Amines, C12-14-branched alkyl, dodecylbenzenesulfonates (1:1)

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.18 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

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

88.2 mg/m³

Explanation for the modification of the dose descriptor starting point:

Regarding absorption, in the absence of reliable data for both the starting route (oral) and the end route (inhalation), worst case assumptions were made. It was assumed that a limited absorption occurs by the oral route, leading to a low (conservative) internal NOAEL. To secure a conservative external NOAEL, a maximum absorption should be assumed for the inhalation route (i.e.; 100%) leading to a low external NOAEL. Thus, in the case of oral-to- inhalation extrapolation, it is proposed to include a default factor of 2, i.e. the absorption percentage by oral route is half that of the inhalation absorption as suggested in ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012).

To convert the oral NOAEL into inhalatory NOAEC, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 0.38 m3/kg bw/8 h). For workers a correction was added for the difference between respiratory rates under standard conditions (sRVhuman: 6.7 m3 for an 8 h exposure period) and under conditions of light activity (wRV: 10 m3 for an 8 h exposure period).

The corrected dose descriptor for inhalation is determined using the following equation:

Corrected Inhalatory NOAEC =NOAEL (oral) x 1/SRVrat x ABS(oral-rat)/ABS(inh-human) x sRVhuman/wRV

= [100 mg/kg bw/day] x  [1/0.38 m3/kg bw/day] x [1/2] X [6.7 m3/10m3].

Thus, the corrected dose descriptor for inhalation is 88.2 mg/m3 for workers.

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.

AF for differences in duration of exposure:

6

Justification:

Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.

AF for interspecies differences (allometric scaling):

1

Justification:

Table R.8-4 ECHA REACH Guidance. Assessment factor not to be used for inhalation route since the differences in the metabolic rate/bw has already been taken into account in the corrected dose descriptor.

AF for other interspecies differences:

2.5

Justification:

Table R.8-4 ECHA REACH Guidance. Assessment factor not to be used for inhalation route since the differences in the metabolic rate/bw has already been taken into account in the corrected dose descriptor.

AF for intraspecies differences:

5

Justification:

Default factor for worker. Table R.8-6 ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Explanation for the modification of the dose descriptor starting point:

In accordance with Annex VIII, Section 8.5.2, Column 2 of REACH, testing by the inhalation route was waived due to low vapour pressure and a use pattern resulting in exposure to humans being considered negligible.  No acute toxicity hazard (leading to classification & labelling) has been identified for the substance following oral exposure.  No acute inhalation hazard is therefore identified for this substance.

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:

0.333 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

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

For systemic hazard assesment via the dermal route of exposure, route-to-route extrapolation from the oral NOAEL value was considered appropriate. As no data on dermal penetration are available, dermal absorption is considered to be the same as oral absorption (i.e. 100 %). Therefore the dermal NOAEL is considered the same as the oral NOAEL (ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012)).

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.

AF for differences in duration of exposure:

6

Justification:

Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.

AF for interspecies differences (allometric scaling):

4

Justification:

Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance.

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.

AF for intraspecies differences:

5

Justification:

Default factor for worker. Table R.8-6 ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - workers

NOAEL (systemic toxicity) = 100 mg/kg bw/day; OECD 422 (2018)

