Linalyl acetate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.75 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

75

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

236.2 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

Overall assessment factor (AF):

10

Dose descriptor:

other: NESIL

Value:

23 620 mg/m³

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

236.2 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

Overall assessment factor (AF):

10

Dose descriptor starting point:

other: NESIL

Value:

23 620 mg/m³

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - workers

For linalyl acetate, no suitable animal data adressing systemic toxicity after repeated exposure are available. Since linalyl acetate is expected to be hydrolysed to its metabolite linalool, repeated dose studies on linalool were included via read-across (see read across justification document). Furthermore, comparable toxicity profiles were noted for linalool and dehydrolinalool (CAS 29171 -20 -8) in acute toxicity studies and repeated dose studies, leading to alpha-2u-globulin nephropathy, metabolic enzyme induction in the liver, hypersalivation and sedation / ataxia after repeated application. Therefore the available repeated dose studies on dehydrolinalool were adopted to support the hazard assessment of linalyl acetate by read-across.

For the derivation of DNELs for systemic effects after long term exposure, the oral subacute 28 day repeated dose study in rats using linalool (HLA642-460), and the subchronic 90 day repeated dose dermal study in rats using linalool (T&O 79-201) were chosen.

The NOAEL of the 28 day gavage study was chosen as point of departure for derivation of the inhalative long term systemic DNEL by route to route extrapolation. On the basis of the present toxicokinetic data, linalool is rapidly and completely absorbed in rats after oral administration (Parke 1974), supporting the assumption, that 100% bioavailablilty after oral adoministration can be considered.

For the worker, the following DNELs were derived:

The NOAEL of the subacute oral study was set at 117 mg/kg bw/d linalool for males and females. For derivation of the inhalative DNEL, the oral NOAEL was converted into a corrected inhalative NOAEC of 206 mg/m3 according to the procedure, recommended in the current guidance document (R8, ECHA 2008).

NOAEC_{inhal corrected}= 117*(1/0.38)*(100/100)*(6.7/10) = 206 mg/m3

Additionally an assessment factor (AF) of 75 (R8 ECHA 2008: allometric scaling = 1; remaining differences = 2.5; intraspezies = 5; exposure duration = 6 (subacute to chronic); dose-response = 1; quality of whole database = 1: AF = 1 x 2.5 x 5 x 6 x 1 x 1 = 75) was calculated. Consequently, the inhalative long-term systemic DNEL derived was 2.75 mg/m3 for the worker.

For derivation of the systemic dermal DNEL, the NOAEL of the subchronic 90 day dermal study (250 mg/kg bw/d) was chosen as the point of departure and an assessment factor (AF) of 100 was applied (R8 ECHA2008: allometric scaling = 4; remaining differences = 2.5; intraspezies = 5; exposure duration = 2 (subchronic to chronic); dose-response = 1; quality of whole database = 1: AF = 4 x 2.5 x 5 x 2 x 1 x 1 = 100) was calculated. Consequently, the dermal long-term systemic DNEL derived was 2.5 mg/kg bw/d for the worker.

To assess the DNEL for local effects after long term dermal exposure, data for skin sensitization were considered. Quantitiative information on the threshold for skin sensitization in animals can be derived from the present LLNAs (weighed EC3 value of 9.5%* or 2375 µg/cm²; Sköld 2005, RCC 2002, BASF 2017) and can be confirmed by a state-of-the-art human repeated insult patch test (HRL 2017). The HRIPT available represents a well performed study, in which 99 subjects (24 males, 75 females) received 9 applications of 0.3 ml aliquot of 2% (2362 μg/cm²) Linalylacetate in 3:1 DEP: EtOH for 24 hours in 3 successive weeks. Approximately 2 weeks after the last induction application, a 24 h challenge application with 2% (2362 μg/cm²) Linalylacetate in 3:1 DEP: EtOH was made to a naive site. When reactions to challenge were read 24 h, 48 h, 72 h and 96 h post patching, no skin sensitizing effects were observed.

