Zinc dodecyl hydrogen disulphate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

17.6 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: Guidance on Assessment Factors to Derive a DNEL (ECETOC, Technical Report No. 110)

Overall assessment factor (AF):

3

Dose descriptor starting point:

NOAEL

Value:

7.55 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

52.9 mg/m³

Explanation for the modification of the dose descriptor starting point:

To correct the route-to-route extrapolation from an oral NOAEL in humans to an inhalative NOAEC in humans the no observed effect level has to be corrected as follows:

Corrected starting point for the inhalative route for workers:

= NOAEL(oral) * (1/sRVhuman) * (ABSoral-human/ABSinh-human) * sRVhuman/wRV

= 7.55 mg/kg bw/day * (1/(6.7 m³/person / 70 kg)) * (100%/100%) * 6.7 m³ (8h) /10 m³ (8h)

= 7.55 mg/kg bw/day * (1/0.096 m³/kg bw/day) * 1 * 0.67 m³ = 52.9 mg/m³

Based on the toxicokinetic data, it can be assumed that the systemic bioavailability will be high both after oral and inhalation exposure.

(sRV = standard respiratory volum, ABSinh-human = inhalation absorption rate in humans, wRV = worker respiratory volume)

Thus, the corrected starting point for workers was 52.9mg/m³ for inhalation.

AF for dose response relationship:

1

Justification:

NOAEL is chosen as starting point.

AF for differences in duration of exposure:

1

Justification:

chronic data in humans

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route.

AF for other interspecies differences:

1

Justification:

Human data was used.

AF for intraspecies differences:

3

Justification:

Factor for alkyl sulfates based on ECETOC, Technical Report No. 110. Please refer to the discussion.

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

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:

252 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: Guidance on Assessment Factors to Derive a DNEL (ECETOC, Technical Report No. 110)

Overall assessment factor (AF):

3

Dose descriptor starting point:

NOAEL

Value:

7.55 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

755 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Dermal NOAEL = oral NOAEL*ABS(oral)/ABS(dermal) = 7.55 mg/kg bw/day *(100/1) = 755 mg/kg bw/day. It is assumed that oral absorption is 100% whereas a dermal absorption rate of 1% is considered as shown in the toxikokinetic data.

AF for dose response relationship:

1

Justification:

NOAEL is chosen as starting point.

AF for differences in duration of exposure:

1

Justification:

chronic data from human studies

AF for interspecies differences (allometric scaling):

1

Justification:

human data was used

AF for other interspecies differences:

1

Justification:

Factor for alkyl sulfates based on ECETOC, Technical Report No. 110. Please refer to the discussion.

AF for intraspecies differences:

3

Justification:

Factor for alkyl sulfates based on ECETOC, Technical Report No. 110. Please refer to the discussion.

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:

low hazard (no threshold derived)

Most sensitive endpoint:

repeated dose toxicity

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

The DNEL derivation of C12-14AS Zn (CAS n.a.) is a modified version of the DNEL derivation of the other alkyl sulfates of the AS category. This modification was necessary due to possible human health effects of the counter ion zinc. Being an essential element, zinc plays an important role in many processes in the body. Although zinc deficiency can lead to notable health effects, the risk assessment for an essential element like zinc does not concern deficiencies but excess in exposure over natural background levels. The most relevant effects were observed in repeated dose toxicity studies. These effects were evaluated in latest in an OECD HPV report of a zinc category [1]. “In repeated dose toxicity studies with rats and mice, oral zinc exposure resulted in copper deficiency and pathological changes in the pancreas and the spleen as the most sensitive effects, with a NOAEL of 13.3 mg Zn²⁺/kg bw/day. In studies with human volunteers, women appeared to be more sensitive than men to the effects of repeated zinc supplementation. In women, supplementation at a level of 150 mg Zn²⁺/day (2.5 mg/kg bw/day, based on a body weight of 60 kg; LOAEL) resulted in clinical signs such as headache, nausea and gastric discomfort, and in indications for disturbance of copper homeostasis. The NOAEL in women supplemented with zinc was 50 mg Zn²⁺/day (0.83 mg/kg bw/day).”

To cover these uncertainties this low NOAEL for Zn²⁺was used to derive a DNEL which also covers these possible effects of zinc. Recalculating the effect levels to C12-14AS Zn in respect to the molecular weight (MW C12-14AS Zn = 595 g/mol and MW Zn = 65.39 g/mol) leads to the following effect levels for C12-14AS Zn:

NOAEL (human) = 7.55 mg/kg bw/day.

