Hexanoic acid, 3,5,5-trimethyl-, tin(2+) salt (2:1)

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

9.2 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):

10

Modified dose descriptor starting point:

NOAEC

Value:

91.7 mg/m³

Explanation for the modification of the dose descriptor starting point:

No dose descriptor for the inhalation route is available; therefore route to route extrapolation is used to convert the oral NOAEL. Detailed information is given in the discussion.

AF for dose response relationship:

1

Justification:

The starting point for the DNEL calculation is a NOAEL, therefore the default assessment factor of 1 for a standard procedure is considered appropriate.

AF for differences in duration of exposure:

2

Justification:

Sub-chronic to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

It is not necessary to apply an allometric scaling factor because the starting point has been corrected for differences in respiratory volume and this takes account of differences in metabolic rates.

AF for other interspecies differences:

1

Justification:

An assessment factor of 2.5 for remaining species differences is not considered necessary due to the similar metabolic fate of 3,5,5-trimethylhexanoic acid among mammals: Beta-oxidation of 3-methyl-branched fatty acids is blocked by the 3-methyl-group which prevents the dehydrogenation step. Instead 3-methyl-branched fatty acids undergo alpha-oxidation in peroxisomes resulting in the formation of a 2-methyl-branched fatty acid shortened by one carbon atom and formyl-CoA which is subsequently converted to formate and CO2 (Casteels, 2003). Degradation of 3,5,5-trimethylhexanoic acid finally results in 2,2-dimethylpropanoic acid containing a tertiary carbon atom which cannot be further degraded, but is conjugated with glucuronic acid and excreted into bile and urine (Dziewiatkowski, Lewis, 1944). No differences in the metabolic pathways between humans and rats are known to justify a further assessment factor of 2.5. Thus a factor of 1 is used for remaining interspecies differences.

AF for intraspecies differences:

5

Justification:

The default factor of 5 for workers was used to take account of intraspecies variability.

AF for the quality of the whole database:

1

Justification:

The key studies were conducted according to modern regulatory standards and were adequately reported.

AF for remaining uncertainties:

1

Justification:

No additional AF was deemed necessary.

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

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:

2.6 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):

40

Modified dose descriptor starting point:

NOAEL

Value:

104 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The dermal NOAEL is determined to be equal to the oral calculated NOAEL. Based on the assumption, that dermal absorption will not be higher than oral absorption, no additional assessment factor deemed necessary for oral-to-dermal extrapolation.

AF for dose response relationship:

1

Justification:

The starting point for the DNEL calculation is a NOAEL, therefore the default assessment factor of 1 for a standard procedure is considered appropriate.

AF for differences in duration of exposure:

2

Justification:

Sub-chronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

The starting point is an oral dose descriptor from a rat study. It is therefore necessary to include an allometric scaling factor of 4 to take account of differences in basal metabolic rates between rats and humans.

AF for other interspecies differences:

1

Justification:

An assessment factor of 2.5 for remaining species differences is not considered necessary due to the similar metabolic fate of 3,5,5-trimethylhexanoic acid among mammals: Beta-oxidation of 3-methyl-branched fatty acids is blocked by the 3-methyl-group which prevents the dehydrogenation step. Instead 3-methyl-branched fatty acids undergo alpha-oxidation in peroxisomes resulting in the formation of a 2-methyl-branched fatty acid shortened by one carbon atom and formyl-CoA which is subsequently converted to formate and CO2 (Casteels, 2003). Degradation of 3,5,5-trimethylhexanoic acid finally results in 2,2-dimethylpropanoic acid containing a tertiary carbon atom which cannot be further degraded, but is conjugated with glucuronic acid and excreted into bile and urine (Dziewiatkowski, Lewis, 1944). No differences in the metabolic pathways between humans and rats are known to justify a further assessment factor of 2.5. Thus a factor of 1 is used for remaining interspecies differences.

AF for intraspecies differences:

5

Justification:

The default factor of 5 for workers was used to take account of intraspecies variability.

AF for the quality of the whole database:

1

Justification:

The key studies were conducted according to modern regulatory standards and were adequately reported.

AF for remaining uncertainties:

1

Justification:

No additional AF was deemed necessary.