Overall, the weighed mean induction threshold concentration based on the LLNAs (2375 µg/cm²) does not lead to skin sensitization in humans as confirmed in the HRIPT with a concentration of 2362 μg/cm² tested. Therefore, a human specific lower potency of Linalylacetate induced skin sensitization compared to the murine test is not to evident, thus, the use of an additional interspecies assessment factor is not applicable. Furthermore, based on the ECHA guidance document (R8 p.23) no extrapolation and no assessment factor is necessary for interspecies differences in sensitivity, where human data are used as the starting point for risk characterization. It is recognized, that a general DNEL must take into account a variation of the threshold for skin sensitization between individuals. This may be due to differences in parameters such as genetic effects, sensitive subpopulations, inherent barrier function, age, gender, and ethnicity (Api et al., 2008). Whereas the latter three are recognized to have some effect on the sensitization threshold, it is generally recognized that genetic differences, the inherent barrier function and especially sensitive subpopulations play a major role (Api et al., 2008). The barrier function of the skin may be compromised which in turn may lead to a greater susceptibility of the individual. At the same time the barrier function is thought to be very similar from infancy to adulthood. The influence of the genetic setting is not well understood, however, may be plausible in the light of the immunological effect under consideration. The term sensitive subpopulations refers mostly to individuals who have previously been sensitized to other substances which may increase the susceptibility to further sensitizers (Api et al., 2006, Api et al., 2008). Overall, an assessment factor of 10 for intraspecies differences is applied to adequately address the combined influence of these effects. The underlying data are based on repeated dermal application of Linalylacetate and the read out covers both, skin irritation and skin sensitization properties at the given concentration. The relevant parameters, i. e. induction of skin irritation and skin sensitization, are considered to depend on threshold concentrations and not on exposure duration. Therefore no assessment factor concerning exposure duration is deemed necessary for the derivation of the long term local dermal DNEL. The concept of threshold concentrations for the induction of these effects is generally well accepted (see e.g. Api et al. 2006 or Api et al. 2008). Furthermore, the ECHA guidance document does not indicate at all, that an assessment factor for exposure duration needs to be taken into account for the derivation of a DNEL for skin sensitization.

Therefore, a DNEL for skin sensitization was set at 236.2 µg/cm2/day based on the confirmed no expected sensitization induction level (NESIL) in a HRIPT (2362 µg/cm2) and an assessment factor of 10 for intraspecies differences. The derived DNEL on the basis of skin sensitization is considered sufficiently conservative to ensure the absence of skin irritation after short or long term exposure. Using this DNEL allows for a quantitative risk characterization for both hazards, i.e. skin irritation and skin sensitization.

Furthermore, Linalyl acetate is to be classified as eye irritant (category 2) according to 1272/2008/EEC. Since no quantitative data addressing the hazard of eye irritation are available, a respective no effect concentration cannot be derived and included in the derivation of the short term/long term local dermal DNEL. However, a qualitative risk characterisation including the implementation of suitable risk management measures is performed in the CSR, when handled undiluted or at higher concentrations during manufacturing, compounding or formulation.

No DNELs were derived for local effects after short term or after long term inhalative exposure and no DNELs were also derived for systemic effects after short term dermal or inhalative exposure, as the substance exhibits no hazardous potential in terms of these endpoints.

• Api AM, Basketter DA, Cadby PA, Cano M-F, Graham E, Gerberick F, Griem P, McNamee P, Ryan CA, Safford B (2006). Dermal Sensitization Quantitative Risk Assessment (QRA) for fragrance ingredients. Technical dossier. March 15, 2006 (revised May 2006).
• Api AM, Basketter, DA, Cadby PA, Cano M-F, Ellis G, Gerberick GF, Griem P, McNamee PM, Ryan CA, Safford R (2008). Dermal sensitization quantitative risk assessment (QRA) for fragrance ingredients. Reg Toxicol Pharmacol 52: 3-23.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.68 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

150

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.25 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

