Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.4 mg/m³

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

5

Dose descriptor starting point:

NOAEL

Value:

25 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

22 mg/m³

Explanation for the modification of the dose descriptor starting point:

According to ECHA Guidance on information requirements and chemical safety assessment R.8, the converted NOAEC is (25 x 6.7)/(0.38 x 10) = 44.1 mg/m3. Although rapid and complete oral absorption can be assumed, no quantitative data are available on oral absorption. Hence, according to the Guidance a conservative correction factor of 2 is applied for oral to inhalation extrapolation, resulting in a NAEC of 22 mg/m3.

AF for dose response relationship:

1

Justification:

NOAEL used as starting point

AF for differences in duration of exposure:

1

Justification:

no AF for differences in duration of exposure necessary as exposure was during sensitive phase of life

AF for interspecies differences (allometric scaling):

1

Justification:

no allometric scaling required for inhalative exposure route

AF for other interspecies differences:

1

Justification:

An assessment factor of 2.5 for remaining differences is not necessary because the metabolic fate of 3, 5, 5-trimethylhexanoic acid is very similar in all mammals. The oxidative degradation of isononanoic acid via ß-oxidation is largely hindered by the methyl groups at uneven positions, i.e. in the uneven 3-position, which also prevents utilisation in the citrate cycle. Moreover, tertiary carbons (5, 5 dimethyl substituents) do not allow ß-oxidation to occur. As a result, significant chain hydroxylation and conjugation reactions of the unchanged isononanoic acid and its hydroxylated metabolites are expected to occur, followed by excretion into bile and urine (Semino, 1998, see Toxicokinetics). These reactions are considered to account for the majority of the biotransformation in mammals, and no difference between the rat and humans is known which would justify an additional assessment factor of 2.5 for remaining differences.

AF for intraspecies differences:

5

Justification:

default assessment factor

AF for the quality of the whole database:

1

Justification:

several reliable studies report consistent data on less severe toxic effects

AF for remaining uncertainties:

1

Justification:

default assessment factor

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

10 mg/m³

Most sensitive endpoint:

skin irritation/corrosion

DNEL derivation method:

other: generic DNEL for skin irritating substances as recommended by Messinger (2014)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

10 mg/m³

Most sensitive endpoint:

skin irritation/corrosion

DNEL derivation method:

other: generic DNEL for skin irritating substances as recommended by Messinger (2014)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.25 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

20

Dose descriptor starting point:

NOAEL

Value:

25 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

25 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The NOAEL can be directly converted into the NOAEL for the dermal route, as there is no indication of differences in absorption between species and routes.

AF for dose response relationship:

1

Justification:

NOAEL used as starting point

AF for differences in duration of exposure:

1

Justification:

no AF for differences in duration of exposure necessary as exposure was during sensitive phase of life

AF for interspecies differences (allometric scaling):

4

Justification:

default factor for allometric scaling

AF for other interspecies differences:

1

Justification:

An assessment factor of 2.5 for remaining differences is not necessary because the metabolic fate of 3, 5, 5-trimethylhexanoic acid is very similar in all mammals.The oxidative degradation of isononanoic acid via ß-oxidation is largely hindered by the methyl groups at uneven positions, i.e. in the uneven 3-position, which also prevents utilisation in the citrate cycle. Moreover, tertiary carbons (5, 5 dimethyl substituents) do not allow ß-oxidation to occur. As a result, significant chain hydroxylation and conjugation reactions of the unchanged isononanoic acid and its hydroxylated metabolites are expected to occur, followed by excretion into bile and urine (Semino, 1998, see Toxicokinetics). These reactions are considered to account for the majority of the biotransformation in mammals, and no difference between the rat and humans is known which would justify an additional assessment factor of 2.5 for remaining differences.

AF for intraspecies differences:

5

Justification:

default assessment factor

AF for the quality of the whole database:

1

Justification:

several reliable studies report consistent data on less severe toxic effects

AF for remaining uncertainties:

1

Justification:

default assessment factor

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Hazard assessment conclusion:

medium hazard (no threshold derived)

Short-term and long-term DNELs - local effects (dermal route)

The substance is classified as skin irritant Category 2 (H315) and Eye irritant Category 1 (H318), but no dose-response data are available, which would allow derivation of a DNEL for local effects. A qualitative risk characterisation (according to the Guidance on Information Requirements and Chemical Safety Assessment, Part E) is performed in the CSR for these effects.

Short-term DNELs - systemic effects (dermal and inhalation route) The substance is not classified for acute inhalation or dermal toxicity and only classified as Cat. 4 for acute oral toxicity. As there are no dose-response data available, no DNELs are derived. According to the suggestions of the Guidance on Information Requirements and Chemical Safety Assessment, Part E, no qualitative hazard has to be regarded.

