Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
18.8 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
DNEL value:
1 409 mg/m³
Explanation for the modification of the dose descriptor starting point:
Route-to-route extrapolation from the oral NOAEL value was performed. Inhalation and oral absorption were assumed to be 100% for the purposes of the DNEL calculation.
AF for dose response relationship:
1
Justification:
Default AF
AF for differences in duration of exposure:
6
Justification:
Sub-acute to Chronic
Justification:
No allometric scaling needed
AF for other interspecies differences:
2.5
Justification:
For Systemic Effects
AF for intraspecies differences:
5
Justification:
Default for Workers
AF for the quality of the whole database:
1
Justification:
Default AF
AF for remaining uncertainties:
1
Justification:
Default AF
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:
2.66 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
DNEL value:
799 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Route-to-route extrapolation from the oral NOAEL value was performed. Dermal and oral absorption were assumed to be 100% for the purposes of the DNEL calculation
AF for dose response relationship:
1
Justification:
Default AF
AF for differences in duration of exposure:
6
Justification:
Sub-acute to Chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Default AF for rat
AF for other interspecies differences:
2.5
Justification:
For Systemic Effects
AF for intraspecies differences:
5
Justification:
Default for Workers
AF for the quality of the whole database:
1
Justification:
Default AF
AF for remaining uncertainties:
1
Justification:
Default AF
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:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

Acute toxicity

ECHA Guidance R.8 (Chapter R.8.1.2.5) indicates that DNELs for acute toxicity are not required if no acute toxicity hazard leading to classification has been identified. Distilled tall oil, maleated is not considered to be acutely toxic following oral or dermal exposure based on LD50 values of >2000 mg/kg for key constituents. A low vapour pressure precludes inhalation exposure indicating a low level of concern for this route of exposure. No DNELs for acute toxicity are therefore necessary.

 

Irritation

Corrosive and irritant effects on the skin and eye are local, concentration-dependent phenomena. However while data available on the two key constituentsindicate that Distilled tall oil, maleated is irritating to eye and skin), the nature of the data is such that no conclusion can be drawn with regard to any dose-response relationship present. No DNEL for irritation can therefore be derived.

 

Sensitisation

The sensitisation potential of Distilled tall oil, maleated is well understood and comprises results from four local lymph node assays, a guinea pig maximisation test and a guinea pig Buehler test available for the key constituents. The results consistently show evidence of a potential to induce skin sensitisation.

 

Intrinsic sensitising potency

ECHA Guidance R.8, Appendix R.8-10, (ECHA, 2010) states that while skin sensitisation is generally regarded as a threshold effect it may be very difficult to derive a threshold and to set a DNEL. Thus the general approach for skin sensitisers involves a qualitative approach where a DNEL is used to judge any remaining/residual risks after the implementation of appropriate risk management measures (RMM) and occupational controls (OC).

 

The extent of the RMM and OC required is dependent on the intrinsic sensitising potency of the substance.

 

For results obtained using the LLNA, intrinsic sensitising potency is based on the EC3 and defined (ECHA (2010), Appendix R.8-10) as follows:

Category

EC3 (%)

Extreme

<0.2%

Strong

>0.2 - <2

Moderate

>2

 

EC3 values of 0.74%, 1.9% and 5.0% were obtained for Rosin, maleated, Rosin, fumarated and Rosin, fumarated, reaction products with formaldehyde, respectively. These indicate a strong to moderate potential to cause skin sensitisation.

 

LLNA data onFatty acids, C14-18 and C16-18-unsatd., maleated, suggest a moderate to strong potential for skin sensitisation with an EC3around 1%.

 

For results obtained using the guinea pig maximisation test, intrinsic sensitising potency is based on the (intradermal) concentration employed during the induction phase of the test together with the incidence of sensitisation following challenge (ECHA, 2010):

Induction conc (%)

Incidence of sensitisation

<0.1

Strong

(30-60%)

Extreme

(>60%)

>0.1-<1

Moderate

(30-60%)

Strong

(>60%)

>1

Moderate

(30-60%)

Moderate

(>60%)

 

Results obtained from a guinea pig maximisation test on Rosin, maleated using an intradermal induction concentration of 0.003% resulted in sensitisation incidences of 79% (10% challenge concentration) and 100% (30% challenge concentration) and are therefore indicative of an extreme sensitiser.

