Lithium dodecyl sulphate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

7.6 mg/m³

Most sensitive endpoint:

developmental toxicity / teratogenicity

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

Modified dose descriptor starting point:

NOAEC

Value:

22.92 mg/m³

Explanation for the modification of the dose descriptor starting point:

Route specific dose descriptor is not available.

AF for dose response relationship:

1

Justification:

NOAEL is chosen as starting point.

AF for differences in duration of exposure:

1

Justification:

No difference in duration

AF for interspecies differences (allometric scaling):

1

Justification:

Human data

AF for other interspecies differences:

1

Justification:

Human data

AF for intraspecies differences:

3

Justification:

The starting point was derived from the most sensitive sub-group of population for the endpoint of concern (pregnant women and their offspring). Therefore, an AF of 3 as recommended in ECETOC, Technical Report No. 110 is used for intraspecies differences.

AF for the quality of the whole database:

1

Justification:

4 different approaches were considered to derive the starting point. Each approach is very conservative in nature. Thus, a factor of 1 is expected to be sufficient.

AF for remaining uncertainties:

1

Justification:

All remaining uncertainties have been covered.

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:

433.3 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

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

Modified dose descriptor starting point:

NOAEL

Value:

1 300 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Adequate route specific dose descriptor is not available.

AF for dose response relationship:

1

Justification:

NOAEL is chosen as starting point.

AF for differences in duration of exposure:

1

Justification:

There is no difference in duration

AF for interspecies differences (allometric scaling):

1

Justification:

Human data

AF for other interspecies differences:

1

Justification:

Human data

AF for intraspecies differences:

3

Justification:

The starting point was derived from the most sensitive sub-group of population for the endpoint of concern (pregnant women and their offspring). Therefore, an AF of 3 as recommended in ECETOC, Technical Report No. 110 is used for intraspecies differences.

AF for the quality of the whole database:

1

Justification:

4 different approaches were considered to derive the starting point. Each approach is very conservative in nature. Thus, a factor of 1 is expected to be sufficient.

AF for remaining uncertainties:

1

Justification:

All remaining uncertainties have been covered.

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:

repeated dose toxicity

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - workers

The DNEL derivation of C12AS Li (CAS 2044-56-6) 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 lithium. In medicine, lithium is used for prophylaxis and treatment of major affective disorders. In-utero exposure to lithium during the first trimester of pregnancy has been reported to be probably associated with an increased risk of cardiac malformations, especially the rare Ebstein's anomaly. To cover these uncertainties a variety of data were assessed to derive a DNEL which also covers this possible teratogenicity of lithium.

Rat studies with lithium

In a chronic repeated dose toxicity study with lithium chloride a NOAEL of 13.9 mg Li/kg bw/d was obtained (Trautner, 1958; section: Repeated dose toxicity). Corrected for molecular weight (approximately 273 g/mol) this corresponds to an NOAEL of 547 mg/kg bw/d for C12AS Li. The NOAEL obtained for the alkyl sulfates is 488 mg/kg bw/d. Thus, the NOAEL of the alkyl sulfates also covers the repeated dose toxicity of lithium.

In a second approach data on reproductive toxicity achieved within the same publication were assessed (Trautner, 1958; section: Toxicity to reproduction).Rats were treated for various times before and during pregnancy with lithium chloride at 13.9 mg Li/kg bw/d. Within these experiments no malformations were observed. However, no detailed examinations for heart malformations were performed. In some of the experiments decreased corpora lutea counts and also decreased numbers of implantations and decreased numbers of viable fetuses were observed. However, pregnancy outcome of other experiments did not show effects on litters. Thus, this study revealed ambiguous results regarding the effects on litter size but gave no indication for a developmental toxicity. Thus, the dose level of 547 mg/kg bw/d achieved within the repeated dose toxicity study may include some uncertainties regarding the implantations. To consider these uncertainties, this dose level is deemed to be a LOAEL as worst case approach.

