Undec-10-enoic acid

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.92 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):

25

Dose descriptor starting point:

NOAEL

Value:

60 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

148 mg/m³

Explanation for the modification of the dose descriptor starting point:

 

1.2             Long-term, inhalation, systemic toxicity

Occupational exposure to undecylenic acid may occur mainly by inhalation of particles or dust. Although it is a solid or a liquid at 21°C with a low vapour pressure, we consider the inhalation route as one of the relevant route for DNEL derivation.

In a 90-day repeated toxicity study performed in rats with undecylenic acid sodium salt (Fabreguettes, 1999), the oral NOAEL for systemic toxicity was 60 mg/kg bw/day.: Cardiomyopathy was recorded at 180 mg/kg bw/d, myocardial degeneration / monocellular aggregation which was reversible during the treatment free period.

 

Step 1) Relevant dose-descriptor:NOAEL_rat= 60 mg/kg bw/d

Step 2) Modification of starting point

-Conversion into inhalation NOAEC (in mg/m³) by using an 8-hour respiratory volume for the rat: 0.38 m³/kg bw

- Correction for activity driven differences of respiratory volumes in workers compared to workers in rest: 6.7 m³/10 m3

-Correcting for inhalation to oral absorption: no factor is add.

-100% of absorption is expeted for both oral and inhalation reoute based on absence if data.

 

The calculation of DNEL is based on the no observed adverse effect level which has to be modified as described in R8 (ECHA, May 2008).  For derivation of the inhalative long-term DNEL, the oral NOAEL had to be extrapolated (oral to inhalative) and corrected for interspecies difference between rat and human by the risk assessors: 0.38 mg/m3 (standard respiration volume rat, 8 hours), 6.7 m3 (standard respiration volume human, 8 hours) and 10 m3 (standard respiration volume worker, 8 hours) and 7d/5d (7 days/week of oral exposure during the study, 5 days/week exposure of the workers). An inhalative NOAEC of 60/0.38*6.7/10*7/5 = 148 mg/m3 was obtained.

 

 

Step 3) Assessment factors

-Interspecies = 2.5 (data on rat)

-Intraspecies = 5 (workers)

-Exposure duration = 2 (subchronic study)

-Dose response = 1 (dose descriptor = NOAEL)

-Quality of database = 1

Global assessment factor = 25

 

Step 4) DNEL calculation

DNEL Value (long term inhalation, systemic)= 148 / 25 = 5,92 mg/m³

 

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

AF for interspecies differences (allometric scaling):

1

AF for other interspecies differences:

2.5

AF for intraspecies differences:

5

AF for the quality of the whole database:

1

AF for remaining uncertainties:

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:

13.72 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):

100

Dose descriptor starting point:

NOAEL

Value:

60 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 372 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

1.3 Long-term, dermal, systemic toxicity

 

Occupational exposure to undecylenic acid may also occur by dermal exposure. Although no dermal repeated dose toxicity studies is available as well as no information on dermal absorption, we derived a dermal DNEL based on the same Oral NOAEL selected for the derivation of the inhalation DNEL.

 

Step 1) Relevant dose-descriptor:NOAEL_rat= 60 mg/kg bw/d

Step 2) Modification of starting point

Correcting for dermal to oral absorption:

* Correction for absorption difference between rat and human, and between dermal and oral absorption: The results of a recent in vitro dermal absorption study revealed an absorption of 6,12 % though human skin (TNO, 2017). As no available data is reported for oral absorption in rats, the oral absorption is considered to be  100 %: According to REACH guidance, the following caclulation is applied for NOAEL correction:

  

• Corrected dermal NOAEL, route    = oral NOAEL x (ABSoral-rat/ABSderm-rat) x (ABSderm-rat/ ABSderm-human)
• = oral NOAEL x (ABSoral-rat/ABSderm-human)X 7d/5d

  (7 days/week of oral exposure during the study, 5 days/week exposure of the workers)

