Reaction mass of tridecanal and 2-methyldodecanal and pentadecanal and 2-methyltetradecanal

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

24 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

Value:

1 763 mg/m³

Explanation for the modification of the dose descriptor starting point:

For aldeyhdes rapid absorption after oral and inhalation exposure is assumed.

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

Justification:

The DNEL is based on a study with subacute exposure duration (28 days, extrapolation subacute to chronic exposure).

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route

AF for other interspecies differences:

2.5

Justification:

Default for remaining toxikokinetic differences

AF for intraspecies differences:

5

Justification:

Default for workers

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:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.33 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):

300

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No data on the dermal absorption are available, in a conservative manner it is assumed that dermal absorption is the same as oral absorption (100 %). Therefore no correction for absorption has to be made for route-to-route extrapolation

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

Justification:

The DNEL is based on a study with subacute exposure duration (28 days, extrapolation subacute to chronic exposure).

AF for interspecies differences (allometric scaling):

4

Justification:

Default for rats

AF for other interspecies differences:

2.5

Justification:

Default for remaining toxicokinetic differences

AF for intraspecies differences:

5

Justification:

Default for workers

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:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Toxicology profile

n/i-C13-C15 aldehyde is a mixture of saturated unbranched and branched long chain aldehydes. The water solubility and vapour pressure are both low. The substance may be rapidly absorbed following oral intake or inhalation exposure. The inhalation exposure is not considered to represent a relevant exposure pathway, based on the low vapour pressure. Following absorption the aldehydes are expected to be predominantly oxidised to the respective carboxylic acids, which may be degraded and utilized via fatty acid oxidation and intermediary metabolism. Long-chain aldehyde dehydrogenases catalyze the initial oxidation step. These enzymes are present in the cytosol at high levels, and also in mitochondria and in microsomes. According to Martini and Murray (1996), the specificity and activity of the enzyme increases with the molar masses, i.e. chain length, of the substrates (values for undecanal: Km ~ 10 µM; Vmax ~ 25 nmol of NADH produced per minute and µg protein; Martini and Murray, 1996). However, chain oxidations by cytochromes P450 may also occur and generate other metabolites than described above. Acids and hydroxylated metabolites may be conjugated and excreted in the urine.

 

No acute toxicity studies with n-/iso C13/C15 aldehydes are available but data from structurally closely related n-undecanal and 3,5,5-trimethylhexanal are used for read-across. Both the oral and dermal LD50 values were >5000 mg/kg bw in the rat. Inhalation exposure is not regarded as being relevant because the very low vapour pressure will only lead to minor air concentrations. Thus the acute toxicity of n-/iso C13/C15 aldehydes is expected to be low.

 

N-/i -undecanal (used in a read across approach: structural analogue) was irritating to the rabbit’s skin at a level that requires classification (Skin Irrit category 2). For the same test material eye irritation was mild and did not gain a level that requires classification. These results suggest that the n/i--C13 -C15 -alheydes are irritating to skin, but not irritating to eyes as well.

n/i-C13 -C15 -aldehyde was a weak sensitizer in the LLNA and requires classification (Skin Sens category 1B), but showed no skin sensitising properties in 104 humans who underwent a HRIPT with a test substance concentration of 10%.

  

N/i-C13 -C15 -aldehyde (100, 300, 1000 mg/kg bw and day; vehicle peanut oil) was tested in a combined OECD TG 422 study for repeated dose/reproduction toxicity in male and female rats (10 rats/sex and dose). There was no systemic toxicity up to and including the top dose, and there were no adverse effects on fertility and development noted. Therefore, the NOAEL was 1000 mg/kg bw and day for systemic toxicity, toxicity to reproduction and development under the conditions of this study. The same NOAEL applies to neurotoxicity that was included in the OECD TG 422 study.

  

Regarding genetic toxicity, n-/i-C13 -C15 -aldehyde was not mutagenic in bacterial (Salmonella typhimurium) or mammalian cells (HPRT assay, read-across from n-undecanal) in vitro, and it was not clastogenic in-vitro (human lymphocytes). All assays were conducted with and without metabolic activation.

 

Overall, n/i-C13 -C15 -aldehyde is of low acute and subacute toxicity, and no target tissue was identified. It is a skin irritant and sensitizer. The DNELs may be derived from the NOAEL (rat, oral, subacute) of 1000 mg/kg bw and day.

 

 

DNEL derivation

The following DNELs were not derived:

DNELs for local effects upon inhalation since there are no information and no dose-response data available for local effects in the respiratory tract.