Human data of lithium

A second publication reported effects of lithium on pregnancy outcome in women (Jacobson, 1992; section: health surveillance data). Mean daily dose of lithium was 927 ± 340 mg. It is expected that this value is based on lithium carbonate (although not clearly stated within the report). Rates of major congenital malformations did not differ between lithium (2.8%) and control (2.4%) group. One heart anomaly within the lithium group was observed. This was found to be the Ebstein's anomaly. Nevertheless also in the control group one heart anomaly was observed. Therefore, there is no clear indication that lithium carbonate causes developmental/ teratogenic effects in humans. However, uncertainties remained with regard to the Ebstein´s anomaly. To cover this uncertainty the dose range was modified. The mean dose was 927 mg lithium carbonate/d. As lithium has a narrow therapeutically range it can be expected that even small increases in dose will have a great impact on effects on human health. When assuming a normal distribution of dose levels observed within the study, approximately 95% of the doses were within the range of mean ± 2xSD. Based on that assumption, 95% of the doses were in a range of 247 to 1607 mg/kg bw/d. Due to the narrow therapeutically range of lithium it was expected that the lower dose (247 mg lithium carbonate/d) will not yield in irresponsible risks for the unborn child. When assuming a 70 kg person and a molecular weight of 273 mg/kg bw for C12AS Li this results in a NAEL of 13.0 mg/kg bw/d. When using the mean dose of 927 mg lithium/d a NOAEL of 48.8 mg/kg bw/d is achieved for C12AS Li. Although no clear indication for teratogenicity was observed the dose of 48.8 mg/kg bw/d was considered to be the LOAEL as worst case approach.

In a last approach the recommended therapeutically doses were used to derive an effect level. The therapeutically dose of LiCO3 is 450 to 900 mg/d. This is equivalent to 85 to 170 mg lithium/d. Based on a molecular weight of 273 g/mol for C12AS Li this corresponds to 47 to 95 mg/kg bw/d (70 kg person). This dose is in general tolerated without serious side effects. However, this therapeutic dose level may raise concern of malformations. Thus, this value was established as LOAEL instead of NOAEL. In the tables below a comparison of key data/values for all approaches is given:

 

Table 1: NOAEL/LOAELs and DNELs resulting from Human data

Factor	LOAEL (mg/kg bw/d)		NAEL (mg/kg bw/d)	Remarks
	47.0*	48.8**	13.0**
Dose-response relationship	3	3	1	In cases where LOAELs were used, no clear adverse effect was observed. In addition the therapeutic dose level is well tolerated. Therefore a factor of 3 is expected to be sufficient in case a LOAEL was used.
Differences in duration	1	1	1	There is no difference in duration
Allometric scaling	1	1	1	Human data
Interspecies differences	1	1	1	Human data
Intraspecies differences	3	3	3	For workers (ECETOC, Technical Report No. 110)
Whole database	1	1	1	As there are 4 different approaches and each approach is calculated conservatively, a factor of 1 is expected to be sufficient.
Remaining uncertainties	1	1	1	All remaining uncertainties have been covered.
Overall AFs	9	9	3	-
DNEL	5.2	5.4	4.3	-

* Calculated from therapeutically dose level

** Derived from Jacobson (1992)

 

Table 1: LOAEL and DNEL resulting from animal study

	LOAEL (mg/kg bw/d)	Remarks
	547*
Dose-response relationship	3	No clear adverse effect was observed, but the dose was chosen as LOAEL. Therefore a factor of 3 is expected to be sufficient.
Differences in duration	1	There is no difference in duration
Allometric scaling	4	Species: rat
Interspecies differences	1	ECETOC, Technical Report No. 110
Intraspecies differences	3	For workers (ECETOC, Technical Report No. 110)
Whole database	1	As there are 4 different approaches and each approach is calculated conservatively, a factor of 1 is expected to be sufficient.
Remaining uncertainties	1	All remaining uncertainties have been covered.
Overall AFs	36	-
DNEL	15.2	-

* Derived from Trautner (1958)

 

The approach resulting in the lowest NOAEL (13.0 mg/kg bw/d) and DNEL (4.3 mg/kg bw/d) was chosen as suited approach for risk assessment.

 

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", May 2008. As starting point the therapeutical dose level 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 NAEL x 1/sRVratx ABSoral-rat/ ABSinh-humanx sRVhuman/wRV

                                            = oral NAEL 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 was 22.92 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 lithium 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 NAEL 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 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 NAEL = oral NOAEL x ABSoral-rat/ABSdermal

                                       = oral NOAEL x 100/1

 

ABS: absorption

Thus, the corrected starting point was 1300 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 3: DNEL derivation for workers
Route	inhalation	dermal	Remarks
Starting Point	22.9mg/m^3	1300 mg/kg bw/d
Dose-response relationship	1	1	NOAEL was chosen
Differences in duration	1	1	There is no difference in duration
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-group of population for the endpoint of concern (pregnant women and their offspring). Therefore, an AF of 3 as recommended in ECETOC, Technical Report No. 110 is used for intraspecies differences.
Whole database	1	1	4 different approaches were considered to derive the starting point. Each approach is very conservative in nature. Thus, a factor of 1 is expected to be sufficient.
Remaining uncertainties	1	1	All remaining uncertainties have been covered.
Overall AFs	3	3	-
DNEL	7.6 mg/m^3	433.3 mg/kg bw/d	-

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:

developmental toxicity / teratogenicity

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

Modified dose descriptor starting point:

NOAEC

Value:

11.3 mg/m³

Explanation for the modification of the dose descriptor starting point:

Route specific dose descriptor is not available.