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)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

Worker:

General considerations:

 

No data on repeated dose toxicity are available for hexanoic acid, 3,5,5-trimethyl-, tin (2+)salt (2:1).

Studies with read-across substances (dissociation products) are available for oral repeated dose toxicity:

•             A reliable oral sub-acute toxicity study in rats for the read-across substance 3,5,5 trimethylhexanionic acid with a

NOAEL of 50 mg/kg bw/d and a LOAEL of 200 mg/kg bw/d.

•             Furthermore data from a reliable one –generation study in rats with the same substance revealing a NOAEL of

0.12 % in diet for systemic effect in parents and offspring, leading to corresponding body doses of 79 – 228 mg/kg bw/d.

•             Reliable data from a sub-chronic study in the rat with tin chloride revealed a NOEL of 1900 ppm with corresponding body doses

of 121 – 414 mg/kg bw/d for males and 132 to 318 mg/kg bw/d for females.

Taking the lower NOEL boundary of 121 mg/kg bw/ day from tin chloride data, this value is higher than the NOAELs derived for 3,5,5 trimethylhexanionic acid. In addition it has to be considered that the tin value is a real no effect level. Therefore 3,5,5 trimethylhexanionic acid data were considered appropriate as starting point for DNEL derivation.

The NOAEL value of 79 mg/kg bw/d (lowest boundary of dose range) from the one generation study with 3,5,5 trimethylhexanionic acid was chosen as a starting point for derivation of the DNEL du to the following reasoning:

•             NOAEL values of sub-chronic and sub-acute studies are in the same range, and the large gap between NOAEL and LOAEL

in the sub-acute study makes the slightly higher NOAEL of sub-chronic study plausible.

 •            Effects in both studies are observed for comparable endpoints.

 •             The study is of sub-chronic duration.

Reflecting molecular weight differences between 3,5,5 trimethylhexanionic acid andhexanoic acid, 3,5,5-trimethyl-, tin (2+)salt (2:1)a converting factor of 1.32 was used for extrapolation.

The resulting NOAEL of 104 mg/kg bw/d was used as starting point for DNEL derivation.

 

DNEL_{long–term systemic dermal}

Route to route extrapolation oral to dermal:

The dermal NOAEL is determined to be equal to the oral NOAEL. Based on the assumption, that dermal absorption will not be higher than oral absorption, no additional assessment factor deemed necessary for oral-to-dermal extrapolation.

 

 

DNEL_{long –term systemic inhalation}

Route to route extrapolation oral to inhalation:

For the derivation of a NOAEC for the worker the following corrections have to be applied to the oral NOAEL (rat).

For converting the oral NOAEL (rat) to an inhalation NOAEC for worker the oral NOAEL (rat) is multiplied with 1/0.38 m³/kg bw/8h (default respiratory volume in rat, Table R.8.2 of CSR guidance) to give the corresponding rat inhalation 8h-NOAEC (no-observed adverse effect concentration). Due to the absence of route specific information a default factor of 2 is included by assuming 50 % for oral absorption (ABS oral-rat) and 100 % absorption after inhalation (ABS inh-human). To obtain the starting point for workers, a factor of 0.67 is applied to account for the differences in inhalation rates between animals at rest and humans involved in light activity.

For workers the corrected inhalation NOAEC is calculated according to the following equation:

corrected inhalation NOAEC = oral NOAEL x 1/sRV ratx ABS oral-rat/ ABS inh-human x sRV human/ wRV1

= 104 x 1/0.38 x50/100 x 6.7/10

The corrected inhalation NOAEC worker(8h) is therefore:

= 91.7 mg/m³(8h-TWA)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.26 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):

20

Modified dose descriptor starting point:

NOAEC

Value:

45.2 mg/m³

Explanation for the modification of the dose descriptor starting point:

No dose descriptor for the inhalation route is available; therefore route to route extrapolation is used to convert the oral NOAEL. Detailed information is given in the discussion.

AF for dose response relationship:

1

Justification:

The starting point for the DNEL calculation is a NOAEL, therefore the default assessment factor of 1 for a standard procedure is considered appropriate.

AF for differences in duration of exposure:

2

Justification:

Sub-chronic to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

It is not necessary to apply an allometric scaling factor because the starting point has been corrected for differences in respiratory volume and this takes account of differences in metabolic rates.