Route to route extrapolation: oral to inhalation

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. As starting point the most sensitive NOAEL found in woman was chosen for the risk assessment.

The conversion of an oral NOAEL into an inhalatory NOAEC 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 NOAEC = oral NOAEL x 1/sRVhuman x ABSoral-human/ ABSinh-human x sRVhuman/wRV

                                            = oral NOAEL x 1/0.096m³/kg bw x 1 x 6.7 m³/10 m³

 

sRV: standard respiratory volume (6.7 m³/person, standard body weight human = 70 kg, this leads to 0.096 m³/kg bw), ABS: absorption, wRV: worker respiratory volume

 

Thus, the corrected starting point was 52.9 mg/m³.

 

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. As the absorption rate of zinc and alkyl sulfates via the oral route is almost complete no factor was used for absorption differences.

 

Route to route extrapolation: oral to dermal

To convert an oral NOAEL into a dermal NOAEL, the differences in absorption between routes have to be accounted for.

The dermal absorption of AS is relatively poor as can be expected from an anionic molecule which tends to bind to the skin surface (HERA, 2002; Howes, 1975; Black & Howes, 1980). Experimental animal data with14C-labelled C12AS Na in guinea pigs showed that 0.35% of the applied dose of 3 µmol was absorbed (Prottey & Ferguson, 1975). Therefore including a default assumption of 1% for all modelled exposures will display a sufficient conservative approach.

 

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

                                       = oral NOAEL x 100/1

 

ABS: absorption

Thus, the corrected starting point was 755 mg/kg bw/d.

 

In addition it is assumed that only workers will come in contact with the neat substances. Due to the known irritating potential of undiluted AS it is common to use personal protective equipment like gloves to avoid dermal contact therewith considering local DNELs as obsolete.

 

Table 1: DNEL derivation for workers:
route	inhalation	dermal	Remarks
Starting point	52.9 mg/m³	755 mg/kg bw/day
Dose-response relationship	1	1	The NOAEL was used
Difference in duration	1	1	No differences
Allometric scaling	1	1	Human data
Interspecies differences	1	1	Human data
Intraspecies differences	3	3	The starting point was derived from the most sensitive sub-population for the endpoint of concern (women). Therefore, an AF of 3 as recommended in ECETOC, technical report 110 is used as intraspecies difference.
Whole database	1	1	As zinc was evaluated in an OECD HPV program, a factor of 1 is expected to be sufficient.
Remaining uncertainties	1	1	All remaining uncertainties have been covered.
Overall AFs	3	3	-
DNEL	17.6	252	-

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.3 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: Guidance on Assessment Factors to Derive a DNEL (ECETOC, Technical Report No. 110)

Overall assessment factor (AF):

5

Dose descriptor starting point:

NOAEL

Value:

7.55 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

26.4 mg/m³

Explanation for the modification of the dose descriptor starting point:

To correct the route-to-route extrapolation from an oral NOAEL in humans to an inhalative NOAEC in humas the no observed effect level has to be corrected as follows:

Corrected starting point for the inhalative route for general population:

= NOAEL(oral) * (1/sRVhuman) * (ABSoral-human/ABSinh-human)

= 7.55 mg/kg bw/day * (1/(20 m³/person / 70 kg)) * (100%/100%)

= 7.55 mg/kg bw/day * (1/0.29 m³/kg bw/day) * 1 = 26.4 mg/m³

Based on the toxicokinetic data, it can be assumed that the systemic bioavailability will be high both after oral and inhalation exposure.

(sRV = standard respiratory volum, ABSinh-human = inhalation absorption rate in humans, wRV = worker respiratory volume)

Thus, the corrected starting point for workers was 26.4mg/m³ for inhalation.

AF for dose response relationship:

1

Justification:

NOAEL is chosen as starting point.

AF for differences in duration of exposure:

1

Justification:

chronic data from human studies were used

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route.

AF for other interspecies differences:

1

Justification:

Factor for alkyl sulfates based on ECETOC, Technical Report No. 110. Please refer to the discussion.

AF for intraspecies differences:

5

Justification:

Factor for alkyl sulfates based on ECETOC, Technical Report No. 110. Please refer to the discussion.

