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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
282 mg/m³
Most sensitive endpoint:
effect on fertility
DNEL related information
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
200 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
DNEL related information
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

Long-term exposure - systemic effects

Dermal

Two long-term studies were available, from which a DNEL value can be derived:

In a 90-day oral toxicity study performed in rats with fatty acids, C18-unsaturated, dimers (CAS No. 61788-89-4), the NOAEL for systemic toxicity was 741 and 855 mg/kg bw/day for males and females, respectively.

In a Two-Generation Reproduction Toxicity Study with tall oil fatty acids (CAS No. 61790-12-3), the oral NOAEL for both systemic and reproductive effects was 10% test material in diet, corresponding to approximate doses of 4000 and 5000 mg/kg bw/day for males and females, respectively.

On the basis of structure analogy (monomeric vs. dimeric fatty acids) and study duration, the reproduction toxicity study was considered more adequate for DNEL derivation of the monomeric members of the chemical category. Based on sensitivity, the NOAEL value of 4000 mg/kg bw/day for male rats was selected as relevant dose descriptor.

For the dermal exposure route, the dose descriptor is converted into a corrected starting point by route-to route extrapolation.

Due to their physicochemical properties, the skin penetration potential of monomeric fatty acids (isooctadecanoic acid, CAS No. 30399-84-9; octadecanoic acid, branched and linear, CAS No. 68201-37-6; C16-C18 and C18-unsaturated, branched and linear, CAS No. 68955-98-6) is expected to be very low. Penetration of the stratum corneum is facilitated by high lipophilicity, but because of the low solubility in water, transfer into the epidermis and hence dermal uptake is likely to be low.

Taking this information into account, along with the weight of evidence that monomeric C16 and C18 fatty acids are negligibly absorbed through human (in vitro) and rat skin (in vitro and in vivo) (Howes, 1975), absorption through human skin in vivo is considered to be not significant. In terms of the assessment of systemic long-term effects upon dermal exposure, a dermal absorption of 20% of the oral absorption was assumed as a worst case scenario. Thus, a modification factor of 0.2 was applied for correction of differences between dermal and oral absorption, yielding a dermal NAEL of 20000 mg/kg bw/day.

The DNEL for long-term effects is derived by applying an assessment factor (AF) for allometric scaling of 4, an interspecies AF of 2.5, an intraspecies (human) AF of 5 for worker, and an additional AF of 2 to account for exposure duration (extrapolation subchronic – chronic). This results in a total AF of 100. Applying this total AF to the dermal NAEL mentioned above, results in a DNEL for dermal long-term effects of 200 mg/kg bw/day. Taking into account the modification factor for differences between oral and dermal absorption, the overall AF is 20 (0.2 x 100).

The following table summarises the DNEL calculation steps and applied modification/assessment factors.

 

Step 1) Relevant dose descriptor

NOAEL(oral, rat) = 4000 mg/kg bw/day

Step 2) Modification of starting point

Correction for differences between dermal and oral absorption




0.2

Step 3) Assessment factors

Interspecies
Intraspecies
Exposure duration
Quality of data base



4 x 2.5
5
2
1

DNEL value

200 mg/kg bw/day
(4000/[0.2 x 4 x 2.5 x 5 x 2 x 1])

 

Inhalation

For the inhalative exposure route, the dose descriptor mentioned above (NOAEL = 4000 mg/kg bw/day) should be converted into a corrected starting point by route-to route extrapolation.

The dose descriptor is converted into an inhalatory NAEC (in mg/m³) first by using an 8 h standard respiratory volume of 0.38 m³/kg bw for the rat. Additionally, differences between oral and inhalative absorption should be taken into account. Based on physicochemical properties and toxicokinetic information, absorption through epithelial barriers is generally expected to be low. In view of the fact that for (dietary) fatty acids of lower molecular weight oral absorption is facilitated by fluids present in the gastrointestinal but not in the respiratory tract, absorption through the lung epithelium is not expected to be higher than through the intestinal epithelium. Therefore, for the oral-to-inhalation extrapolation, a factor of 1 (no difference in absorption) is included and considered to sufficiently account for differences in oral and inhalative absorption. Finally, a further modification factor of 0.67 is applied to account for differences in 8 h inhalative volumes between workers in rest (6.7 m³) and workers under light activity (10 m³). This results in an inhalatory NAEC of 7052.6 mg/m³/day.

