Alcohols, C16-18 (even numbered, C18-unsatd.), ethoxylated, and alcohols C20-22 (even numbered), sulfates, ammonium salts

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.8 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):

50

Modified dose descriptor starting point:

NOAEC

Value:

441 mg/m³

Explanation for the modification of the dose descriptor starting point:

Derived from lowest NOAEL oral.

Derived from lowest NOAEL oral

AF for dose response relationship:

1

Justification:

Lowest NOAEL chosen for DNEL-derivation.

AF for differences in duration of exposure:

2

Justification:

Subchronic to chronic.

AF for interspecies differences (allometric scaling):

1

Justification:

Not required for inhalation route.

AF for other interspecies differences:

2.5

Justification:

According to ECHA Guidance document R8.

AF for intraspecies differences:

5

Justification:

According to ECHA Guidance document R8.

AF for the quality of the whole database:

1

Justification:

The quality of the repeated dose toxicity database is good.

AF for remaining uncertainties:

2

Justification:

To cover the uncertainty of the read-across.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

12.5 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):

200

Modified dose descriptor starting point:

NOAEL

Value:

2 500 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Derived from lowest NOAEL oral taking into account dermal absorbtion.

AF for dose response relationship:

1

Justification:

Lowest NOAEL chosen for DNEL-derivation.

AF for differences in duration of exposure:

2

Justification:

Subchronic to chronic.

AF for interspecies differences (allometric scaling):

4

Justification:

According to ECHA Guidance document R8.

AF for other interspecies differences:

2.5

Justification:

According to ECHA Guidance document R8.

AF for intraspecies differences:

5

Justification:

According to ECHA Guidance document R8.

AF for the quality of the whole database:

1

Justification:

The quality of the repeated dose toxicity database is good.

AF for remaining uncertainties:

2

Justification:

To cover the uncertainty of the read-across.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

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:

medium hazard (no threshold derived)

Additional information - workers

Alkyl sulfates are the major constituents of the test item (C20-22 AS NH4). Minor constituents are the alkyl ethersulfates. Approximately 10% of the constituents are non-sulfated material, e.g. fatty alcohols. As no repeated dose toxicity data are available for test item this endpoint was covered by read-across to shorter chained alkyl sulfates (AS), alkyl ethersulfates (AES) and the free alcohol (C22FA, docosanol). Several repeated dose toxicity studies for the read-across substances are available. C12AS Na (CAS 151-21-3) was tested in a 90 day feeding study on rats at dietary levels of 40, 200, 1000 or 5000 ppm (corresponding to 3, 17, 86 or 430 mg/kg bw/day; Walker et al., 1967). The NOAEL was established at the highest dose level of 5000 ppm (430 mg/kg bw/day). Synthetic alkylethersulfate (AES) - C12-15AES Na (ethoxylation degree of 3) and natural C12AES Na (ethoxylation degree of 3) were tested in a 90 days rat diet study at dose levels of 0, 40, 200, 1000 and 5000 ppm active material, corresponding to 0, 2, 10, 50 and 250 mg/kg bw/day (Walker, 1967). The NOAEL was established greater than 250 mg/kg bw/day. Docosanol (C22FA) was administered by oral gavage to rats at doses of 0, 10, 100, or 1000 mg/ kg bw/day for at least 26 weeks. Adverse effects were not observed. Thus, the NOAEL was established at the highest dose level of 1000 mg/kg bw/day. Next to the subchronic oral toxicity study a reproductive toxicity study with C22FA is available. Rats were administered 0, 10 00, or 1000 mg /kg bw/day by gavage. Males were treated daily for 71 days prior to mating, during mating, and until termination. Females were treated with the test substance for 15 days prior to mating, during mating, and up to Day 17 of gestation. No maternal toxicity or reproductive toxicity was observed. Hence, the NOAEL was 1000 mg/kg bw/day for both parental and fetal toxicity. C22FA was administered to New Zealand white rabbits at 0, 125, 500, or 2000 mg /kg bw/day by gavage daily from Day 6 to Day 19 of gestation. Females were sacrificed on Day 29 and their uterine contents were examined. Based on the absence of maternal and developmental toxicity under the conditions of this study, the NOAEL was 2000 mg/kg bw/day, the highest dose tested. Two developmental toxicity studies are available with C12AS Na. The test substance was administered orally by gavage at dose levels of 0, 0.2, 2, 300 and 600 mg/kg bw/day once daily from Day 6 to Day 15 of gestation for rats and Day 19 of gestation for rabbits, respectively. The NOAEL within these studies were established at 300 mg/kg bw/d for maternal toxicity and greater

