Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

7.6 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Dose descriptor starting point:

NOAEL

Value:

85 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

188.8 mg/m³

Explanation for the modification of the dose descriptor starting point:

The substance fulfils the REACH information requirements in accordance with ECHA guidance R7.5-7.7 (2016) for assessing long-term systemic toxicity. Since no repeated dose inhalation study is available, route-to-route extrapolation from the oral exposure route is performed. The starting point is the NOAEL from the 9-months oral study in rats; 85 mg/kg bw/day.

This oral rat NOAEL is converted to an inhalation NOAEC for rats by using a default respiratory volume for the rat corresponding to 8 hours (0.38 m³/kg bw/day). A factor for route-to-route extrapolation is included based on experimentally derived oral absorption (90%) and the default inhalation absorption values (R.7.12. June 2017). The resulting rat inhalation NOAEC is converted into inhalation worker NOAEC by correction for respiratory rate based on activity (6.7 m³for normal light activity versus 10 m³for worker activity) and by correction for 5 day exposure (7 days exposure per week in the study versus 5 days per week for workers): 85 * (1/0.38) * (90/100)* (6.7/10) * (7/5) = 188.8 mg/m³.

AF for dose response relationship:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose,…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEL, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

2

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. For a sub-chronic toxicity study, an assessment factor of 2 is to be applied, as a standard procedure.

AF for interspecies differences (allometric scaling):

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, as long as route-to-route extrapolation is not needed, allometric scaling should not be applied in cases where the dose unit (original or transformed) in experimental animal studies are expressed as concentrations (e.g. in mg/m³ air, ppm in diet, or mg/L in the drinking water) as these are assumed to be already scaled according to the allometric principle, since ventilation rate and food intake directly depend on the basal metabolic rate. In this case, route-to-route extrapolation is performed form an oral feeding study. The derived NOAEL is modified according to allometric principles to a NOAEC (mg/m³), therefore additional assessment factor for allometric scaling is not needed.

AF for other interspecies differences:

2.5

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, interspecies differences result from variation in the sensitivity of species due to differences in toxicokinetics and toxicodynamics. Some of the toxicokinetic differences can be explained by differences in body size (and related differences in basal metabolic rate). As no substance-specific data are available, the standard procedure for threshold effects is followed. As a default, an additional factor of 2.5 for interspecies differences (other than allometric scaling), i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part) is applied.

AF for intraspecies differences:

5

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, intraspecies differences in human result from a multitude of biological factors such as genetic polymorphism affecting e.g. toxicokinetics/metabolism, age, gender, health status and nutritional status. For workers, as standard procedure for threshold effects a default assessment factor of 5 is to be used, based on the fact that this sub population does not cover the very young, the very old, and the very ill.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

AF for remaining uncertainties:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, there are no remaining uncertainties. Since there are no further uncertainties, the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

119 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

NOAEL

Value:

85 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

11 900 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The substance fulfils the REACH information requirements in accordance with ECHA guidance R7.5-7.7 (2016) for assessing long-term systemic toxicity. Since no repeated dose dermal study is available, route-to-route extrapolation from the oral exposure route is performed. The starting point is the NOAEL from the 9-months oral study in rats; 85 mg/kg bw/day.

Based on data from a dermal absorption study of a C12LAS homologue in isolated human epidermis (Howes, 1975) that indicated < 0.065% of the applied dose penetrated the skin in 48 hours. An oral absorption value of 90% was experimentally derived. A route-to-route factor of 100, instead of 90/0.065=1384.6, was conservatively assumed. A correction for 5 day exposure is performed (7 days exposure per week in the study versus 5 days per week for workers): 85 * 100 * (7/5) = 11 900 mg/kg bw/day.

AF for dose response relationship:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose,…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEL, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

2

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. For a sub-chronic toxicity study, an assessment factor of 2 is to be applied, as a standard procedure.

AF for interspecies differences (allometric scaling):

4

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, differences in metabolic rate (allometric scaling) should be accounted for by extrapolation of doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight to the power of 0.75. This results in different default allometric scaling factors for the different animal species when compared with humans. For rats, the default assessment factor, as a standard procedure, is 4.