 

Different criteria apply to interpretation of results obtained using the Buehler test (ECHA Guidance R.8 (Appendix R.8-10)):

Induction conc (%)

Incidence of sensitisation

<0.2

Strong

(15-60%)

Extreme

(>60%)

>0.2-<20

Moderate

(15-60%)

Strong

(>60%)

>20

Moderate

(15-60%)

Moderate

(>60%)

  

Results obtained from a Buehler test on Rosin, maleated using an induction concentration of 80% gave a sensitisation incidence of 80% (5% challenge concentration) indicative of a moderate sensitiser.

 

Given the range of outcomes obtained (1 extreme; 2 strong; 2 moderate), it will be assumed for the purposes of risk characterisation that distilled tall oil, maleated has a strong potential to cause sensitisation following skin contact.

 

Derivation of a DNEL for sensitisation

ECHA Guidance R.8, Appendix R.8-10 (ECHA, 2010), indicates that the EC3 concentration from a LLNA test can be taken as a LOAEL for the induction of skin sensitisation (ECHA, 2010) after conversion into an equivalent dose per unit area of skin (μg/cm2).

Distilled tall oil, maleated is a complex UVCB reaction product. In the absence of skin sensitisation data on the material itself and in view of the range of EC3 values obtained from data on key constituents and/or related materials, it is not possible to derive a reliable value that can be used in a quantitative risk assessment. A qualitative assessment will be carried out based on an assumption that Distilled tall oil, maleated has a strong potential to cause skin sensitisation.

 

 

Repeated dose toxicity

Rosin, fumarated was administered in the diet to male and female rats at concentrations of 0, 1000 ppm, 3000 ppm and 10000 ppm for approximately 6-7 weeks. Food consumption and mean body weights were decreased in both sexes at 10000 ppm and 3000 ppm, with high dose animals also showing an increase in total bilirubin (both sexes) and decreased adrenal weight (females only).  The lower of these two values will be used as the NOAEL for the repeated dose toxicity. This is considered a scientifically defensible since, apart from poor palatability and associated body weight reduction following exposure to 10000 ppm test substance, no clearly adverse effects were apparent. The NOAEL for repeated dose toxicity of Rosin, fumarated is therefore 221-228 mg/kg bw/d for males and 196-292 mg/kg bw/d for females. A NOAEL of 196 mg/kg bw/d will be used for the purposes of DNEL derivation.

 

In a combined repeat dose reproductive/developmental toxicity study, the test material (Fatty acids, C14-18 and C16-18-unsatd., maleated) was administered daily via oral gavage at doses of 0, 100, 300, and 1000 mg/kg bw/day to Wistar rats (12/sex/dose) in a propylene glycol vehicle. Male rats were treated for a period of 35 days (14 days pre-mating, 14 days mating/post-mating period followed by an additional week) while female rats were treated for approximately 47 days (14 days pre-mating, for up to 7 days mating period, through gestation till PPD 4). A satellite group of nulliparous and non-pregnant female rats (5/sex/dose) was also employed in the study and treated with the test material for a period of 35 days. No signs of mortality or clinical toxicity were observed through the study period. Body weight and food consumption remained unaffected post-treatment with the test material. Effects on prothrombin time in mid and high dose groups were observed but not considered toxicologically significant. Clinical chemistry, urinalysis, and neurobehavioral parameters appeared unaffected through the study period. Slightly lower weights of kidneys were recorded for males at 300 and 1000 mg/kg bw/day (Mid and High dose). The changes were not associated with any findings in clinical pathology or microscopic changes and were regarded as physiological variation. Test material related microscopic findings were found at 1000 mg/kg bw/day (High dose) in stomach, in the form of hyper/paraceratosis of the non-glandular gastric mucosa. This minimal to mild multifocal change occurred in 4 of 5 males and 2 of 5 females. There were no microscopic findings related to treatment at 100 or 300 mg/kg bw/day. These findings are indicative of local irritation and analogous structures do not exist in man. Necroscopy did not reveal any remarkable findings. Based on the observations of this sub-acute oral toxicity study; the NOAEL was determined to be 1000 mg/kg bw/day.