AF for other interspecies differences:

1

Justification:

An assessment factor of 2.5 for remaining species differences is not considered necessary due to the similar metabolic fate of 3,5,5-trimethylhexanoic acid among mammals: Beta-oxidation of 3-methyl-branched fatty acids is blocked by the 3-methyl-group which prevents the dehydrogenation step. Instead 3-methyl-branched fatty acids undergo alpha-oxidation in peroxisomes resulting in the formation of a 2-methyl-branched fatty acid shortened by one carbon atom and formyl-CoA which is subsequently converted to formate and CO2 (Casteels, 2003). Degradation of 3,5,5-trimethylhexanoic acid finally results in 2,2-dimethylpropanoic acid containing a tertiary carbon atom which cannot be further degraded, but is conjugated with glucuronic acid and excreted into bile and urine (Dziewiatkowski, Lewis, 1944). No differences in the metabolic pathways between humans and rats are known to justify a further assessment factor of 2.5. Thus a factor of 1 is used for remaining interspecies differences.

AF for intraspecies differences:

10

Justification:

The default factor of 10 for consumers will therefore be used to take account of intraspecies variability.

AF for the quality of the whole database:

1

Justification:

The key studies were conducted to modern regulatory standards and were adequately reported.

AF for remaining uncertainties:

1

Justification:

No additional AF was deemed necessary.

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

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:

1.3 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):

80

Modified dose descriptor starting point:

NOAEL

Explanation for the modification of the dose descriptor starting point:

The dermal NOAEL is determined to be equal to the oral calculated NOAEL. Based on the assumption, that dermal absorption will not be higher than oral absorption, no additional assessment factor deemed necessary for oral-to-dermal extrapolation.

AF for dose response relationship:

1

Justification:

The starting point for the DNEL calculation is a NOAEL, therefore the default assessment factor of 1 for a standard procedure is considered appropriate.

AF for differences in duration of exposure:

2

Justification:

Sub-chronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

The starting point is an oral dose descriptor from a rat study. It is therefore necessary to include an allometric scaling factor of 4 to take account of differences in basal metabolic rates between rats and humans.

AF for other interspecies differences:

1

Justification:

An assessment factor of 2.5 for remaining species differences is not considered necessary due to the similar metabolic fate of 3,5,5-trimethylhexanoic acid among mammals: Beta-oxidation of 3-methyl-branched fatty acids is blocked by the 3-methyl-group which prevents the dehydrogenation step. Instead 3-methyl-branched fatty acids undergo alpha-oxidation in peroxisomes resulting in the formation of a 2-methyl-branched fatty acid shortened by one carbon atom and formyl-CoA which is subsequently converted to formate and CO2 (Casteels, 2003). Degradation of 3,5,5-trimethylhexanoic acid finally results in 2,2-dimethylpropanoic acid containing a tertiary carbon atom which cannot be further degraded, but is conjugated with glucuronic acid and excreted into bile and urine (Dziewiatkowski, Lewis, 1944). No differences in the metabolic pathways between humans and rats are known to justify a further assessment factor of 2.5. Thus a factor of 1 is used for remaining interspecies differences.

AF for intraspecies differences:

10

Justification:

The default factor of 10 for consumers will be used to take account of intraspecies variability.

AF for the quality of the whole database:

1

Justification:

The key studies were conducted to modern regulatory standards and were adequately reported.

Justification:

No additional AF was deemed necessary.

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

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.3 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):

80

Modified dose descriptor starting point:

NOAEL

AF for dose response relationship:

1

Justification:

he starting point for the DNEL calculation is a NOAEL, therefore the default assessment factor of 1 for a standard procedure is considered appropriate.

AF for differences in duration of exposure:

2

Justification:

Sub-chronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

The starting point is an oral dose descriptor from a rat study. It is therefore necessary to include an allometric scaling factor of 4 to take account of differences in basal metabolic rates between rats and humans.