AF for other interspecies differences:

2.5

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, interspecies differences result from variation in the sensitivity of species due to differences in toxicokinetics and toxicodynamics. Some of the toxicokinetic differences can be explained by differences in body size (and related differences in basal metabolic rate). As no substance-specific data are available, the standard procedure for threshold effects is followed. As a default, an additional factor of 2.5 for interspecies differences (other than allometric scaling), i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part) is applied.

AF for intraspecies differences:

5

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, intraspecies differences in human result from a multitude of biological factors such as genetic polymorphism affecting e.g. toxicokinetics/metabolism, age, gender, health status and nutritional status. For workers, as standard procedure for threshold effects a default assessment factor of 5 is to be used, based on the fact that this sub population does not cover the very young, the very old, and the very ill.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

AF for remaining uncertainties:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, there are no remaining uncertainties. Since there are no further uncertainties, the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

low hazard (no threshold derived)

Hazard assessment conclusion:

medium hazard (no threshold derived)

Correction of dose descriptors if needed (for example route-to-route extrapolation), application of assessment factors and derivation of the endpoint specific DN(M)EL

LAS is manufactured from linear alkylbenzene (LAB) in self-contained, enclosed systems and is primarily used as a detergent surfactant. LAS is used in light-duty liquid dishwashing compounds, heavy-duty liquid and powder laundry detergents, all-purpose cleaners and industrial cleaners. Industrial cleaning professionals and consumers may be exposed to small amounts of LAS contained in these products.

The potential for employee exposure is limited and infrequent. The low vapor pressure of LAS and the controls used in its manufacture limit its emission to air. Any wastes or spills generated during manufacture are collected and incinerated or placed in landfills. Worker exposure is controlled through engineering controls and the use of personal protective equipment (PPE). No oral exposure from workers is expected from these uses. Though workers are required to use standard PPE, there is potential for dermal exposure. Since the LAS can also be used in detergents used by the public, DNELs will be derived for both the worker and consumer populations.

Given the above uses, and as recommended in Chapter R.8 of the REACH guidance documents, long-term DNELs were derived for workers potentially exposed through the dermal and inhalation routes of exposure. No DNEL for the oral route is required for workers due to the lack of exposure. As noted in R.8, “for most substances and exposure scenarios the DNEL_long-termwill be sufficient for controlling risks.” In addition, because LAS is used in consumer products, long-term DNELs for oral, dermal, and inhalation exposures for consumers are also calculated.

Overall, LAS shows relatively low toxicity, with an acute oral LD₅₀of 1080 mg/kg and no effects observed in acute dermal testing at 2000 mg/kg. Undiluted LAS is irritating to the skin and eyes and is classified under the CLP as category 2 and 1 irritants, respectively. LAS is not a skin sensitizer and is not mutagenic. Effects in long-term repeated dose studies lasting up to 9 months (subchronic studies) are related to enzymatic, body and organ weight reductions but not mortality. No significant reproductive or developmental effects were observed in long-term testing. The most appropriate NOAEL from the long-term oral repeated dose toxicity test (85 mg/kg based on decreases in enzymatic activity in the 145 mg/kg bw/d dose in the Yoneyama et al. 1976 study) is the value used as a starting point for deriving the DNEL_{long-term,
oral,}the DNEL_{long-term, dermal}, and the DNEL_{long-term,
inhalation}, as appropriate, for worker and consumer exposures. The NOAEL of 85 mg/kg is most appropriate because it is the highest NOAEL below the lowest LOAEL in long-term studies.

Selection of the critical DNEL(s)/DMELs and/or qualitative/semi-quantitative descriptor for critical health effects

For the human health endpoints, the most relevant/critical DNELs for LAS are considered to be the DNEL_long-termfor dermal and inhalation exposures in workers and for oral, dermal and inhalation exposures in consumers. In workers, these were calculated to be equivalent to 119 mg/kg and 7.6 mg/m³for dermal and inhalation, respectively. In consumers, these were calculated to be 0.425 mg/kg bw/d, 42.5 mg/kg bw/d and 1.3 mg/m³for oral, dermal and inhalation exposures, respectively.