Long-term dermal exposure - systemic effects

No data on toxicity after long-term dermal exposure are available. A DNEL for dermal exposure can be derived from oral exposure toxicity data.

A reliable 28-days study in rats revealed a NOAEL of 50 mg/kg bw/d with a LOAEL of 200 mg/kg bw/d (BASF, 2002). A reliable one-generation range-finding rat study yielded a NOAEL of 0.12% in food for systemic effects in parents and offspring, corresponding to parental body doses of 79-228 mg/kg bw/d. The LOAEL was 0.25% (165-500 mg/kg bw/d) (Exxon, 1998).

A reliable developmental toxicity study in rats (BASF, 2013) furthermore showed a NOAEL of 60 mg/kg bw/d (maternal and developmental toxicity) and a NOAEL of 250 mg/kg bw/d (maternal and developmental toxicity) was observed in a reliable developmental toxicity study in rabbits (Envigo, 2019).

In a 90d study (BASF, 2013) a NOAEL of 5 mg/kg bw/day has been observed (based on peroxisomal proliferation and alpha-2u nephropathy). However, kidney effects observed in male animals are specific for rodents and do therefore not have to be considered relevant for humans. Also effects observed in the liver of test animals in the mid and high dose groups (30 and 120 mg/kg bw/day) don't have to be considered relevant for humans. Increased liver weights in male and female animals (mid and high dose group) as well as fat vacuolation (minimal to slight) have been observed while at the same time an increase of PAL CoA was noted. It can therefore be assumed that the observed effects are not relevant for humans as those are significantly less senstitive regarding PPARalpha activation. This interpretation is furthermore supported by the results described for the 28d study mentioned above (BASF, 2002) where animals from a satellite group (200 mg/kg bw) showed a complete reversibility of liver effects. Thus, the observed effects can be assumed to be transient and not adverse. With regard to DNEL derivation from this 90d study, a NOAEL of 120 mg/kg bw/day would result.

Based on the results of a GLP conform EOGRTS according to OECD 443 (Covance, 2019) a No Observed Adverse Effect Level (NOAEL) for systemic toxicity in male rats was not established at first. The NOAEL would lie below 5 mg/kg/day due to hyaline droplets with associated degenerative changes (basophilic tubules and granular casts) - alpha- 2u-globulin nephropathy considered adverse at all dose levels. It is however acknowledged that this finding is male rat specific and generally considered to be of no relevance to humans. Thus excluding this finding the NOAEL for male rats is 120 mg/kg/day (highest dose tested).

The NOAEL for systemic and developmental reproductive toxicity in adult female rats was concluded to be 25 mg/kg/day based on poor clinical condition necessitating the humane kill of five females receiving 120 mg/kg/day during late gestation/early lactation. No effects on fertility were observed up to the highest dose tested (NOAEL fertility: 120 mg/kg bw/d).

A dose of 25 mg/kg/day is also concluded to be the NOAEL for the offspring based on lower post implantation and live birth survival indices resulting in a low total and live litter size at 120 mg/kg/day. It has to be mentioned that this difference occurred at a dose-level, which was not tolerated in five dams. This NOAEL of 25 mg/kg bw/d is the most relevant one with regard to DNEL derivation.

The NOAEL of 25 mg/kg bw/day from the EOGRTS (Covance, 2019) was selected as starting point for the derivation of the DNEL, because

a) the study was of subchronic duration,

b) exposure of pups was during sensitive windows of development,

c) exposure of females was also during a sensitive window (no effects observed in non-pregnant females in the 90d-study at 120 mg/kg bw/d),

d) LOAELs observed in the available 90d study (BASF, 2013), 28d study (BASF, 2002) respectively 1gen study (Exxon, 1998) and in the developomental tox studies (BASF, 2013 and Envigo, 2019) are above this NOAEL from the EOGRTS .

This NOAEL can be directly converted into the NOAEL for the dermal route, as there is no indication of differences in absorption between species and routes. Default factors are used for inter- and intraspecies and exposure duration extrapolation, with the following exception:

A factor of 1 is used for remaining interspecies differences: An assessment factor of 2.5 for remaining differences is not necessary because the metabolic fate of 3, 5, 5-trimethylhexanoic acid is very similar in all mammals. The oxidative degradation of isononanoic acid via ß-oxidation is largely hindered by the methyl groups at uneven positions, i.e. in the uneven 3-position, which also prevents utilisation in the citrate cycle. Moreover, tertiary carbons (5, 5 dimethyl substituents) do not allow ß-oxidation to occur. As a result, significant chain hydroxylation and conjugation reactions of the unchanged isononanoic acid and its hydroxylated metabolites are expected to occur, followed by excretion into bile and urine (Semino, 1998, see Toxicokinetics).