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

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:

151 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: Guidance on Assessment Factors to Derive a DNEL (ECETOC, Technical Report No. 110)

Overall assessment factor (AF):

5

Dose descriptor starting point:

NOAEL

Value:

7.55 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

755 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Dermal NOAEL = oral NOAEL*ABS(oral)/ABS(dermal) = 7.55 mg/kg bw/day *(100/1) = 755 mg/kg bw/day. It is assumed that oral absorption is 100% whereas a dermal absorption rate of 1% is considered as shown in the toxikokinetic data.

AF for dose response relationship:

1

Justification:

NOAEL is chosen as starting point.

AF for differences in duration of exposure:

1

Justification:

chronic data from human studies

AF for interspecies differences (allometric scaling):

1

Justification:

Species: human

AF for other interspecies differences:

1

Justification:

Factor for alkyl sulfates based on ECETOC, Technical Report No. 110. Please refer to the discussion.

AF for intraspecies differences:

5

Justification:

Factor for alkyl sulfates based on ECETOC, Technical Report No. 110. Please refer to the discussion.

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:

low hazard (no threshold derived)

Most sensitive endpoint:

repeated dose toxicity

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.51 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: Guidance on Assessment Factors to Derive a DNEL (ECETOC, Technical Report No. 110)

Overall assessment factor (AF):

5

Dose descriptor starting point:

NOAEL

Value:

7.55 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

not applicable

AF for dose response relationship:

1

Justification:

NOAEL is chosen as starting point.

AF for differences in duration of exposure:

1

Justification:

chronic data from human studies

AF for interspecies differences (allometric scaling):

1

Justification:

Species: human

AF for other interspecies differences:

1

Justification:

Factor for alkyl sulfates based on ECETOC, Technical Report No. 110. Please refer to the discussion.

AF for intraspecies differences:

5

Justification:

Factor for alkyl sulfates based on ECETOC, Technical Report No. 110. Please refer to the discussion.

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

acute toxicity

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

As starting point a modified NOAEL of Zn (0.83 mg/kg bw/day) as found in the OECD HPV report [1] was used which was recalculated to C12-14AS Zn. The modified NOAEL of C12-14AS Zn is 7.55 mg/kg bw/day.

Route to route extrapolation: oral to inhalation

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. The conversion of an oral NOAEL into an inhalatory NOAEC is performed using the following equations:

 

Corrected inhalatory NOAEC = oral NOAEL x 1/sRVhuman x ABSoral-human/ ABSinh-human

                                            = 7.55 mg/kg bw/day x (1/(20 m³/person/ 70 kg)) x (100%/100%)

                                        

sRV: standard respiratory volume, ABS: absorption

 

Thus, the corrected starting point was 26.4 mg/m³.

 

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. As the absorption rate of zinc and alkyl sulfates via the oral route is almost complete no factor was used for absorption differences.

 

Route to route extrapolation: oral to dermal

To convert an oral NOAEL into a dermal NOAEL, the differences in absorption between routes have to be accounted for.

The dermal absorption of AS is relatively poor as can be expected from an anionic molecule which tends to bind to the skin surface (HERA, 2002; Howes, 1975; Black & Howes, 1980). Experimental animal data with14C-labelled C12AS Na in guinea pigs showed that 0.35% of the applied dose of 3 µmol was absorbed (Prottey & Ferguson, 1975). Therefore including a default assumption of 1% for all modelled exposures will display a sufficient conservative approach.

 

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

                                       = oral NOAEL x 100/1

 

ABS: absorption

Thus, the corrected starting point was 755 mg/kg bw/d.

 

In addition it is assumed that only workers will come in contact with the neat substances. Due to the known irritating potential of undiluted AS it is common to use personal protective equipment like gloves to avoid dermal contact therewith considering local DNELs as obsolete.

Table 2: DNEL derivation for general population:
route	inhalation	dermal	oral	Remarks
Starting point	26.4 mg/m³	755 mg/kg bw/day	7.55 mg/kg bw/day
Dose-response relationship	1	1	1	The NOAEL was used
Difference in duration	1	1	1	No differences
Allometric scaling	1	1	1	Human data
Interspecies differences	1	1	1	Human data
Intraspecies differences	5	5	5	The starting point was derived from the most sensitive sub-population for the endpoint of concern (women). Therefore, an AF of 5 as recommended in ECETOC, technical report 110 is used as intraspecies difference.
Whole database	1	1	1	As zinc was evaluated in an OECD HPV program, a factor of 1 is expected to be sufficient.
Remaining uncertainties	1	1	1	All remaining uncertainties have been covered.
Overall AFs	5	5	5	-
DNEL	5.3	151	1.51	-