Discussion

LAS is not considered to be significantly hazardous to human health under most conditions. Acute toxicity studies via the oral exposure route resulted in an LD₅₀of 1080 mg/kg, and a toxicity via the dermal exposure route resulted in no mortality at 2000 mg/kg. Significant irritation effects were observed in acute skin and eye irritation studies when tested with undiluted 100% doses. These effects were sufficient for classification as category 2 and 1 for skin and eye irritation, respectively, under the CLP criteria. When the undiluted dose was quickly rinsed, effects were still observed but were reversible within 7 to 14 days. Mortality was not observed in repeated dose studies; effects seen were reduced body weight gain, either reductions or increases in organ weights, and enzymatic activity effects. No significant effects were observed in a reproductive toxicity study at the highest dose tested (350 mg/kg bw/d). Effects in two developmental studies were only observed at doses that were maternally toxic.

In addition, mutagenicity studies using both in vitro and in vivo methods demonstrate that LAS was not mutagenic.

The DNEL derivation focuses on the long-term exposure to workers via both the dermal and inhalation routes and the long-term exposure to consumers via the oral, dermal, and inhalation routes. The NOAEL used to derive the DNELs was the highest NOAEL below the lowest LOAEL from the repeated dose toxicity subchronic test with rats exposed orally in the drinking water for 9 months. The resulting DNEL_long-termvalues for dermal and inhalation exposures to workers were 119 mg/kg bw/d and 7.6 mg/m³, respectively.The resulting DNEL_long-termvalues for oral, dermal and inhalation exposures to consumers were 0.425 mg/kg bw/d, 42.5 mg/kg/d and 1.3 mg/m³.

LAS is classified as a category 4 oral toxicant, a category 2 skin irritant, and a category 1 eye irritant under the CLP regulation. It does not meet the criteria for classification as a PBT or vPvB.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.3 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor starting point:

NOAEL

Value:

85 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

66.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

The substance fulfils the REACH information requirements in accordance with ECHA guidance R7.5-7.7 (2016) for assessing long-term systemic toxicity. Since no repeated dose inhalation study is available, route-to-route extrapolation from the oral exposure route is performed. The starting point is the NOAEL from the 9-months oral study in rats; 85 mg/kg bw/day.

This oral rat NOAEL is converted to an inhalation NOAEC for rats by using a default respiratory volume for the rat corresponding to 24 hours (1.15 m³/kg bw/day). A factor for route-to-route extrapolation is included based on experimentally derived oral absorption (90%) and the default inhalation absorption values (R.7.12. June 2017): 85 * (1/1.15) * (90/100) = 66.5 mg/m³.

AF for dose response relationship:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEL, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

2

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. For a sub-chronic toxicity study, an assessment factor of 2 is to be applied, as a standard procedure.

AF for interspecies differences (allometric scaling):

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, as long as route-to-route extrapolation is not needed, allometric scaling should not be applied in cases where the dose unit (original or transformed) in experimental animal studies are expressed as concentrations (e.g. in mg/m³ air, ppm in diet, or mg/L in the drinking water) as these are assumed to be already scaled according to the allometric principle, since ventilation rate and food intake directly depend on the basal metabolic rate. In this case, route-to-route extrapolation is performed form an oral feeding study. The derived NOAEL is modified according to allometric principles to a NOAEC (mg/m³), therefore additional assessment factor for allometric scaling is not needed.

AF for other interspecies differences:

2.5

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, interspecies differences result from variation in the sensitivity of species due to differences in toxicokinetics and toxicodynamics. Some of the toxicokinetic differences can be explained by differences in body size (and related differences in basal metabolic rate). As no substance-specific data are available, the standard procedure for threshold effects is followed. As a default, an additional factor of 2.5 for interspecies differences (other than allometric scaling), i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part) is applied.

AF for intraspecies differences:

10

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, intraspecies differences in human result from a multitude of biological factors such as genetic polymorphism affecting e.g. toxicokinetics/metabolism, age, gender, health status and nutritional status. For consumers, as standard procedure for threshold effects a default assessment factor of 10 is to be used, based on the fact that the all sub-populations are covered in this population: the very young, the very old, and the very ill.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

AF for remaining uncertainties:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, there are no remaining uncertainties. Since there are no further uncertainties, the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

42.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

85 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

8 500 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The substance fulfils the REACH information requirements in accordance with ECHA guidance R7.5-7.7 (2016) for assessing long-term systemic toxicity. Since no repeated dose dermal study is available, route-to-route extrapolation from the oral exposure route is performed. The starting point is the NOAEL from the 9-months oral study in rats; 85 mg/kg bw/day.

