (100%/50%) = 48 mg/kg bw.

DNEL = 48 mg/kg bw/(1 x 6 x 4 x 2.5 x 10 x 1 x 1) = 0.08 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 24 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 = 24 mg/kg bw x (1/1.15 m³/kg/day) x (100%/10%) x 0.5 = 104.35 mg/m³

DNEL = 104.35 mg/m³/(1 x 6 x 1 x 2.5 x 10 x 1 x 1) = 0.696 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).