Long-term systemic hazard assessment for this substance is based on a subacute toxicity study conducted on rats in accordance with OECD 422 under GLP (2018).  The substance was administered to 30 male and 30 female Crl:WI(Han) strain  rats by oral gavage at dose levels of 100, 300 and 500 mg/kg bw/day. In addition, 10 male and 10 female were used as control rats and were treated with the corn oil vehicle only.  The test item was administered to male rats for 42 consecutive days and to female rats for up to 61 days (pre-pairing, throughout gestation, and during the first 2 weeks of lactation).  Although there was no recovery phase, this is not a guideline requirement. The key findings in this study one male mortality at 500 mg/kg bw/day which was unexplained. Other key clinical findings included, at 500 mg/kg bw/day, lower mean body weight, eight females experiencing total litter loss between PND 0 and 2, with 22 to 100 % of stillborn pups in females that successfully littered, centrilobular hepatocyte hypertrophy and/or increased hepatocellular glycogen of the liver, thyroid follicular cell hypertrophy, nonglandular stomach, epithelial hyperplasia and orthokeratotic hyperkeratosis decreased lymphocyte cellularity in the cortex and medulla of the thymus, adrenal cortical hypertrophy with adrenal enlargement. Observations at mid or high dose included; dose-dependent incidence of stillborn pups, lower mean body weights were evident in pups. Other observations were; urogenital staining, wet abdominal fur, salivation, piloerection, changes in body posture, dose‑related increase in ataxia, high stepping, walking on toes, slow deliberate movements, and incidences of rears in male. Mean adjusted liver, thyroid, and kidney weights were increased, increased glucose, cholesterol calcium, inorganic phosphate, and urine output. In all dose groups, mottled and/or pale discolouration in the liver, discolouration in kidney, thick and/or raised focus, epithelial hyperplasia and orthokeratotic hyperkeratosis were recorded in the stomach, as were follicular cell hypertrophy of the thyroid, centrilobular hepatocyte hypertrophy, nephropathy and hyaline droplets, with increased gradings. In female decreased number of rears was also noted during the lactation phase, increased mean water consumption and elevated cholesterol and glucose levels was observed at mid to high dose group.

The No Observed Adverse Effect Level (NOAEL) for systemic toxicity was considered to be 100 mg/kg/day for both males and females, taking into account that findings observed in clinical pathology at this dose level in males were confined to changes in the liver and thyroid gland, and male rat specific changes in the kidney. These effects in males were not considered adverse.

The hazard conclusion for reproductive and developmental toxicology were as follows (OECD 422, 2018):

NOAEL(fertility) = No hazard identified

NOAEL(development) = No hazard identified

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.289 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

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

43.48 mg/m³

Explanation for the modification of the dose descriptor starting point:

Concerning absorption, in the absence of reliable data for both the starting route (oral) and the end route (inhalation), worst case assumptions were made. It was assumed that a limited absorption occurs by the oral route, leading to a low (conservative) internal NOAEL. To secure a conservative external NOAEL, a maximum absorption should be assumed for the inhalation route (i.e.; 100%) leading to a low external NOAEL. Thus, in the case of oral-to- inhalation extrapolation, it is proposed to include a default factor of 2, i.e. the absorption percentage by oral route is half that of the inhalation absorption as suggested in ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012).

To convert the oral NOAEL into inhalatory NOAEC, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 1.15 m3/kg bw/24 h).

The corrected dose descriptor for inhalation is determined using the following equation:

Corrected Inhalator NOAEC = 1/sRVrat x ABSoral-rat/ABSinh-rat x ABSinh-rat/ABSinh-human

= [100 mg/kg bw/day] x [1/1.15 m3/kg bw/ day] x [1/2] x [1/1]

Thus, the corrected dose descriptor for inhalation is 43.480 mg/m3 for the general population.

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.

AF for differences in duration of exposure:

6

Justification:

Default factor for a sub-acute. Table R.8-5 ECHA REACH Guidance.

AF for interspecies differences (allometric scaling):

1

Justification:

Table R.8-4 ECHA REACH Guidance. Assessment factor not to be used for inhalation route since the differences in metabolic rate/bw has already been taken into account for the corrected dose descriptor.

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

Default factor for general population. Table R.8-6 ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Explanation for the modification of the dose descriptor starting point:

In accordance with Annex VIII, Section 8.5.2, Column 2 of REACH, testing by the inhalation route was waived due to low vapour pressure and a use pattern resulting in exposure to humans being considered negligible.  No acute toxicity hazard (leading to classification & labelling) has been identified for the substance following oral exposure.  No acute inhalation hazard is therefore identified for this substance.

