Bis(C12-C13)alkyl-2-hydroxybutandioate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

24 mg/m³

DNEL related information

Overall assessment factor (AF):

12.5

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:

3.4 mg/kg bw/day

DNEL related information

Overall assessment factor (AF):

50

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

Additional information - workers

The oral and dermal LD50 of Bis(C12 -C13)alkyl-2 -hydroxybutanedioate was found to be > 2000 mg/kg bodyweight. Therefore, the substance is practically nontoxic after short-term exposure. Therefore, a DNEL after short-time exposure must not need derived. No local effect was observed with the substance. According to the guidance on information requirements and chemical safety assessment chapter R8 for this endpoint no DNEL could be derived.

Long term exposure systemic effects

In experimental conditions, on the basis of a total evaluation of the results obtained, the test material Bis(C12-C13)alkyl-2-hydroxybutandioate did not cause any local or general toxicity after subacute dermal exposition (28 d) in rabbits. The NOAEL was determined to be 10 mL/kg bw/day (1000 mg/kg bw/d). Data for subchronic toxicity of Bis(C12-C13)alkyl-2-hydroxybutandioate were not identified.

To assess the risk of long-term exposure - systemic effects for bis(C12 -C13) alkyl-2 -hydroxybutandioate, data for di-2 -ethylhexyl adipate and

DTDA and the metabolites malic acid and C12, C13 -Alcohols as supporting substance will be used based on the similarity of their structures

(Justification in more detail is presented in endpoint summary to section 7.1.1 - basic toxicokinetics).

 

For the metabolite Malic acid the NOAEL of two oral chronic studies was 5000 ppm (rat) and 50000 ppm (dog). Therefore. the substance has a low toxicity.

For the metabolite C12, 13 -Alcohols, we have a subacute study with an oral NOAEL of 300 mg/kg bw/day (Sasol, 1993). This study is critisized because the effects seen in this study are not ascribed to a dose response effect but rather are associated with the method of dosing. A read-across from a reliable 13-week dietary study in rats using Hexanol reported a NOAEL of 1127 mg/kg bw/day and no adverse effects were noted at any of the dose levels administered during the study (Scientific Associates Inc. 1966).

 

For di-2-ethylhexyl adipate, several valid studies concerning repeated dose toxicity are available. Besides a 28 day oral study (Miyata, 2006), the substance was investigated by NTP in subchronic and chronic studies in two species (rat and mouse) (NTP, 1982). In addition, there is an oral one-generation reproduction toxicity study with an exposure period of 10 weeks for parental animals (Cefic, 1989).

The most critical NOAEL was observed in the one-generation study (170 mg/kg bw/day - effects on the offspring: reduced total litter weight and reduced mean litter size). At the same time, this is the lowest NOAEL determined in repeated dose toxicity studies. This value will be taken for derivation of a DNEL for Bis(C12-C13)alkyl-2-hydroxybutandioate.

 

DNELs for Bis(C12-C13)alkyl-2-hydroxybutandioate

The NOAEL of 170 mg/kg bw/day determined for di-2-ethylhexyl adipate is used for the DNEL-derivation.

Worker long term exposure - systemic effects (oral, dermal and inhalation) DNELs were calculated form the NOAEL, assuming a 100 % dermal

(worst case) and inhalation rate.

DNEL dermal - systemic effects

According to ECHA TGD Guidance on information requirements and chemical safety assessment -Chapter R.8: Characterisation of dose[concentration]-response for human health, the NOAEL oral can be used for the deduction of a DNEL dermal without further adjustment. As default, absorption for oral and dermal route is considered equal as long as more definite experimental information is not available.

Assessment factors used are a) allometric scaling factor of 4, b) factor for remaining interspecies differences of 2.5, c) intraspecies factor (worker) of 5. The factor for sub-chronic to chronic exposure extrapolation is set to 1 as for developmental effects chronic exposure is not relevant. With a starting point NOAEL dermal of 170 mg/kg bw/day and an overall assessment factor of 50, a DNEL of 3.4 mg/kg bw/day for

Bis(C12-C13)alkyl-2-hydroxybutandioate is calculated.

 

DNEL inhalation -systemic effects

The corrected worker inhalation starting point was the corrected NOAEC of 300 mg/m3 and was derived form the oral NOAEL of 170 mg/kg bw/day multiplying by the inverse of the standard respiratory volume of the rat during an 8 hour period (2.63) and multiplied by the ratio of standard respiratory volume for humans to the 8 hour worker standard respiratory volume (0.67). The corrected starting point was adjusted by a factor of 12.5

(factor for remaining interspecies differences 2.5, intraspecies factor (worker) 5, factor for sub-chronic to chronic exposure extrapolation 1, see above) resulting in an calculated DNEL of 24 mg/m3.