600 mg/kg bw/d for developmental toxicity for rat and rabbits, respectively. The available repeated dose toxicity studies of the read across substances administered via diet provide a coherent picture on the subchronic oral toxicity of alcohols, alkylsulfates and alkyl ethersulfates. Also oral gavage of fatty alcohol did not result in any signs of systemic toxicity within the reproduction toxicity studies. However application of C12AS Na via gavage resulted in maternal toxicity. This maternal toxicity may be related to local irritation, as shorter chained alkyl sulfates are known to have irritating properties. To cover the uncertainties which may occur due to the read across the lowest NOAEL (250 mg/kg bw/d; Walker et al., 1967) was chosen for risk assessment. Since there is no dose descriptor for every exposure route, dose descriptors were converted into a correct starting point by route-to-route extrapolation based on the ECHA guidance document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health", November, 2012. Conversion of oral NOAEL to inhalatory NAEC As starting point the dietary NOAEL of 250 mg/kg bw/day (Walker, 1967) of the subchronic oral toxicity study was chosen for the risk assessment. The conversion of an oral NOAEL into an inhalatory NAEC is performed using the following equations; for workers the resulting concentration needs to be additionally corrected for the difference between basal caloric demand and caloric demand under light activity:

Corrected inhalatory NAEC = oral NOAEL x 1/sRVrat x ABSoral-rat/ ABSinh-human x sRVhuman/wRV

= oral NOAEL x 1/0.38m³/kg bw x 1 x 6.7 m³/10 m³

sRV: standard respiratory volume, ABS: absorption, wRV: worker respiratory volume

Thus, the corrected starting point for inhalation route was 250 x 6.7 / (0.38 x 10) = 441 mg/ m³

DNEL derivation using the inhalatory NAEC

In the ECHA Guidance a factor of 2 is suggested for the extrapolation from oral to inhalation absorption. On the contrary, the Technical guidance document on risk assessment in support of Commission directive 93/67/EEC, 2003 appendix IV A and B gives a number of physico-chemical properties that normally determine oral, inhalation and dermal absorption. These parameters

include molecular weight, log Kow, pKa values and for inhalation also particle size distribution,

vapour pressure etc. Molecules with a molecular weight < 500 and a log Kow between 0 and 4 can be assumed to be

well absorbed equivalently by the oral and inhalation route. Oral absorption may be reduced for acids and bases depending on their pKa value and their possibility of absorption in the gastrointestinal tract. More lipophilic substances may be better absorbed in the gastrointestinal tract due to the solubilisation with bile acids and thus oral absorption may be higher than inhalation

absorption. The majority of components of the test item have a molecular weight of < 500 g/mol and a log Kow of 2.11. In addition the substance is moderately soluble in water (approximately 236 mg/L). Therefore it can be expected, that the molecule will be well absorbed after oral application. A good oral absorption of alkyl sulfates was also reported by Wibbertman et al. (2011). They reported 74-98% of an oral dose of C18AS Na to be excreted via the urine, indicating an almost complete absorption. Unless valid data suggest that inhalation leads to higher absorption than oral ingestion, equal absorption will be assumed when extrapolating from

oral to inhalation route. Thus, the factor of 2 is considered to be not relevant for the test item when extrapolating from oral to inhalation route. A factor of 2 for the differences in exposure duration was applied to extrapolate from the subchronic to the chronic situation. Further factors were applied according to ECHA guidance document R8 for remaining differences (2.5) and intraspecies differences (5) as well as a factor of 2 to cover uncertainties of the read-across. The inhalatory DNEL is calculated to be 8.8 mg/m3.

Conversion of oral NOAEL to dermal NAEL for systemic toxicity

To convert an oral NOAEL into a dermal NAEL, the differences in absorption between routes as well as differences in dermal absorption between rats and humans have to be accounted for. The dermal absorption of AS is relatively poor as can be expected from an ionic molecule (Wibbertman et al. (2011)). The percutaneous absorption of C12AS Na was reported to be < 1 %. Taking into account

that the data were achieved with AS of C12 chain length instead of C20-24 AS NH4 a default value of 10% was chosen for risk assessment. This default value is given in ECHAs Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (November, 2012). Thus, an absorption rate of 10 % after dermal application was used to correct the dermal NAEL for the differences in the absorption rate.