The DNEL for long-term exposure is derived by applying an assessment factor (AF) for remaining interspecies differences of 2.5, an intraspecies (human) AF of 5 for worker, and an additional AF of 2 to account for exposure duration (extrapolation subchronic – chronic). This results in a total AF of 25. Applying this total AF to the inhalatory NAEC mentioned above, results in an inhalation DNEL for systemic effects after long-term exposure of 282.105 mg/m³.

The following table summarises the DNEL calculation steps and applied modification/assessment factors.

 

Step 1) Relevant dosedescriptor

NOAEL(oral, rat) = 4000 mg/kg bw/day

Step 2) Modification of starting point

Conversion into inhalatory NAEC (in mg/m³) by using an 8-h standard respiratory volume for the rat

Correction for differences between dermal and oral absorption

Correction for differences in 8-h inhalative volumes between workers in rest and workers under light activity





0.38 m³/kg bw

 

1

 

 

6.7 m³/10 m³

Step 3) Assessment factors

Interspecies
Intraspecies
Exposure duration
Quality of data base



2.5
5
2
1

DNEL value

282.105 mg/m³
(4000 x [1/0.38] x 1 x [6.7/10] x [1/(2.5 x 5 x 2 x 1)])

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
69.565 mg/m³
Most sensitive endpoint:
effect on fertility
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
100 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
DNEL related information
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
20 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
DNEL related information
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

Long-term exposure - systemic effects

Dermal

Two long-term studies were available, from which a DNEL value can be derived:

In a 90-day oral toxicity study performed in rats with fatty acids, C18-unsaturated, dimers (CAS No. 61788-89-4), the NOAEL for systemic toxicity was 741 and 855 mg/kg bw/day for males and females, respectively.

In a Two-Generation Reproduction Toxicity Study with tall oil fatty acids (CAS No. 61790-12-3), the oral NOAEL for both systemic and reproductive effects was 10% test material in diet, corresponding to approximate doses of 4000 and 5000 mg/kg bw/day for males and females, respectively.

On the basis of structure analogy (monomeric vs. dimeric fatty acids) and study duration, the reproduction toxicity study was considered more adequate for DNEL derivation of the monomeric members of the chemical category. Based on sensitivity, the NOAEL value of 4000 mg/kg bw/day for male rats was selected as relevant dose descriptor.

For the dermal exposure route, the dose descriptor is converted into a corrected starting point by route-to route extrapolation.

Due to their physicochemical properties, the skin penetration potential of monomeric fatty acids (isooctadecanoic acid, CAS No. 30399-84-9; octadecanoic acid, branched and linear, CAS No. 68201-37-6; C16-C18 and C18-unsaturated, branched and linear, CAS No. 68955-98-6) is expected to be very low. Penetration of the stratum corneum is facilitated by high lipophilicity, but because of the low solubility in water, transfer into the epidermis and hence dermal uptake is likely to be low.

Taking this information into account, along with the weight of evidence that monomeric C16 and C18 fatty acids are negligibly absorbed through human (in vitro) and rat skin (in vitro and in vivo) (Howes, 1975), the absorption of fatty acids, C18-unsaturated, dimers through human skin in vivo is considered to be not significant. In terms of the assessment of systemic long-term effects upon dermal exposure, a dermal absorption of 20% of the oral absorption was assumed as a worst case scenario. Thus, a modification factor of 0.2 was applied for correction of differences between dermal and oral absorption, yielding a dermal NAEL of 20000 mg/kg bw/day.