Long-term exposure - local effects

 

The irritation potential of Bis(C12-C13)alkyl-2-hydroxybutandioate is low as demonstrated in acute skin and eye irritant tests. Dose descriptors for

long term exposure local effects are not available. DNELs for long-term-exposure local effects are not derived.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

10.44 mg/m³

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

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.7 mg/kg bw/day

DNEL related information

Overall assessment factor (AF):

100

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:

1.7 mg/kg bw/day

DNEL related information

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

Additional information - General Population

The oral and dermal LD50 of Bis(C12 -C13)alkyl-2 -hydroxybutanedioate was found to be > 2000 mg/kg bodyweight. Therefore the substance is practically nontoxic after short-term exposure. Therefore a DNEL after short-time exposure must not need derived. No local effect was observed with the substance. According to the guidance on information requirments and chemical safety assessment chapter R8 for this endpoint no DNEL could be derived.

Long term exposure systemic effects

In experimental conditions, on the basis of a total evaluation of the results obtained, the test material Bis(C12-C13)alkyl-2-hydroxybutandioate did not cause any local or general toxicity after subacute dermal expoaure (28 d) in rabbits. The NOAEL was determined to be 10 mL/kg bw/day (1000 mg/kg bw/d).

Data for subchronic toxicity of Bis(C12-C13)alkyl-2-hydroxybutandioate were not identified.

To assess the risk of long-term exposure - systemic effects for Bis(C12-C13)alkyl-2-hydroxybutandioate, data for di-2 -ethylhexyl adipate and DTDA and the metabolites malic acid and C12, C13 -Alcohols as supporting substance will be used based on the structural relationship

(Justification in more detail is presented in endpoint summary to section 7.1.1 - basic toxicokinetics).

 

For the metabolite Malic acid the NOAEL of two oral chronic studies was 5000 ppm (rat) and 50000 ppm (dog). Therefore the substance has a low toxicity.

For the metabolite C12, 13 -Alcohols we have a subacute study with an oral NOAEL of 300 mg/kg bw/day (Sasol, 1993). This study is critised because the effects seen in this study are not ascribed to a dose response effect but rather are associated with the method of dosing. A read-across from a reliable 13-week dietary study in rats using Hexanol reported a NOAEL of 1127 mg/kg bw/day and no adverse effects were noted at any of the dose levels administered during the study (Scientific Associates Inc. 1966).

 

For di-2-ethylhexyl adipate, several valid studies concerning repeated dose toxicity are available. Besides a 28 day oral study (Miyata, 2006), the substance was investigated by NTP in subchronic and chronic studies in two species (rat and mouse) (NTP, 1982). In addition, there is an oral one-generation reproduction toxicity study with an exposure period of 10 weeks for parental animals (Cefic, 1989).

The most critical NOAEL was observed in the one-generation study (170 mg/kg bw/day - effects on the offspring: reduced total litter weight and reduced mean litter size). In this study the LOAEL of maternal toxicity was 1080 mg/kg bw/d. At the same time, this is the lowest NOAEL determined in repeated dose toxicity studies. This value will be taken for derivation of a DNEL for Bis(C12-C13)alkyl-2-hydroxybutandioate.

It is important additionally to note that for the structure "2 -Ethylhexyl" Fetotoxicity and Reprotoxicity are regarded as most sensitive endpoints and that these effects are considered as unlikely for the Bis(C12 -C13)alkyl-2 -hydroxybutandioate. Therefore to mention this study and to take these results is "worst case".

 

DNELs for Bis(C12-C13)alkyl-2-hydroxybutandioate

The NOAEL of 170 mg/kg bw/day determined for di-2-ethylhexyl adipate is used for the DNEL-derivation.

General population long-term exposure - systemic effects (oral, dermal and inhalation) DNELs were calculated form the NOAEL, assuming a 100 % dermal (worst case) and inhalation absorption rate.

DNEL dermal and oral- systemic effects

According to ECHA TGD Guidance on information requirements and chemical safety assessment -Chapter R.8: Characterisation of dose[concentration]-response for human health, the NOAEL oral can be used for the deduction of a DNEL dermal without further adjustment. As default, absorption for oral and dermal route is considered equal as long as more definite experimental information is not available.

Assessment factors used are a) allometric scaling factor of 4, b) factor for remaining interspecies differences of 2.5, c) intraspecies factor (general population) of 10. The factor for sub-chronic to chronic exposure extrapolation is set to 1 as for developmental effects chronic exposure is not relevant. With a starting point NOAEL dermal of 170 mg/kg bw/day and an overall assessment factor of 100, a DNEL of 1.7 mg/kg bw/day for

Bis(C12-C13)alkyl-2-hydroxybutandioate is calculated.

 

DNEL inhalation -systemic effects

The corrected worker inhalation starting point was the corrected NOAEC of 300 mg/m3 and was derived form the oral NOAEL of 170 mg/kg bw/day multiplying by the inverse of the standard respiratory volume of the rat during an 24 hour period (0.87). The corrected starting point was adjusted by a factor of 25 (factor for remaining interspecies differences 2.5, intraspecies factor (general population) 10, factor for sub-chronic to chronic exposure extrapolation 1, see above) resulting in an calculated DNEL of 10.44 mg/m3.

Long-term exposure - local effects

 

The irritation potential of Bis(C12-C13)alkyl-2-hydroxybutandioate is low as demonstrated in acute skin and eye irritant tests. Dosedescriptors for

long term exposure local effects are not available. DNELs for long-term-exposure local effects are not derived.