Corrected dermal NAEL = oral NOAEL x ABSoral-rat/ABSdermal

= oral NOAEL mg/kg bw/d x 100% / 10%

ABS: absorption

Thus, the corrected starting point for dermal route was 250 x 100 / 10 = 2500 mg/kg bw/d. DNEL derivation using the dermal NAEC. A factor of 2 for the differences in exposure duration was applied to extrapolate from the subchronic to the chronic situation. Further factors were applied according to ECHA guidance document R8 for remaining differences (2.5), allometric scaling (4), intraspecies differences (5) as well as a factor of 2 to cover uncertainties of the read-across. The dermal systemic DNEL is calculated to be 12.5 mg/kg bw/d. Short-term exposure scenarios will not be assessed. Only long-term DNELs for workers are considered to be relevant. The oral route is not relevant for workers. In addition it is assumed that only workers will come in contact with the neat substances. Within an Guinea Pig Maximisation Test according to OECD Guideline 406, 4/10 animals at the 24 h reading and 1/10 animals upon the 48 h reading showed skin reactions after challenge with 3% of the test item. Induction was performed with 1% test substance. Therefore this study represents a borderline result for classification as Skin sensitizing Category 1B (≥30%). It should be mentioned that the study size of 10 animals is low when assuming this borderline result and the fact that C20-24 AS NH4 showed irritating properties within the acute dermal toxicity study as skin irritation is a confounding factor when scoring skin reactions within a skin sensitization study. Although, alkyl sulfates are also not known for skin sensitising properties (Wibertmann, 2011), C20-24 AS NH4 is allocated to the moderate hazard band according to ECHAs Guidance on information requirements and chemical safety assessment Part E: Risk Characterisation (November, 2012). Therefore, local dermal effects need to be addressed via qualitative risk assessment and no local dermal DNELs will be derived. Therefore, also long-term systemic DNELs are not required but derived for the sake of completeness.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.2 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):

100

Modified dose descriptor starting point:

NOAEC

Value:

217.4 mg/m³

Explanation for the modification of the dose descriptor starting point:

Derived from lowest NOAEL oral.

AF for dose response relationship:

1

Justification:

Lowest NOAEL chosen for DNEL-derivation.

AF for differences in duration of exposure:

2

Justification:

Subchronic to chronic.

AF for interspecies differences (allometric scaling):

1

Justification:

Not required for inhalation route.

AF for other interspecies differences:

2.5

Justification:

According to ECHA Guidance document R8.

AF for intraspecies differences:

10

Justification:

According to ECHA Guidance document R8.

AF for the quality of the whole database:

1

Justification:

The quality of the repeated dose toxicity database is good.

AF for remaining uncertainties:

2

Justification:

To cover the uncertainty of the read-across.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6.25 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):

400

Modified dose descriptor starting point:

NOAEL

Value:

2 500 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Derived from lowest NOAEL oral.

AF for dose response relationship:

1

Justification:

Lowest NOAEL chosen for DNEL-derivation.

AF for differences in duration of exposure:

2

Justification:

Subchronic to chronic.

AF for interspecies differences (allometric scaling):

4

Justification:

According to ECHA Guidance document R8.

AF for other interspecies differences:

2.5

Justification:

According to ECHA Guidance document R8.

AF for intraspecies differences:

10

Justification:

According to ECHA Guidance document R8.

AF for the quality of the whole database:

1

Justification:

The quality of the repeated dose toxicity database is good.

AF for remaining uncertainties:

2

Justification:

To cover the uncertainty of the read-across.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.625 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):

400

Modified dose descriptor starting point:

NOAEL

Value:

250 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Not applicable.

AF for dose response relationship:

1

Justification:

Lowest NOAEL chosen for DNEL-derivation.

AF for differences in duration of exposure:

2

Justification:

Subchronic to chronic.

AF for interspecies differences (allometric scaling):

4

Justification:

According to ECHA Guidance document R8.

AF for other interspecies differences:

2.5

Justification:

According to ECHA Guidance document R8.

AF for intraspecies differences:

10

Justification:

According to ECHA Guidance document R8.

AF for the quality of the whole database:

1

Justification:

The quality of the repeated dose toxicity database is good.

AF for remaining uncertainties:

2

Justification:

To cover the uncertainty of the read-across.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

The available repeated dose toxicity studies of the read across substances administered via diet provide a coherent picture on the subchronic oral toxicity of alcohols, alkylsulfates and alkyl ethersulfates and the lowest NOAEL (250 mg/kg bw/d; Walker et al., 1967) was chosen for risk assessment. For a detailed discussion on the repeated dose toxicity studies please refer to the workers discussion. Since there is no dose descriptor for every exposure route, dose descriptors were converted into a correct starting point by route-to-route extrapolation based on the ECHA guidance document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health", November, 2012.