Based on data from a dermal absorption study of a C12LAS homologue in isolated human epidermis (Howes, 1975) that indicated < 0.065% of the applied dose penetrated the skin in 48 hours. An oral absorption value of 90% was experimentally derived. A route-to-route factor of 100, instead of 90/0.065=1384.6, was conservatively assumed: 85 * 100 = 8 500 mg/kg bw/day.

AF for dose response relationship:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEL, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

2

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. For a sub-chronic toxicity study, an assessment factor of 2 is to be applied, as a standard procedure.

AF for interspecies differences (allometric scaling):

4

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, differences in metabolic rate (allometric scaling) should be accounted for by extrapolation of doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight to the power of 0.75. This results in different default allometric scaling factors for the different animal species when compared with humans. For rats, the default assessment factor, as a standard procedure, is 4.

AF for other interspecies differences:

2.5

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, interspecies differences result from variation in the sensitivity of species due to differences in toxicokinetics and toxicodynamics. Some of the toxicokinetic differences can be explained by differences in body size (and related differences in basal metabolic rate). As no substance-specific data are available, the standard procedure for threshold effects is followed. As a default, an additional factor of 2.5 for interspecies differences (other than allometric scaling), i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part) is applied.

AF for intraspecies differences:

10

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, intraspecies differences in human result from a multitude of biological factors such as genetic polymorphism affecting e.g. toxicokinetics/metabolism, age, gender, health status and nutritional status. For consumers, as standard procedure for threshold effects a default assessment factor of 10 is to be used, based on the fact that the all sub-populations are covered in this population: the very young, the very old, and the very ill.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

AF for remaining uncertainties:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, there are no remaining uncertainties. Since there are no further uncertainties, the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

low hazard (no threshold derived)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.425 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

85 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The substance fulfils the REACH information requirements in accordance with ECHA guidance R7.5-7.7 (2016) for assessing long-term systemic toxicity. The starting point is the NOAEL from the 9-months oral study in rats; 85 mg/kg bw/day.

AF for dose response relationship:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEL, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

2

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. For a sub-chronic toxicity study, an assessment factor of 2 is to be applied, as a standard procedure.

AF for interspecies differences (allometric scaling):

4

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, differences in metabolic rate (allometric scaling) should be accounted for by extrapolation of doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight to the power of 0.75. This results in different default allometric scaling factors for the different animal species when compared with humans. For rats, the default assessment factor, as a standard procedure, is 4.

AF for other interspecies differences:

2.5

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, interspecies differences result from variation in the sensitivity of species due to differences in toxicokinetics and toxicodynamics. Some of the toxicokinetic differences can be explained by differences in body size (and related differences in basal metabolic rate). As no substance-specific data are available, the standard procedure for threshold effects is followed. As a default, an additional factor of 2.5 for interspecies differences (other than allometric scaling), i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part) is applied.

AF for intraspecies differences:

10

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, intraspecies differences in human result from a multitude of biological factors such as genetic polymorphism affecting e.g. toxicokinetics/metabolism, age, gender, health status and nutritional status. For consumers, as standard procedure for threshold effects a default assessment factor of 10 is to be used, based on the fact that the all sub-populations are covered in this population: the very young, the very old, and the very ill.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

AF for remaining uncertainties:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, there are no remaining uncertainties. Since there are no further uncertainties, the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

medium hazard (no threshold derived)

Correction of dose descriptors if needed (for example route-to-route extrapolation), application of assessment factors and derivation of the endpoint specific DN(M)EL

LAS is manufactured from linear alkylbenzene (LAB) in self-contained, enclosed systems and is primarily used as a detergent surfactant. LAS is used in light-duty liquid dishwashing compounds, heavy-duty liquid and powder laundry detergents, all-purpose cleaners and industrial cleaners. Industrial cleaning professionals and consumers may be exposed to small amounts of LAS contained in these products.