Modification of Relevant Dose Descriptors to the Correct Starting Point

Relevant dose descriptors have been developed for the different endpoints and routes of exposure (see Guidance Document, Chapter R.8, Appendix R.8-2). The values are provided below. For potential dermal and inhalation exposures, route-to-route extrapolations from the oral NOAEL value were performed. Dermal, inhalation and oral absorption is assumed to be 100% for the purposes of the DNEL calculation.

Distilled tall oil, Maleated is a UVCB substance derived from natural sources and typical analysis shows it comprises a mixture of unsaturated fatty acids – primarily C18 (~75%) and mixed rosin acids (~25%).

Repeat dose systemic toxicity data are available for fatty acids, C14-18 and C16-18-unsatd., maleated and Rosin, fumarated. As the R groups are derived from distilled oil, the ratio of unsaturated C18 and rosin acids R groups in the molecule are likely to be proportional to the levels found in the parent distilled tall oil. The NOAEL value used as the starting point for systemic DNEL derivation is calculated proportionally, to give an estimated DNEL.

 

The NOAEL value is derived from two combined dermal repeat dose/reproductive toxicity screening study in rats (Grόsz, 2013 and Inveresk Research, 2004).

Based on the above calculation, a NOAEL of 799 mg/kg bw/d was derived ((75% x 1000 mg/kg bw/d) + (25% x 196 mg/kg bw/d)).

Dermal route:

The corrected dermal NOAEL is:

dermal NOAEL = oral NOAEL * (ABSoral-rat/ABSderm-human)

dermal NOAEL = 799* (100/100)

dermal NOAEL = 799 mg/kg/d

Thus, the corrected dose descriptor for dermal route is 799 mg/kg/day.

Inhalation:

To convert oral NOAEL into inhalatory NOAEC, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 0.38 m3/kg bw/8 h).

For workers a correction was added for the difference between respiratory rates under standard conditions (sRVhuman: 6.7 m3 for an 8-h exposure period) and under conditions of light activity (wRV: 10 m3 for an 8-h exposure period).

The corrected inhalation NOAEC for workers is:

inhalatory NOAEC = oral NOAEL * (1/ sRV rat 8h) * (ABS oral / ABS inh) * (sRV human / wRV)

inhalatory NOAEC = 799 * (1/0.38) * (100/100) * (6.7 / 10)

inhalatory NOAEC = 1409 mg/m3

Thus, the corrected dose descriptor for inhalation is 1409 mg/m3 for workers.

Application of Assessment Factors to the Corrected Dose Descriptors

Endpoint-specific DNEL values were derived from the corrected dose descriptors after application of assessment factors (AF). The AFs were based on the procedures described by the ECHA (ECHA Guidance Chapter R8, Table R8-6, November 2012).

 

 Assessment factors (ECHA Guidance Chapter R8, Table R8-6, November 2012)

Long-term DNEL Assessment Factors (Dermal)

Assessment Factor

Worker

Exposure Duration

6 (subacute to chronic)

 

Interspecies

 

2.5 (for systemic effects)

 

4 (Allometric scaling for rats)

 Intraspecies

5 (for worker)

 

 Issues related to dose-response

1

Quality of whole database

 

1

DNEL Worker long-term dermal-systemic = 799 / 300 = 2.66 mg/kg bw/day

 

 

Assessment factors (ECHA Guidance Chapter R8, Table R8-6, November 2012)

Long-term DNEL Assessment Factors (Inhalation)

Assessment Factor

Worker

Exposure Duration

6 (subacute to chronic)

 

Interspecies

 

 

2.5 (for systemic effects)

 Intraspecies

5 (for worker)

 

 Issues related to dose-response

1

Quality of whole database

 

1

 

DNEL Worker long-term inhalation-systemic = 1409 / 75 = 18.8 mg/m3

 