Conversion of oral NOAEL to inhalatory NAEC

As starting point the dietary NOAEL of 250 mg/kg bw/day (Walker, 1967) of the subchronic oral toxicity study was chosen for the risk assessment. The conversion of an oral NOAEL into an inhalatory NAEC is performed using the following equations:

Corrected inhalatory NAEC                     = oral NOAEL x 1/sRVrat x ABSoral-rat/ ABSinh-human

                                         = oral NOAEL mg/kg bw/d x 1/1.15m³/kg bw x 1

sRV: standard respiratory volume, ABS: absorption

Thus, the corrected starting point for inhalation route was 250 / 1.15 = 217.4 mg/ m³

DNEL derivation using the inhalatory NAEC

In the ECHA Guidance a factor of 2 is suggested for the extrapolation from oral to inhalation absorption. On the contrary, the Technical guidance document on risk assessment in support of Commission directive 93/67/EEC, 2003 appendix IV A and B gives a number of physico-chemical properties that normally determine oral, inhalation and dermal absorption. These parameters include molecular weight, log Kow, pKa values and for inhalation also particle size distribution, vapour pressure etc. Molecules with a molecular weight < 500 and a log Kow between 0 and 4 can be assumed to be well absorbed equivalently by the oral and inhalation route. Oral absorption may be reduced for acids and bases depending on their pKa value and their possibility of absorption in the gastrointestinal tract. More lipophilic substances may be better absorbed in the gastrointestinal tract due to the solubilisation with bile acids and thus oral absorption may be higher than inhalation absorption. C20-24 AS NH4 has a molecular weight of ≤ 400 g/mol and a log Kow of 2.11. In addition the substance is moderately soluble in water (approximately 236 mg/L). Therefore the molecule will be well absorbed after oral application. A good oral absorption of alkyl sulfates was also reported by Wibbertman et al. (2011). They reported 74-98% of an oral dose of C18AS Na to be excreted via the urine, indicating an almost complete absorption. Unless valid data suggest that inhalation leads to higher absorption than oral ingestion, equal absorption will be assumed when extrapolating from oral to inhalation route. Thus, the factor of 2 is considered to be not relevant for C20-24 AS NH4 when extrapolating from oral to inhalation route. A factor of 2 for the differences in exposure duration was applied to extrapolate from the subchronic to the chronic situation. Further factors were applied according to ECHA guidance document R8 for remaining differences (2.5) and intraspecies differences (10) as well as a factor of 2 to cover uncertainties of the read-across. The inhalatory DNEL is calculated to be 2.2 mg/m3.

Conversion of oral NOAEL to dermal NAEL for systemic toxicity

To convert an oral NOAEL into a dermal NAEL, the differences in absorption between routes as well as differences in dermal absorption between rats and humans have to be accounted for. The dermal absorption of AS is relatively poor as can be expected from an ionic molecule (Wibbertman et al. (2011)). The percutaneous absorption of C12AS Na was reported to be <1%. Taking into account that the data were achieved with AS of C12s instead of C20-24 AS NH4 a default value of 10% was chosen for risk assessment. This default value is given in ECHAs Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (November, 2012). Thus, an absorption rate of 10 % after dermal application was used to correct the dermal NAEL for the differences in the absorption rate.

Corrected dermal NAEL = oral NOAEL x ABSoral-rat/ABSdermal

                                         = oral NOAEL mg/kg bw/d x 100% / 10%

ABS: absorption

Thus, the corrected starting point for dermal route was 250 x 100 / 10 = 2500 mg/kg bw/d.

DNEL derivation using the dermal NAEC

A factor of 2 for the differences in exposure duration was applied to extrapolate from the subchronic to the chronic situation. Further factors were applied according to ECHA guidance document R8 for remaining differences (2.5), allometric scaling (4) and intraspecies differences (10) as well as a factor of 2 to cover uncertainties of the read-across. The dermal systemic DNEL is calculated to be 6.25 mg/kg bw/d.

DNEL derivation for oral route

A factor of 2 for the differences in exposure duration was applied to extrapolate from the subchronic to the chronic situation. Further factors were applied according to ECHA guidance document R8 for remaining differences (2.5), allometric scaling (4) and intraspecies differences (10) as well as a factor of 2 to cover uncertainties of the read-across. The oral systemic DNEL is calculated to be 0.625 mg/kg bw/d. The general population is not expected to come into contact with the neat substance as no direct consumer uses exist. Therefore short-term exposure scenarios will not be assessed. Only long-term systemic DNELs for general population are considered relevant.