DNELs for short term exposure since the substance is of low acute toxicity and no dose-response information is available.

DNEL for local effects upon dermal exposure since dermal contact should be avoided because of the irritating/sensitising properties. A qualitative assessment is described in the CSR.

 

Workers:

Short term exposure: no DNELs derived; see justification above

Long term exposure:

Inhalation: the NOAEL of 1000 mg/kg bw and day (rat, oral, subacute) may be used to calculate, according to the guidance document R.8, a corrected inhalation NOAEC of 1763 mg/m³ for workers. Assessment factors for intraspecies differences (5; workers), interspecies ( 2.5 for remaining toxicokinetic differences) and for the duration of treatment (subacute > chronic; 6) may be used and result in a DNEL of 24 mg/m³.

Dermal: the NOAEL of 1000 mg/kg bw and day (rat, oral, subacute) may be used to calculate, according to the guidance document R8. Assessment factors for intraspecies differences (5; workers), interspecies ( 4 for allometric scaling from the rat, 2.5 for remaining toxicokinetic differences) and for the duration of treatment (subacute > chronic; 6) may be used and result in a DNEL of 3.3 mg/kg bw/day.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.8 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):

150

Modified dose descriptor starting point:

NOAEC

Value:

870 mg/m³

Explanation for the modification of the dose descriptor starting point:

For aldeyhdes rapid absorption after oral and inhalation exposure is assumed.

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

Justification:

The DNEL is based on a study with subacute exposure duration (28 days, extrapolation subacute to chronic exposure).

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route

AF for other interspecies differences:

2.5

Justification:

Default for remaining toxikokinetic differences

AF for intraspecies differences:

10

Justification:

Default for general population

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:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.67 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

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No data on the dermal absorption are available, in a conservative manner it is assumed that dermal absorption is the same as oral absorption (100 %). Therefore no correction for absorption has to be made for route-to-route extrapolation

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

Justification:

The DNEL is based on a study with subacute exposure duration (28 days, extrapolation subacute to chronic exposure).

AF for interspecies differences (allometric scaling):

4

Justification:

Default for rats

AF for other interspecies differences:

2.5

Justification:

Default for remaining toxicokinetic differences

AF for intraspecies differences:

10

Justification:

Default for general population

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:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.67 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

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

no route to route extrapolation neccessary (oral study)

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

Justification:

The DNEL is based on a study with subacute exposure duration (28 days, extrapolation subacute to chronic exposure).

AF for interspecies differences (allometric scaling):

4

Justification:

Default for rats

AF for other interspecies differences:

2.5

Justification:

Default for remaining toxicokinetic differences

AF for intraspecies differences:

10

Justification:

Default for general population

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:

no hazard identified

Additional information - General Population

DNEL derivation

The following DNELs were not derived:

 

DNELs for short term exposure since the substance is of low acute toxicity, and no dose-response information is available.

DNELs for local effects upon dermal exposure since skin contact should be avoided because of the irritating/sensitising properties. A qualitative assessment is described in the CSR.

DNELs for local effects upon inhalation since there are no information and no dose-response data available for local effects in the respiratory tract.

 

Long term exposure:

Dermal:

The NOAEL of 1000 mg/kg bw and day (rat, oral, subacute) may be used to calculate a DNEL of 1.67 mg/kg bw and day by route-to-route extrapolation, using an overall assessment factor of 600 (route-to-route extrapolation = 1, allometric factor = 4; remaining interspecies difference = 2.5, intraspecies differences = 10; duration of experiment (subacute --> chronic = 6).

Inhalation:

The NOAEL of 1000 mg/kg bw and day (rat, oral, subacute) may be used to calculate, according to the guidance document R.8, a corrected inhalation NOAEC of 870 mg/m³ for the general population. Assessment factors for intraspecies differences (10; general public) remaining toxicokinetic differences (2.5) and for the duration of treatment (subacute --> chronic; 6) may be used and result in a DNEL of 5.8 mg/m³.

 

Oral:

The NOAEL of 1000 mg/kg bw and day (rat, oral, subacute) may be used to calculate a DNEL of 1.67 mg/kg bw and day, using an overall assessment factor of 600 (allometric factor = 4; remaining toxicokinetic differences = 2.5, intraspecies differences = 10; duration of experiment (subacute > chronic =6).

 

Default intraspecies factors should be used because n/i-C13 -C15 -aldehyde is irritating to the skin.