Endpoint for risk characterisation

Experimental results indicating a potential to cause sensitisation by skin contact, with associated classification underRegulation (EC) No. 1272/2008, indicate that Distilled tall oil, maleated may present a risk to workers during normal handling and use. Qualitative risk characterisation (ECHA, 2010) will therefore be conducted on this endpoint.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.63 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):
150
Modified dose descriptor starting point:
NOAEC
DNEL value:
695 mg/m³
Explanation for the modification of the dose descriptor starting point:
Route-to-route extrapolation from the oral NOAEL value was performed. Inhalation and oral absorption were assumed to be 100% for the purposes of the DNEL calculation.
AF for dose response relationship:
1
Justification:
Default AF
AF for differences in duration of exposure:
6
Justification:
Sub-acute to Chronic
Justification:
No allometric scaling required
AF for other interspecies differences:
2.5
Justification:
For Systemic Differences
AF for intraspecies differences:
10
Justification:
General Population Deafult AF
AF for the quality of the whole database:
1
Justification:
Default AF
AF for remaining uncertainties:
1
Justification:
Default AF
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:
1.33 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
DNEL value:
799 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Route-to-route extrapolation from the oral NOAEL value was performed. Dermal and oral absorption were assumed to be 100% for the purposes of the DNEL calculation
AF for dose response relationship:
1
Justification:
Default AF
AF for differences in duration of exposure:
6
Justification:
Sub-acute to Chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric Scaling for rat
AF for other interspecies differences:
2.5
Justification:
For systemic differences
AF for intraspecies differences:
10
Justification:
General Population default AF
AF for the quality of the whole database:
1
Justification:
Default AF
AF for remaining uncertainties:
1
Justification:
Default AF
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:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.33 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
DNEL value:
799 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Default AF
AF for differences in duration of exposure:
6
Justification:
Sub-acute to Chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling for rats
AF for other interspecies differences:
2.5
Justification:
For systemic differences
AF for intraspecies differences:
10
Justification:
General population default AF
AF for the quality of the whole database:
1
Justification:
Default AF
AF for remaining uncertainties:
1
Justification:
Default AF
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

Acute toxicity

ECHA Guidance R.8 (Chapter R.8.1.2.5) indicates that DNELs for acute toxicity are not required if no acute toxicity hazard leading to classification has been identified. Distilled tall oil, maleated is not considered to be acutely toxic following oral or dermal exposure based on LD50 values of >2000 mg/kg for key constituents.. A low vapour pressure precludes inhalation exposure indicating a low level of concern for this route of exposure. No DNELs for acute toxicity are therefore necessary.

 

Irritation

Corrosive and irritant effects on the skin and eye are local, concentration-dependent phenomena. However while data available on the two key constituentsindicate that Distilled tall oil, maleated is irritating to eye and skin), the nature of the data is such that no conclusion can be drawn with regard to any dose-response relationship present. No DNEL for irritation can therefore be derived.

 

Sensitisation

The sensitisation potential of Distilled tall oil, maleated is well understood and comprises results from four local lymph node assays, a guinea pig maximisation test and a guinea pig Buehler test available for the key constituents. The results consistently show evidence of a potential to induce skin sensitisation.

 

Intrinsic sensitising potency

ECHA Guidance R.8, Appendix R.8-10, (ECHA, 2010) states that while skin sensitisation is generally regarded as a threshold effect it may be very difficult to derive a threshold and to set a DNEL. Thus the general approach for sensitisers involves a qualitative approach where a DNEL is used to judge any remaining/residual risks after the implementation of appropriate risk management measures (RMM) and occupational controls (OC).

 

The extent of the RMM and OC required is dependent on the intrinsic sensitising potency of the substance.

 

For results obtained using the LLNA, intrinsic sensitising potency is based on the EC3 and defined (ECHA (2010), Appendix R.8-10) as follows:

Category

EC3 (%)

Extreme

<0.2%

Strong

>0.2 - <2

Moderate

>2

 

EC3 values of 0.74%, 1.9% and 5.0% were obtained for Rosin, maleated, Rosin, fumarated and Rosin, fumarated, reaction products with formaldehyde, respectively. These indicate a strong to moderate potential to cause skin sensitisation.

 

LLNA data onFatty acids, C14-18 and C16-18-unsatd., maleated, suggest a moderate to strong potential for skin sensitisation with an EC3around 1%.

 

For results obtained using the guinea pig maximisation test, intrinsic sensitising potency is based on the (intradermal) concentration employed during the induction phase of the test together with the incidence of sensitisation following challenge (ECHA, 2010):

 

Induction conc (%)

Incidence of sensitisation

<0.1

Strong

(30-60%)

Extreme

(>60%)

>0.1-<1

Moderate

(30-60%)

Strong

(>60%)

>1

Moderate

(30-60%)

Moderate

(>60%)

 

Results obtained from a guinea pig maximisation test on Rosin, maleated using an intradermal induction concentration of 0.003% resulted in sensitisation incidences of 79% (10% challenge concentration) and 100% (30% challenge concentration) and are therefore indicative of an extreme sensitiser.