AF for dose response relationship:

1

Justification:

NOAEL is chosen as starting point.

AF for differences in duration of exposure:

1

Justification:

There is no difference in duration

AF for interspecies differences (allometric scaling):

1

Justification:

Human data

AF for other interspecies differences:

1

Justification:

Human data

AF for intraspecies differences:

5

Justification:

The starting point was derived from the most sensitive sub-group of population for the endpoint of concern (pregnant women and their childs). Therefore, an AF of 5 as recommended in ECETOC, Technical Report No. 110 is used for intraspecies differences.

AF for the quality of the whole database:

1

Justification:

4 different approaches were considered to derive the starting point. Each approach is very conservative in nature. Thus, a factor of 1 is expected to be sufficient.

AF for remaining uncertainties:

1

Justification:

All remaining uncertainties have been covered.

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:

260 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

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

Modified dose descriptor starting point:

NOAEL

Value:

1 300 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Adequate route specific dose descriptor is not available.

AF for dose response relationship:

1

Justification:

NOAEL is chosen as starting point.

AF for differences in duration of exposure:

1

Justification:

There is no difference in duration

AF for interspecies differences (allometric scaling):

1

Justification:

Human data

AF for other interspecies differences:

1

Justification:

Human data

AF for intraspecies differences:

5

Justification:

The starting point was derived from the most sensitive sub-group of population for the endpoint of concern (pregnant women and their childs). Therefore, an AF of 5 as recommended in ECETOC, Technical Report No. 110 is used for intraspecies differences.

AF for the quality of the whole database:

1

Justification:

4 different approaches were considered to derive the starting point. Each approach is very conservative in nature. Thus, a factor of 1 is expected to be sufficient.

AF for remaining uncertainties:

1

Justification:

All remaining uncertainties have been covered.

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:

repeated dose toxicity

Acute/short term exposure

Hazard assessment conclusion:

medium 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:

2.6 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

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

Modified dose descriptor starting point:

NOAEL

Value:

13 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:

There is no difference in duration

AF for interspecies differences (allometric scaling):

1

Justification:

Human data

AF for other interspecies differences:

1

Justification:

Human data

AF for intraspecies differences:

5

Justification:

The starting point was derived from the most sensitive sub-group of population for the endpoint of concern (pregnant women and their childs). Therefore, an AF of 5 as recommended in ECETOC, Technical Report No. 110 is used for intraspecies differences.

AF for the quality of the whole database:

1

Justification:

4 different approaches were considered to derive the starting point. Each approach is very conservative in nature. Thus, a factor of 1 is expected to be sufficient.

AF for remaining uncertainties:

1

Justification:

All remaining uncertainties have been covered.

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:

high hazard (no threshold derived)

Additional information - General Population

As starting point a modified NAEL (13.0 mg/kg bw/d) of Jacobson (1992) was used. This theoretical NAEL results in the lowest DNELs. For a detailed discussion please refer to the discussion of workers.

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", May 2008. The conversion of an oral NAEL into an inhalatory NAEC is performed using the following equations:

 

Corrected inhalatory NAEC = oral NAEL x 1/sRVratx ABSoral-rat/ ABSinh-human

                                            = oral NAEL x 1/1.15 m³/kg bw x 1

 

sRV: standard respiratory volume, ABS: absorption

 

Thus, the corrected starting point was 11.3 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 lithium 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 NAEL 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 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 NAEL = oral NAEL x ABSoral-rat/ABSdermal

                                       = oral NAEL x 100/1

 

ABS: absorption

Thus, the corrected starting point was 1300 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 3:DNEL derivation for general population

Route	inhalation	dermal	oral	Remarks
Starting Point	11.3 mg/m3	1300 mg/kg bw/d	13 mg/kg bw/d
Dose-response relationship	1	1	1	NOAEL was chosen
Differences in duration	1	1	1	There is no difference in duration
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-group of population for the endpoint of concern (pregnant women and their childs). Therefore, an AF of 5 as recommended in ECETOC, Technical Report No. 110 is used for intraspecies differences.
Whole database	1	1	1	As there are 4 different approaches and each approach is conservative 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	2.26 mg/m^3	260 mg/kg bw/d	2.6 mg/kg bw/d	-