200

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

236.2 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

Overall assessment factor (AF):

10

Dose descriptor:

other: NESIL

Value:

23 620 mg/m³

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

236.2 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

Overall assessment factor (AF):

10

Dose descriptor starting point:

other: NESIL

Value:

23 620 mg/m³

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.2 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

600

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - General Population

For linalyl acetate, no suitable animal data adressing systemic toxicity after repeated exposure are available. Since linalyl acetate is expected to be hydrolysed to its metabolite linalool, repeated dose studies on linalool were included via read-across (see read across justification document). Furthermore, comparable toxicity profiles were noted for linalool and dehydrolinalool (CAS 29171 -20 -8) in acute toxicity studies and repeated dose studies, leading to alpha-2u-globulin nephropathy, metabolic enzyme induction in the liver, hypersalivation and sedation / ataxia after repeated application. Therefore the available repeated dose studies on dehydrolinalool were adopted to support the hazard assessment of linalyl acetate by read-across.

For the derivation of DNELs for systemic effects after long term exposure, the oral subacute 28 day repeated dose study in rats using linalool (HLA642-460), and the subchronic 90 day repeated dose dermal study in rats using linalool (T&O 79-201) were chosen.

The NOAEL of the 28 day gavage study was chosen as point of departure for derivation of the inhalative long term systemic DNEL by route to route extrapolation. On the basis of the present toxicokinetic data, linalool is rapidly and completely absorbed in rats after oral administration (Parke 1974), supporting the assumption, that 100% bioavailablilty after oral adoministration can be considered.

For the consumer, the following DNELs were derived:

The NOAEL of the subacute oral study was set at 117 mg/kg bw/d linalool for males and females.

For an oral long term systemic DNEL, an assessment factor (AF) of 600 (R8, ECHA 2008: allometric scaling = 4; remaining differences = 2.5; intraspezies = 10; exposure duration = 6 (subacute to chronic); dose-response = 1; quality of whole database = 1: AF = 4 x 2.5 x 10 x 6 x 1 x 1 = 600) was calculated. Consequently, the oral long-term systemic DNEL derived was 0.195 mg/kg bw/d for the consumer.

For derivation of the inhalative DNEL, the oral NOAEL was converted into a corrected inhalative NOAEC of 101.7 mg/m3 according to the procedure, recommended in the current guidance document (R8, ECHA 2008).

NOAEC_{inhal corrected}= 117*(1/1.15)*(100/100)= 101.7 mg/m3

Additionally an assessment factor (AF) of 150 (R8, ECHA 2008: allometric scaling = 1; remaining differences = 2.5; intraspezies = 10; exposure duration = 6 (subacute to chronic); dose-response = 1; quality of whole database = 1: AF = 1 x 2.5 x 10 x 6 x 1 x 1 = 150) was calculated. Consequently, the inhalative long-term systemic DNEL derived was 0.68 mg/m3 for the consumer.

For derivation of the systemic dermal DNEL, the NOAEL from the subchronic 90 day dermal study (250 mg/kg bw/d) was chosenas the point of departure and an assessment factors (AF) of 200 was applied (R8 ECHA 2008: allometric scaling = 4; remaining differences = 2.5; intraspezies = 10; exposure duration = 2 (subchronic to chronic); dose-response = 1; quality of whole database = 1: AF = 4 x 2.5 x 5 x 2 x 1 x 1 = 200) was calculated. Consequently, the dermal long-term systemic DNEL derived was 1.25 mg/kg bw/d for the consumer.