 

Different criteria apply to interpretation of results obtained using the Buehler test (ECHA Guidance R.8 (Appendix R.8-10)):

 

Induction conc (%)

Incidence of sensitisation

<0.2

Strong

(15-60%)

Extreme

(>60%)

>0.2-<20

Moderate

(15-60%)

Strong

(>60%)

>20

Moderate

(15-60%)

Moderate

(>60%)

  

Results obtained from a Buehler test on Rosin, maleated using an induction concentration of 80% gave a sensitisation incidence of 80% (5% challenge concentration) indicative of a moderate sensitiser.

 

Given the range of outcomes obtained (1 extreme; 2 strong; 2 moderate), it will be assumed for the purposes of risk characterisation that Distilled tall oil, maleated has a strong potential to cause sensitisation following skin contact.

 

Derivation of a DNEL for sensitisation

ECHA Guidance R.8, Appendix R.8-10 (ECHA, 2010), indicates that the EC3 concentration from a LLNA test can be taken as a LOAEL for the induction of skin sensitisation (ECHA, 2010) after conversion into an equivalent dose per unit area of skin (μg/cm2).

Distilled tall oil, maleated is a complex UVCB reaction product. In the absence of skin sensitisation data on the material itself and in view of the range of EC3 values obtained from data on key constituents and/or related materials, it is not possible to derive a reliable value that can be used in a quantitative risk assessment. A qualitative assessment will be carried out based on an assumption that Distilled tall oil, maleated has a strong potential to cause skin sensitisation.

 

Repeated dose toxicity

Rosin, fumarated was administered in the diet to male and female rats at concentrations of 0, 1000 ppm, 3000 ppm and 10000 ppm for approximately 6-7 weeks. Food consumption and mean body weights were decreased in both sexes at 10000 ppm and 3000 ppm, with high dose animals also showing an increase in total bilirubin (both sexes) and decreased adrenal weight (females only).  The lower of these two values will be used as the NOAEL for the repeated dose toxicity. This is considered a scientifically defensible since, apart from poor palatability and associated body weight reduction following exposure to 10000 ppm test substance, no clearly adverse effects were apparent. The NOAEL for repeated dose toxicity of Rosin, fumarated is therefore 221-228 mg/kg bw/d for males and 196-292 mg/kg bw/d for females. A NOAEL of 196 mg/kg bw/d will be used for the purposes of DNEL derivation.

In a combined repeat dose reproductive/developmental toxicity study, the test material (Fatty acids, C14-18 and C16-18-unsatd., maleated) was administered daily via oral gavage at doses of 0, 100, 300, and 1000 mg/kg bw/day to Wistar rats (12/sex/dose) in a propylene glycol vehicle. Male rats were treated for a period of 35 days (14 days pre-mating, 14 days mating/post-mating period followed by an additional week) while female rats were treated for approximately 47 days (14 days pre-mating, for up to 7 days mating period, through gestation till PPD 4). A satellite group of nulliparous and non-pregnant female rats (5/sex/dose) was also employed in the study and treated with the test material for a period of 35 days. No signs of mortality or clinical toxicity were observed through the study period. Body weight and food consumption remained unaffected post-treatment with the test material. Effects on prothrombin time in mid and high dose groups were observed but not considered toxicologically significant. Clinical chemistry, urinalysis, and neurobehavioral parameters appeared unaffected through the study period. Slightly lower weights of kidneys were recorded for males at 300 and 1000 mg/kg bw/day (Mid and High dose). The changes were not associated with any findings in clinical pathology or microscopic changes and were regarded as physiological variation. Test material related microscopic findings were found at 1000 mg/kg bw/day (High dose) in stomach, in the form of hyper/paraceratosis of the non-glandular gastric mucosa. This minimal to mild multifocal change occurred in 4 of 5 males and 2 of 5 females. There were no microscopic findings related to treatment at 100 or 300 mg/kg bw/day. These findings are indicative of local irritation and analogous structures do not exist in man. Necroscopy did not reveal any remarkable findings. Based on the observations of this sub-acute oral toxicity study; the NOAEL was determined to be 1000 mg/kg bw/day.