The potential for employee exposure is limited and infrequent. The low vapor pressure of LAS and the controls used in its manufacture limit its emission to air. Any wastes or spills generated during manufacture are collected and incinerated or placed in landfills. Worker exposure is controlled through engineering controls and the use of personal protective equipment (PPE). No oral exposure from workers is expected from these uses. Though workers are required to use standard PPE, there is potential for dermal exposure. Since the LAS can also be used in detergents used by the public, DNELs will be derived for both the worker and consumer populations.

Given the above uses, and as recommended in Chapter R.8 of the REACH guidance documents, long-term DNELs were derived for workers potentially exposed through the dermal and inhalation routes of exposure. No DNEL for the oral route is required for workers due to the lack of exposure. As noted in R.8, “for most substances and exposure scenarios the DNEL_long-termwill be sufficient for controlling risks.” In addition, because LAS is used in consumer products, long-term DNELs for oral, dermal, and inhalation exposures for consumers are also calculated.

Overall, LAS shows relatively low toxicity, with an acute oral LD₅₀of 1080 mg/kg and no effects observed in acute dermal testing at 2000 mg/kg. Undiluted LAS is irritating to the skin and eyes and is classified under the CLP as category 2 and 1 irritants, respectively. LAS is not a skin sensitizer and is not mutagenic. Effects in long-term repeated dose studies lasting up to 9 months (subchronic studies) are related to enzymatic, body and organ weight reductions but not mortality. No significant reproductive or developmental effects were observed in long-term testing. The most appropriate NOAEL from the long-term oral repeated dose toxicity test (85 mg/kg based on decreases in enzymatic activity in the 145 mg/kg bw/d dose in the Yoneyama et al. 1976 study) is the value used as a starting point for deriving the DNEL_{long-term,
oral,}the DNEL_{long-term, dermal}, and the DNEL_{long-term,
inhalation}, as appropriate, for worker and consumer exposures. The NOAEL of 85 mg/kg is most appropriate because it is the highest NOAEL below the lowest LOAEL in long-term studies.

Selection of the critical DNEL(s)/DMELs and/or qualitative/semi-quantitative descriptor for critical health effects

For the human health endpoints, the most relevant/critical DNELs for LAS are considered to be the DNEL_long-termfor dermal and inhalation exposures in workers and for oral, dermal and inhalation exposures in consumers. In workers, these were calculated to be equivalent to 119 mg/kg and 7.6 mg/m³for dermal and inhalation, respectively. In consumers, these were calculated to be 0.425 mg/kg bw/d, 42.5 mg/kg bw/d and 1.3 mg/m³for oral, dermal and inhalation exposures, respectively.

Discussion

LAS is not considered to be significantly hazardous to human health under most conditions. Acute toxicity studies via the oral exposure route resulted in an LD₅₀of 1080 mg/kg, and a toxicity via the dermal exposure route resulted in no mortality at 2000 mg/kg. Significant irritation effects were observed in acute skin and eye irritation studies when tested with undiluted 100% doses. These effects were sufficient for classification as category 2 and 1 for skin and eye irritation, respectively, under the CLP criteria. When the undiluted dose was quickly rinsed, effects were still observed but were reversible within 7 to 14 days. Mortality was not observed in repeated dose studies; effects seen were reduced body weight gain, either reductions or increases in organ weights, and enzymatic activity effects. No significant effects were observed in a reproductive toxicity study at the highest dose tested (350 mg/kg bw/d). Effects in two developmental studies were only observed at doses that were maternally toxic.

In addition, mutagenicity studies using both in vitro and in vivo methods demonstrate that LAS was not mutagenic.

The DNEL derivation focuses on the long-term exposure to workers via both the dermal and inhalation routes and the long-term exposure to consumers via the oral, dermal, and inhalation routes. The NOAEL used to derive the DNELs was the highest NOAEL below the lowest LOAEL from the repeated dose toxicity subchronic test with rats exposed orally in the drinking water for 9 months. The resulting DNEL_long-termvalues for dermal and inhalation exposures to workers were 119 mg/kg bw/d and 7.6 mg/m³, respectively. The resulting DNEL_long-termvalues for oral, dermal and inhalation exposures to consumers were 0.425 mg/kg bw/d, 42.5 mg/kg/d and 1.3 mg/m³.

LAS is classified as a category 4 oral toxicant, a category 2 skin irritant, and a category 1 eye irritant under the CLP regulation. It does not meet the criteria for classification as a PBT or vPvB.