To assess the DNEL for local effects after long term dermal exposure, data for skin sensitization were considered. Quantitiative information on the threshold for skin sensitization in animals can be derived from the present LLNAs (weighed EC3 value of 9.5%* or 2375 µg/cm²; Sköld 2005, RCC 2002, BASF 2017) and can be confirmed by a state-of-the-art human repeated insult patch test (HRL 2017). The HRIPT available represents a well performed study, in which 99 subjects (24 males, 75 females) received 9 applications of 0.3 ml aliquot of 2% (2362 μg/cm²) Linalylacetate in 3:1 DEP: EtOH for 24 hours in 3 successive weeks. Approximately 2 weeks after the last induction application, a 24 h challenge application with 2% (2362 μg/cm²) Linalylacetate in 3:1 DEP: EtOH was made to a naive site. When reactions to challenge were read 24 h, 48 h, 72 h and 96 h post patching, no skin sensitizing effects were observed.

Overall, the weighed mean induction threshold concentration based on the LLNAs (2375 µg/cm²) does not lead to skin sensitization in humans as confirmed in the HRIPT with a concentration of 2362 μg/cm² tested. Therefore, a human specific lower potency of Linalylacetate induced skin sensitization compared to the murine test is not to evident, thus, the use of an additional interspecies assessment factor is not applicable. Furthermore, based on the ECHA guidance document (R8 p.23) no extrapolation and no assessment factor is necessary for interspecies differences in sensitivity, where human data are used as the starting point for risk characterization. It is recognized, that a general DNEL must take into account a variation of the threshold for skin sensitization between individuals. This may be due to differences in parameters such as genetic effects, sensitive subpopulations, inherent barrier function, age, gender, and ethnicity (Api et al., 2008). Whereas the latter three are recognized to have some effect on the sensitization threshold, it is generally recognized that genetic differences, the inherent barrier function and especially sensitive subpopulations play a major role (Api et al., 2008). The barrier function of the skin may be compromised which in turn may lead to a greater susceptibility of the individual. At the same time the barrier function is thought to be very similar from infancy to adulthood. The influence of the genetic setting is not well understood, however, may be plausible in the light of the immunological effect under consideration. The term sensitive subpopulations refers mostly to individuals who have previously been sensitized to other substances which may increase the susceptibility to further sensitizers (Api et al., 2006, Api et al., 2008). Overall, an assessment factor of 10 for intraspecies differences is applied to adequately address the combined influence of these effects. The underlying data are based on repeated dermal application of Linalylacetate and the read out covers both, skin irritation and skin sensitization properties at the given concentration. The relevant parameters, i. e. induction of skin irritation and skin sensitization, are considered to depend on threshold concentrations and not on exposure duration. Therefore no assessment factor concerning exposure duration is deemed necessary for the derivation of the long term local dermal DNEL. The concept of threshold concentrations for the induction of these effects is generally well accepted (see e.g. Api et al. 2006 or Api et al. 2008). Furthermore, the ECHA guidance document does not indicate at all, that an assessment factor for exposure duration needs to be taken into account for the derivation of a DNEL for skin sensitization.

Therefore, a DNEL for skin sensitization was set at 236.2 µg/cm2/day based on the confirmed no expected sensitization induction level (NESIL) in a HRIPT (2362 µg/cm2) and an assessment factor of 10 for intraspecies differences. The derived DNEL on the basis of skin sensitization is considered sufficiently conservative to ensure the absence of skin irritation after short or long term exposure. Using this DNEL allows for a quantitative risk characterization for both hazards, i.e. skin irritation and skin sensitization.

No DNELs were derived for local effects after short term or after long term inhalative exposure and no DNELs were also derived for systemic effects after short term dermal or inhalative exposure, as the substance exhibits no hazardous potential in terms of these endpoints.

• Api AM, Basketter DA, Cadby PA, Cano M-F, Graham E, Gerberick F, Griem P, McNamee P, Ryan CA, Safford B (2006). Dermal Sensitization Quantitative Risk Assessment (QRA) for fragrance ingredients. Technical dossier. March 15, 2006 (revised May 2006).
• Api AM, Basketter, DA, Cadby PA, Cano M-F, Ellis G, Gerberick GF, Griem P, McNamee PM, Ryan CA, Safford R (2008). Dermal sensitization quantitative risk assessment (QRA) for fragrance ingredients. Reg Toxicol Pharmacol 52: 3-23.