 

Modification of Relevant Dose Descriptors to the Correct Starting Point

Relevant dose descriptors have been developed for the different endpoints and routes of exposure (see Guidance Document, Chapter R.8, Appendix R.8-2). The values are provided below. For potential dermal and inhalation exposures, route-to-route extrapolations from the oral NOAEL value were performed.

 

Dermal, inhalation and oral absorption is assumed to be 100% for the purposes of the DNEL calculation.

Dermal route:

 

Distilled tall oil, Maleated is a UVCB substance derived from natural sources and typical analysis shows it comprises a mixture of unsaturated fatty acids – primarily C18 (~75%) and mixed rosin acids (~25%).

Repeat dose systemic toxicity data are available for fatty acids, C14-18 and C16-18-unsatd., maleated and Rosin, fumarated. As the R groups are derived from distilled oil, the ratio of unsaturated C18 and rosin acids R groups in the molecule are likely to be proportional to the levels found in the parent distilled tall oil. The NOAEL value used as the starting point for systemic DNEL derivation is calculated proportionally, to give an estimated DNEL.

 

The NOAEL value is derived from two combined dermal repeat dose/reproductive toxicity screening study in rats (Grόsz, 2013 and Inveresk Research, 2004).

Based on the above calculation, a NOAEL of 799 mg/kg bw/d was derived ((75% x 1000 mg/kg bw/d) + (25% x 196 mg/kg bw/d)).

The corrected dermal NOAEL is:

dermal NOAEL = oral NOAEL * (ABSoral-rat/ABSderm-human)

dermal NOAEL = 799 * (100/100)

dermal NOAEL = 799 mg/kg/d

 

Thus, the corrected dose descriptor for dermal route is 799 mg/kg/day.

 

Inhalation:

To convert oral NOAEL into inhalatory NOAEC, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 1.15 m3/kg bw/24 h).

The corrected inhalation NOAEC for general population is:

inhalatory NOAEC = oral NOAEL * (1/ sRV rat 24h) * (ABS oral / ABS inh)

inhalatory NOAEC= 799 * (1/1.15) * (100/100)

inhalatory NOAEC = 695 mg/m3

Thus, the corrected dose descriptor for inhalation is 695 mg/m3for the general population.

Application of Assessment Factors to the Corrected Dose Descriptors

Endpoint-specific DNEL values were derived from the corrected dose descriptors after application of assessment factors (AF). The AFs were based on the procedures described by the ECHA (ECHA Guidance Chapter R8, Table R8-6, November 2012).

 Assessment factors (ECHA Guidance Chapter R8, Table R8-6, November 2012)

Long-term DNEL Assessment Factors (Dermal)

Assessment Factor

General Population

Exposure Duration

6 (subacute to chronic)

 

Interspecies

 

2.5 (for systemic effects)

 

4 (Allometric scaling for rats)

 Intraspecies

10 (for General Population)

 

 Issues related to dose-response

1

Quality of whole database

 

1

DNEL General Population long-term dermal-systemic = 799 / 600 = 1.33 mg/kg bw/day

 

 

Assessment factors (ECHA Guidance Chapter R8, Table R8-6, November 2012)

Long-term DNEL Assessment Factors (Inhalation)

Assessment Factor

General Population

Exposure Duration

6 (subacute to chronic)

 

Interspecies

 

 

2.5 (for systemic effects)

 Intraspecies

10 (for General Population)

 

 Issues related to dose-response

1

Quality of whole database

 

1

DNEL General Population long-term inhalation-systemic = 695 / 150 = 4.63 mg/m3

 

Assessment factors (ECHA Guidance Chapter R8, Table R8-6, November 2012)

Long-term DNEL Assessment Factors (Oral)

Assessment Factor

General Population

Exposure Duration

6 (subacute to chronic)

 

Interspecies

 

2.5 (for systemic effects)

 

4 (Allometric scaling for rats)

 Intraspecies

10 (for General Population)

 

 Issues related to dose-response

1

Quality of whole database

 

1

DNEL General Population long-term oral-systemic = 799 / 600 = 1.33 mg/kg bw/day

 

 

Endpoint for risk characterisation

Experimental results indicating a potential to cause sensitisation by skin contact, with associated classification underRegulation (EC) No. 1272/2008, indicate that Distilled tall oil, maleated may present a risk to the general population during normal handling and use. Qualitative risk characterisation (ECHA, 2010) will therefore be conducted on this endpoint.