•     Corrected dermal LOAEL = 60 x 100/6,12x7/5 =1372 mg/kg/day

Step 3) Assessment factors

-Interspecies = 2.5 x 4 (data on rat)

-Intraspecies = 5 (workers)

-Exposure duration = 2 (subchronic study)

-Dose response = 1 (dose descriptor = NOAEL)

-Quality of database = 1

Global assessment factor = 100

 

Step 4) DNEL calculation

DNEL Value (long term dermal, systemic)= 1372 / 100 = 13,72 mg/kg/day

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

AF for interspecies differences (allometric scaling):

4

AF for other interspecies differences:

2.5

AF for intraspecies differences:

5

AF for the quality of the whole database:

1

AF for remaining uncertainties:

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:

low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - workers

1 -Workers

Undecylenic acid can be present as a solid or a liquid, considering the melting point of 21°C. The dustiness is low.

During unloading, unpacking and charging, dermal and/or inhalation contact is possible with:

-       solid substance

-       airborne dust.

Dermal and/or inhalation contact is possible during breaching of the system with

-       liquid substance

-       evaporated substance.

That is the reason why we consider the inhalation and dermal route as relevant exposure, and corresponding long term DNEL will therefore be derived

 

1.1             Short term, inhalation or dermal, local toxicity

Regarding acute toxicity, the DNEL_acuteonly needs to be derived in case the substance is labelled for an acute toxicity hazard and when peak exposures substantially higher than the DNEL_long-termare possible. As both criteria do not apply for undecylenic acid, the derivation of a DNEL_acuteis not necessary.

Regarding local toxicity, although undecylenic acid is classified irritant to the skin and eyes, no substantially high peak exposure are expected in the plant. Furthermore, the workers are therefore obliged to wear safety goggles, protective work clothes, gloves when handling the substance and respiratory protection if handling high concentrations.

 

 

 

1.3 Long-term, dermal, systemic toxicity

 

Occupational exposure to undecylenic acid may also occur by dermal exposure. Although no dermal repeated dose toxicity studies is available as well as no information on dermal absorption, we derived a dermal DNEL based on the same Oral NOAEL selected for the derivation of the inhalation DNEL.

 

Step 1) Relevant dose-descriptor:NOAEL_rat= 60 mg/kg bw/d

Step 2) Modification of starting point

Correcting for dermal to oral absorption:

* Correction for absorption difference between rat and human, and between dermal and oral absorption: The results of a recent in vitro dermal absorption study revealed an absorption of 6,12 % though human skin (TNO, 2017). As no available data is reported for oral absorption in rats, the oral absorption is considered to be  100 %: According to REACH guidance, the following caclulation is applied for NOAEL correction:

  

• Corrected dermal NOAEL, route    = oral NOAEL x (ABSoral-rat/ABSderm-rat) x (ABSderm-rat/ ABSderm-human)
• = oral NOAEL x (ABSoral-rat/ABSderm-human)
•     Corrected dermal LOAEL = 60 x 100/6,12 =980,39 mg/kg/day

Step 3) Assessment factors

-Interspecies = 2.5 x 4 (data on rat)

-Intraspecies = 5 (workers)

-Exposure duration = 2 (subchronic study)

-Dose response = 1 (dose descriptor = NOAEL)

-Quality of database = 1

Global assessment factor = 100

 

Step 4) DNEL calculation

DNEL Value (long term dermal, systemic)= 980,39 / 100 = 9,8 mg/kg/day

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.04 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):

50

Dose descriptor starting point:

NOAEL

Value:

60 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

52.17 mg/m³

Explanation for the modification of the dose descriptor starting point:

see below justification

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

AF for interspecies differences (allometric scaling):

2.5

AF for other interspecies differences:

4

AF for intraspecies differences:

5

AF for the quality of the whole database:

1

AF for remaining uncertainties:

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:

4.9 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):

200

Dose descriptor starting point:

NOAEL

Value:

60 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

980.39 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

2.2 DNEL long term Dermal, systemic effect

In a 90-day repeated toxicity study performed in rats with undecylenic acid (Fabreguettes, 1999), the oral NOAEL for systemic toxicity was 60 mg/kg bw/day.: Cardiomyopathy was recorded at 180 mg/kg bw/d, myocardial degeneration / monocellular aggregation which was reversible during the treatment free period.