AF for other interspecies differences:

1

Justification:

An assessment factor of 2.5 for remaining species differences is not considered necessary due to the similar metabolic fate of 3,5,5-trimethylhexanoic acid among mammals: Beta-oxidation of 3-methyl-branched fatty acids is blocked by the 3-methyl-group which prevents the dehydrogenation step. Instead 3-methyl-branched fatty acids undergo alpha-oxidation in peroxisomes resulting in the formation of a 2-methyl-branched fatty acid shortened by one carbon atom and formyl-CoA which is subsequently converted to formate and CO2 (Casteels, 2003). Degradation of 3,5,5-trimethylhexanoic acid finally results in 2,2-dimethylpropanoic acid containing a tertiary carbon atom which cannot be further degraded, but is conjugated with glucuronic acid and excreted into bile and urine (Dziewiatkowski, Lewis, 1944). No differences in the metabolic pathways between humans and rats are known to justify a further assessment factor of 2.5. Thus a factor of 1 is used for remaining interspecies differences.

AF for intraspecies differences:

10

Justification:

he default factor of 10 for consumers will be used to take account of intraspecies variability.

AF for the quality of the whole database:

1

Justification:

The key studies were conducted to modern regulatory standards and were adequately reported.

AF for remaining uncertainties:

1

Justification:

No additional AF was deemed necessary.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

General population:

General considerations:

 

No data on repeated dose toxicity are available for hexanoic acid, 3,5,5-trimethyl-, tin (2+)salt (2:1).

Studies with read-across substances (dissociation products) are available for oral repeated dose toxicity:

•             A reliable oral sub-acute toxicity study in rats for the read-across substance 3,5,5 trimethylhexanionic acid with a NOAEL of

50 mg/kg bw/d and a LOAEL of 200 mg/kg bw/d.

•             Furthermore data from a reliable one –generation study in rats with the same substance revealing a NOAEL of 0.12 %

in diet for systemic effect in parents and offspring, leading to corresponding body doses of 79 – 228 mg/kg bw/d.

•             Reliable data from a sub-chronic study in the rat with tin chloride revealed a NOEL of 1900 ppm with corresponding body doses

of 121 – 414 mg/kg bw/d for males and 132 to 318 mg/kg bw/d for females.

Taking the lower NOEL boundary of 121 mg/kg bw/ day from tin chloride data, this value is higher than the NOAELs derived for 3,5,5 trimethylhexanionic acid. In addition it has to be considered that the tin value is a real no effect level. Therefore 3,5,5 trimethylhexanionic acid data were considered appropriate as starting point for DNEL derivation.

The NOAEL value of 79 mg/kg bw/d (lowest boundary of dose range) from the one generation study with 3,5,5 trimethylhexanionic acid was chosen as a starting point for derivation of the DNEL du to the following reasoning:

•       NOAEL values of sub-chronic and sub-acute studies are in the same range, and the large gap between NOAEL and LOAEL in the sub-acute study makes the slightly higher NOAEL of sub-chronic study plausible.

 •       Effects in both studies are observed for comparable endpoints.

 •       The study is of sub-chronic duration.

Reflecting molecular weight differences between 3,5,5 trimethylhexanionic acid andhexanoic acid, 3,5,5-trimethyl-, tin (2+)salt (2:1)a converting factor of 1.32 was used for extrapolation.

The resulting NOAEL of 104 mg/kg bw/d was used as starting point for DNEL derivation.

 

DNEL_{long–term systemic dermal}

Route to route extrapolation oral to dermal:

The dermal NOAEL is determined to be equal to the oral calculated NOAEL. Based on the assumption, that dermal absorption will not be higher than oral absorption, no additional assessment factor deemed necessary for oral-to-dermal extrapolation.

 

 

DNEL_{long –term systemic inhalation}

Route to route extrapolation oral to inhalation:

To assess consumer inhalation exposure, the oral NOAEL (rat) is multiplied with 1/1.15 m³/kg bw (Table R.8.2 of CSR guidance) to give the corresponding 24h-NOAEC (no-observed adverse effect concentration). Due to the absence of route specific information a default factor of 2 is included by assuming 50 % for oral absorption (ABS oral-rat) and 100 % absorption after inhalation (ABS inh-human).

For consumers the corrected inhalation NOAEC is calculated according to the following equation:

corrected inhalation NOAEC

= oral NOAEL x 1/sRV rat x ABS oral-rat/ ABS inh-rat x ABS oral-human/ ABS inh-human

= 104 x 1/1.15 x50/100

The corrected inhalation NOAEC consumer (24h) is therefore:

= 45.2 mg/m³(24-h)