These reactions are considered to account for the majority of the biotransformation in mammals, and no difference between the rat and humans is known which would justify an additional assessment factor of 2.5 for remaining differences. Assessment factors for dose-reponse relationship and quality of the database are chosen 1 and 1, respectively, as two reliable studies report consistent data on less severe toxic effects.

A total assessment factor of 20 results as follows: 4 (total interspecies factor; 4 for allometric scaling, 1 for remainig species differences) x 5 (intraspecies factor, workers), 1 (extrapolation from subchronic to chronic exposure not required as exposure was during a sensitive phase of life).

DNEL _{long-term dermal} = NOAEL _rat/ Assessment factor = 25 mg/kg d / 20 = 1.25 mg/kg d

Long-term inhalation exposure - systemic effects

No data on toxicity after long-term inhalation exposure are available. A DNEL for inhalation can be derived from oral exposure toxicity data. The starting point has been chosen as described above for the dermal DNEL.

Conversion of the NOAEL into an inhalatory NAEC:

According to ECHA Guidance on information requirements and chemical safety assessment R.8, the converted NOAEC is (25 x 6.7)/(0.38 x 10) = 44.1 mg/m3.

Although rapid and complete oral absorption can be assumed, no quantitative data are available on oral absorption. Hence, according to the Guidance a conservative correction factor of 2 is applied for oral to inhalation extrapolation, resulting in a NAEC of 22 mg/m3.

A factor of 1 is used for remaining interspecies differences: An assessment factor of 2.5 for remaining differences is not necessary because the metabolic fate of 3, 5, 5-trimethylhexanoic acid is very similar in all mammals. The oxidative degradation of isononanoic acid via ß-oxidation is largely hindered by the methyl groups at uneven positions, i.e. in the uneven 3-position, which also prevents utilisation in the citrate cycle. Moreover, tertiary carbons (5, 5 dimethyl substituents) do not allow ß-oxidation to occur. As a result, significant chain hydroxylation and conjugation reactions of the unchanged isononanoic acid and its hydroxylated metabolites are expected to occur, followed by excretion into bile and urine (Semino, 1998, see Toxicokinetics). These reactions are considered to account for the majority of the biotransformation in mammals, and no difference between the rat and humans is known which would justify an additional assessment factor of 2.5 for remaining differences. Default factor is used for intraspecies extrapolation (5). Assessment factors of 1 are chosen for time extrapolation, dose-reponse relationship and quality of the database, as available studies report consistent data on less severe toxic effects and because, exposure of the offspring was during a sensitive phase of life. A total assessment factor of 5 results for the derivation of the long-term inhalation DNEL for systemic effects.

DNEL_{long-term inhalation}= NAEC_human/ Assessment factor = 22 / 5 = 4.4 mg/m3.

Long-term and short-term DNELs - local effects (inhalation route)

The substance is classified as skin irritant Category 2 (H315) and Eye irritant Category 1 (H318).

No information and no dose-response data are available for local effects in the respiratory tract after repeated exposure. In the absence of substance specific data the generic DNEL value for skin irritating substances as recommended by Messinger (2014), Regulatory Toxicology and Pharmacology, 68:317-324, which is based on a literature review of existing occupational exposure limit for substances with skin irritating properties, is recommended. According to Messinger, 10 mg/m3 represents an "acute and long-term upper cut-off (threshold) values that can be used as inhalation DNEL surrogates for respiratory tract irritation endpoints”.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.1 mg/m³

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Dose descriptor starting point:

NOAEL

Value:

25 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

10.9 mg/m³

Explanation for the modification of the dose descriptor starting point:

According to ECHA Guidance on information requirements and chemical safety assessment R.8, the converted NOAEC is (25/1.15) = 21.7 mg/m3.

Although rapid and complete oral absorption can be assumed, no quantitative data are available on oral absorption. Hence, according to the Guidance a conservative correction factor of 2 is applied for oral to inhalation extrapolation, resulting in a NAEC of 10.9 mg/m3.

AF for dose response relationship:

1

Justification:

NOAEL used as starting point

AF for differences in duration of exposure:

1

Justification:

no AF for differences in duration of exposure necessary as exposure was during sensitive phase of life

AF for interspecies differences (allometric scaling):

1

Justification:

no allometric scaling required for inhalative exposure route

AF for other interspecies differences:

1

Justification:

An assessment factor of 2.5 for remaining differences is not necessary because the metabolic fate of 3, 5, 5-trimethylhexanoic acid is very similar in all mammals. The oxidative degradation of isononanoic acid via ß-oxidation is largely hindered by the methyl groups at uneven positions, i.e. in the uneven 3-position, which also prevents utilisation in the citrate cycle. Moreover, tertiary carbons (5, 5 dimethyl substituents) do not allow ß-oxidation to occur. As a result, significant chain hydroxylation and conjugation reactions of the unchanged isononanoic acid and its hydroxylated metabolites are expected to occur, followed by excretion into bile and urine (Semino, 1998, see Toxicokinetics). These reactions are considered to account for the majority of the biotransformation in mammals, and no difference between the rat and humans is known which would justify an additional assessment factor of 2.5 for remaining differences.