The DNEL for long-term effects is derived by applying an assessment factor (AF) for allometric scaling of 4, an interspecies AF of 2.5, an intraspecies (human) AF of 10 for the general population, and an additional AF of 2 to account for exposure duration (extrapolation subchronic – chronic). This results in a total AF of 200. Applying this total AF to the dermal NAEL mentioned above, results in a DNEL for dermal long-term effects of 100 mg/kg bw/day. Taking into account the modification factor for differences between oral and dermal absorption, the overall AF is 40 (0.2 x 200).

The following table summarises the DNEL calculation steps and applied modification/assessment factors.

 

Step 1) Relevant dose descriptor

NOAEL(oral, rat) = 4000 mg/kg bw/day

Step 2) Modification of starting point

Correction for differences between dermal and oral absorption




0.2

Step 3) Assessment factors

Interspecies
Intraspecies
Exposure duration
Quality of data base



4 x 2.5
10
2
1

DNEL value

100 mg/kg bw/day
(4000/[0.2 x 4 x 2.5 x 10 x 2 x 1])

 

Inhalation

For the inhalative exposure route, the dose descriptor mentioned above (NOAEL = 4000 mg/kg bw/day) should be converted into a corrected starting point by route-to route extrapolation.

The dose descriptor is converted into an inhalatory NAEC (in mg/m³) first by using a 24 h standard respiratory volume of 1.15 m³/kg bw for the rat. Additionally, differences between oral and inhalative absorption should be taken into account. Based on physicochemical properties and toxicokinetic information, absorption through epithelial barriers is generally expected to be low. In view of the fact that for (dietary) fatty acids of lower molecular weight oral absorption is facilitated by fluids present in the gastrointestinal but not in the respiratory tract, absorption through the lung epithelium is not expected to be higher than through the intestinal epithelium. Therefore, for the oral-to-inhalation extrapolation, a factor of 1 (no difference in absorption) is included and considered to sufficiently account for differences in oral and inhalative absorption. This results in an inhalatory NAEC of 3478.3 mg/m³/day.

The DNEL for long-term exposure is derived by applying an assessment factor (AF) for remaining interspecies differences of 2.5, an intraspecies (human) AF of 10 for the general population, and an additional AF of 2 to account for exposure duration (extrapolation subchronic – chronic). This results in a total AF of 50. Applying this total AF to the inhalatory NAEC mentioned above, results in an inhalation DNEL for systemic effects after long-term exposure of 69.565 mg/m³.

The following table summarises the DNEL calculation steps and applied modification/assessment factors.

 

Step 1) Relevant dose descriptor

NOAEL(oral, rat) = 4000 mg/kg bw/day

Step 2) Modification of starting point

Conversion into inhalatory NAEC (in mg/m³) by using an 8-h standard respiratory volume for the rat

Correction for differences between dermal and oral absorption





1.15 m³/kg bw

 

1

Step 3) Assessment factors

Interspecies
Intraspecies
Exposure duration
Quality of data base



2.5
10
2
1

DNEL value

69.565 mg/m³
(4000 x [1/1.15] x 1 x [1/(2.5 x 10 x 2 x 1)])

 

Oral

For the oral exposure route, the same bioavailability for experimental animals and humans is assumed as a worst case. Therefore, no further modifications of the dose descriptor are necessary, corresponding to a modification factor of 1 to account for differences in oral absorption between rats and humans.

The DNEL for long-term effects is derived by applying an assessment factor (AF) for allometric scaling of 4, an interspecies AF of 2.5, an intraspecies (human) AF of 10 for the general population, and an additional AF of 2 to account for exposure duration (extrapolation subchronic – chronic). This results in a total AF of 200. Applying this total AF to the oral NOAEL mentioned above, results in a DNEL for oral long-term effects of 20 mg/kg bw/day.

The following table summarises the DNEL calculation steps and applied modification/assessment factors.

Step 1) Relevant dose descriptor

NOAEL(oral, rat) = 4000 mg/kg bw/day

Step 2) Modification of starting point

Correction for differences in oral absorption between rats and humans




1

Step 3) Assessment factors

Interspecies
Intraspecies
Exposure duration
Quality of data base



4 x 2.5
10
2
1

DNEL value

20 mg/kg bw/day
(4000/[1 x 4 x 2.5 x 10 x 2 x 1])