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:

0.167 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

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

For systemic hazard assesment via the dermal route of exposure, route-to-route extrapolation from the oral NOAEL value was considered appropriate. As no data on dermal penetration are available, dermal absorption is considered to be the same as oral absorption (i.e. 100 %). Therefore the oral NOAEL is considered the same as the dermal NOAEL (ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012))

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.

AF for differences in duration of exposure:

6

Justification:

Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.

AF for interspecies differences (allometric scaling):

4

Justification:

Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance.

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

Default factor for general population. Table R.8-6 ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Explanation for the modification of the dose descriptor starting point:

The study does not need to be conducted because the substance dose not meet the criteria for classification as acute toxicity or STOT SE by oral route and no systemic effects have been observed in in vivo studies with dermal exposure are predicted on the basis of non-testing approaches (e.g. read across, QSAR studies) - [study scientifically not necessary/ other information available]

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.167 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

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No modification of the dose descriptor starting point is required. The endpoint used to derive the DNEL uses the oral route for exposure.

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.

AF for differences in duration of exposure:

6

Justification:

Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.

AF for interspecies differences (allometric scaling):

4

Justification:

Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance.

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

Default factor for general population. Table R.8-6 ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

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

NOAEL (systemic toxicity) = 100 mg/kg bw/day; OECD 422 (2018)

Long-term systemic hazard assessment for this substance is based on a subacute toxicity study conducted on rats in accordance with OECD 422 under GLP (2018).  The substance was administered to 30 male and 30 female Crl:WI(Han) strain  rats by oral gavage at dose levels of 100, 300 and 500 mg/kg bw/day. In addition, 10 male and 10 female were used as control rats and were treated with the corn oil vehicle only.  The test item was administered to male rats for 42 consecutive days and to female rats for up to 61 days (pre-pairing, throughout gestation, and during the first 2 weeks of lactation).  Although there was no recovery phase, this is not a guideline requirement. The key findings in this study one male mortality at 500 mg/kg bw/day which was unexplained. Other key clinical findings included, at 500 mg/kg bw/day, lower mean body weight, eight females experiencing total litter loss between PND 0 and 2, with 22 to 100 % of stillborn pups in females that successfully littered, centrilobular hepatocyte hypertrophy and/or increased hepatocellular glycogen of the liver, thyroid follicular cell hypertrophy, nonglandular stomach, epithelial hyperplasia and orthokeratotic hyperkeratosis decreased lymphocyte cellularity in the cortex and medulla of the thymus, adrenal cortical hypertrophy with adrenal enlargement. Observations at mid or high dose included; dose-dependent incidence of stillborn pups, lower mean body weights were evident in pups. Other observations were; urogenital staining, wet abdominal fur, salivation, piloerection, changes in body posture, dose‑related increase in ataxia, high stepping, walking on toes, slow deliberate movements, and incidences of rears in male. Mean adjusted liver, thyroid, and kidney weights were increased, increased glucose, cholesterol calcium, inorganic phosphate, and urine output. In all dose groups, mottled and/or pale discolouration in the liver, discolouration in kidney, thick and/or raised focus, epithelial hyperplasia and orthokeratotic hyperkeratosis were recorded in the stomach, as were follicular cell hypertrophy of the thyroid, centrilobular hepatocyte hypertrophy, nephropathy and hyaline droplets, with increased gradings. In female decreased number of rears was also noted during the lactation phase, increased mean water consumption and elevated cholesterol and glucose levels was observed at mid to high dose group.

The No Observed Adverse Effect Level (NOAEL) for systemic toxicity was considered to be 100 mg/kg/day for both males and females, taking into account that findings observed in clinical pathology at this dose level in males were confined to changes in the liver and thyroid gland, and male rat specific changes in the kidney. These effects in males were not considered adverse.

The hazard conclusion for reproductive and developmental toxicology were as follows (OECD 422, 2018):

NOAEL(fertility) = No hazard identified

NOAEL(development) = No hazard identified