AF for intraspecies differences:

10

Justification:

default assessment factor

AF for the quality of the whole database:

1

Justification:

several reliable studies report consistent data on less severe toxic effects

AF for remaining uncertainties:

1

Justification:

default assessment factor

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5 mg/m³

Most sensitive endpoint:

skin irritation/corrosion

DNEL derivation method:

other: generic DNEL based on occupational DNEL for skin irritating substances as recommended by Messinger (2014)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5 mg/m³

Most sensitive endpoint:

skin irritation/corrosion

DNEL derivation method:

other: generic DNEL based on occupational DNEL for skin irritating substances as recommended by Messinger (2014)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.6 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

40

Dose descriptor starting point:

NOAEL

Value:

25 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

25 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

This NOAEL can be directly converted into the NOAEL for the dermal route, as there is no indication of differences in absorption between species and routes.

AF for dose response relationship:

1

Justification:

NOAEL used as starting point

AF for differences in duration of exposure:

1

Justification:

no AF for differences in duration of exposure necessary as exposure was during sensitive phase of life

AF for interspecies differences (allometric scaling):

4

Justification:

default assessment factor

AF for other interspecies differences:

1

Justification:

An assessment factor of 2.5 for remaining differences is not necessary because the metabolic fate of 3, 5, 5-trimethylhexanoic acid is very similar in all mammals. The oxidative degradation of isononanoic acid via ß-oxidation is largely hindered by the methyl groups at uneven positions, i.e. in the uneven 3-position, which also prevents utilisation in the citrate cycle. Moreover, tertiary carbons (5, 5 dimethyl substituents) do not allow ß-oxidation to occur. As a result, significant chain hydroxylation and conjugation reactions of the unchanged isononanoic acid and its hydroxylated metabolites are expected to occur, followed by excretion into bile and urine (Semino, 1998, see Toxicokinetics). These reactions are considered to account for the majority of the biotransformation in mammals, and no difference between the rat and humans is known which would justify an additional assessment factor of 2.5 for remaining differences.

AF for intraspecies differences:

10

Justification:

default assessment factor

AF for the quality of the whole database:

1

Justification:

several reliable studies report consistent data on less severe toxic effects

AF for remaining uncertainties:

1

Justification:

default assessment factor

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.6 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

40

Dose descriptor starting point:

NOAEL

Value:

25 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

not applicable

AF for dose response relationship:

1

Justification:

NOAEL used as starting point

AF for differences in duration of exposure:

1

Justification:

no AF for differences in duration of exposure necessary as exposure was during sensitive phase of life

AF for interspecies differences (allometric scaling):

4

Justification:

default factor for allometric scaling

AF for other interspecies differences:

1

Justification:

An assessment factor of 2.5 for remaining differences is not necessary because the metabolic fate of 3, 5, 5-trimethylhexanoic acid is very similar in all mammals.The oxidative degradation of isononanoic acid via ß-oxidation is largely hindered by the methyl groups at uneven positions, i.e. in the uneven 3-position, which also prevents utilisation in the citrate cycle. Moreover, tertiary carbons (5, 5 dimethyl substituents) do not allow ß-oxidation to occur. As a result, significant chain hydroxylation and conjugation reactions of the unchanged isononanoic acid and its hydroxylated metabolites are expected to occur, followed by excretion into bile and urine (Semino, 1998, see Toxicokinetics). These reactions are considered to account for the majority of the biotransformation in mammals, and no difference between the rat and humans is known which would justify an additional assessment factor of 2.5 for remaining differences.

AF for intraspecies differences:

10

Justification:

default assessment factor

AF for the quality of the whole database:

1

Justification:

several reliable studies report consistent data on less severe toxic effects

AF for remaining uncertainties:

1

Justification:

default assessment factor

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Hazard assessment conclusion:

medium hazard (no threshold derived)

Short-term and long-term DNELs - local effects (dermal route)

The substance is classified as skin irritant Category 2 (H315) and Eye irritant Category 1 (H318), but no dose-response data are available, which would allow derivation of a DNEL for local effects. A qualitative risk characterisation (according to the Guidance on Information Requirements and Chemical Safety Assessment, Part E) is performed in the CSR for these effects.

Short-term DNELs - systemic effects (oral, dermal and inhalation route) The substance is not classified for acute inhalation or dermal toxicity and only classified as Cat. 4 for acute oral toxicity. As there are no dose-response data available, no DNELs are derived. According to the suggestions of the Guidance on Information Requirements and Chemical Safety Assessment, Part E, no qualitative hazard has to be regarded.