Relevant dose-descriptor:NOAEL_rat= 60 mg/kg bw/d (Fabreguettes, 1999)

* Correction for absorption difference between rat and human, and between dermal and oral absorption: The results of a recent in vitro dermal absorption study revealed an absorption of 6,12 % though human skin (Maas, 2018). As no available data is reported for oral absorption in rats, the oral absorption is considered to be  100 %: According to REACH guidance, the following caclulation is applied for NOAEL correction:

• Corrected dermal NOAEL, route    = oral NOAEL x (ABSoral-rat/ABSderm-rat) x (ABSderm-rat/ ABSderm-human)
• = oral NOAEL x (ABSoral-rat/ABSderm-human)
•     Corrected dermal LOAEL = 60 x 100/6,12 =980,39 mg/kg/day
• Assessment factors
• -Interspecies = 2.5 x 4 (data on rat)
• -Intraspecies = 10 (Gen pop)
• -Exposure duration = 2 (subchronic study)
• -Dose response = 1 (dose descriptor = NOAEL)
• -Quality of database = 1
• Global assessment factor = 200  
• DNEL calculation: DNEL Value (long term dermal, systemic)= 980,39 / 200 = 4,9 mg/kg/day

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

AF for interspecies differences (allometric scaling):

4

AF for other interspecies differences:

2.5

AF for intraspecies differences:

10

AF for the quality of the whole database:

1

AF for remaining uncertainties:

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:

low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.3 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):

200

Modified dose descriptor starting point:

NOAEL

Value:

60 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

2.2 DNEL long term oral, systemic effect

In a 90-day repeated toxicity study performed in rats with undecylenic acid (Fabreguettes, 1999), the oral NOAEL for systemic toxicity was 60 mg/kg bw/day.: Cardiomyopathy was recorded at 180 mg/kg bw/d, myocardial degeneration / monocellular aggregation which was reversible during the treatment free period.

 

Step 1) Relevant dose-descriptor:NOAEL_rat= 60 mg/kg bw/d

Step 2) Modification of starting point

No difference in oral absorption is expected between rats and humans. 100% of abosrption is taken for oral absorption

 

Step 3) Assessment factors

-Interspecies = 2.5 x 4 (data on rat)

-Intraspecies = 10 (general population)

-Exposure duration = 2 (subchronic study)

-Dose response = 1 (dose descriptor = NOAEL)

-Quality of database = 1

Global assessment factor = 200

 

Step 4) DNEL calculation

DNEL Value (long term dermal, systemic)= 60 / 200 = 0.3 mg/kg/day

 

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

AF for interspecies differences (allometric scaling):

4

AF for other interspecies differences:

2.5

AF for intraspecies differences:

10

AF for the quality of the whole database:

1

AF for remaining uncertainties:

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:

low hazard (no threshold derived)

Additional information - General Population

General population

Exposure with undecylenic acid is expected to be low as it is used as an intermediate. Undecylenic acidis an organic unsaturated fatty acid derived from natural castor oil.It is used as an intermediate in the manufacturing of food aroma and in the manufacture of musk fragrances for perfumes.Undecylenic acid is a natural fungicide and is used as an intermediate in the manufacturing of anti fungus products for pharmaceutical and cosmetic use. It is further used as an intermediate in the synthesis of fine chemicals and the manufacture of polymers of salts for anti-corrosive additives and of products that enter the formulation of anti-dandruff shampoo.

If there is exposure, it will be minor and mainly occur via dermal and oral route.