Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

11.14 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

Overall assessment factor (AF):

25

Dose descriptor starting point:

NOAEL

Value:

316 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

278.6 mg/m³

Explanation for the modification of the dose descriptor starting point:

See additional information.

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:

3.16 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

Overall assessment factor (AF):

100

Dose descriptor starting point:

NOAEL

Value:

316 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

316 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

See additional information.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

190 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

Overall assessment factor (AF):

10

Hazard assessment conclusion:

low hazard (no threshold derived)

Hazard assessment conclusion:

low hazard (no threshold derived)

Selection of the relevant dose descriptor (starting point):

The available key study for repeated dose toxicity, i.e. an oral (feeding) subchronic repeated dose toxicity study in rats, has been identified as suitable basis for the derivation of the systemic DNELs of Tetrahydrolinalool (OECD TG 408, GLP, BASF 2019; 50C0267/10C194).

In this study, decreased body weight changes, shortened prothrombin time, changed energy metabolism and alpha-2u-globulinuria were observed at a dose level of 15000 ppm (982 mg/kg bw/d males, 1118 mg/kg bw/d females), i.e. the highest dose tested. Thus, the oral administration of Tetrahydrolinalool via diet over a period of 3 months revealed adverse effects and the no observed adverse effect level (NOAEL) was 5000 ppm in males (316 mg/kg bw/d) and females (384 mg/kg bw/d). In the EOGRTS available (OECD TG 443, GLP, BASF 2022; 91R0267/10S213), NOAELs for systemic toxicty of the parental F0 and offspring F1 generation (4000 ppm resulting in mean doses of 278/ ~340 mg/kg bw/d in F0/F1 males and 345/ ~360 mg/kg bw/d in F0/F1 females) as well as the NOAEL for developmental toxicity (4000 ppm resulting in 431 mg/kg bw/d) were comparable to the NOAELs derived in the subchronic repeated dose toxicity study. No effects on fertility was observed up to the highest dose tested. In a developmental toxicity study in rabbits (acc. to OECD 414,GLP), the NOAEL derived for maternal toxicity was determined at 150 mg/kg bw/d based on clinical toxic signs (incl. mortality), decreased body weights and food consumption at 500 mg/kg bw/d (BASF 2022; 40R0267/10R214). No evidence for toxicologically relevant adverse effects on the offspring (especially fetal morphology) was observed in this study.

Thus the NOAEL for males (316 mg/kg bw/d) from the subchronic repeated dose toxicity study was used as a suitable point of departure for the derivation of the respective DNELs, covering also maternal and offspring effects observed in the EOGRTS.

Additionally, pregnancy-specific DNELs are derived, using the maternal NOAEL determined in the rabbit teratogenicity study, to compare if this point of departure results in lower/more conservative DNELs.

Route to route extrapolation:

No valid experimental data on absorption of Tetrahydrolinalool are available. However, for the structurally related Linalool, a rapid and complete uptake in rats after oral administration was described. Considering molecular weight and Po/w of tetrahydrolinalool, a certain rate of dermal penetration is to be expected, however, this uptake is assumed to be significantly lower than via the oral route. On the basis of the low vapour pressure, the exposure with tetrahydrolinalool via inhalation as a vapour is low. According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information to include a default factor in the case of inhalation-to-oral extrapolation, assuming 50% oral and 100% inhalation absorption. Based on the absence of experimental data for the dermal penetration of Tetrahydrolinalool, a default factor of 1 for oral-to-dermal extrapolation is used for the DNEL derivation, assuming a comparable oral and dermal absorption as a worst case.

Workers – Hazard via inhalation route

Long term, systemic inhalation DNEL

For derivation of the long-term systemic inhalative DNEL for Tetrahydrolinalool, the oral systemic no adverse effect level of the subchronic repeated dose toxicity study (316 mg/kg bw/d) was taken as a basis and converted into a corrected inhalative NOAEC of 278.6 mg/m3 according to the procedure, recommended in the current guidance document (R8, ECHA 2008). Applying all assessment factors, the inhalative long-term systemic DNEL was set at 11.14 mg/m3 for the worker.

Long-term – inhalation, systemic effects

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 316 mg/kg bw/day	Subchronic repeated dose toxicity study in rats, oral (OECD 408)
Step 2) Modification of starting point	50%/100% 0.38 m³/kg bw 6.7 m³/10 m³	Ratio of oral (rat) to inhalation (human) absorption (default value, as proposed in the REACH guidance (R.8.4.2) Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance (R.8.4.2) Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m³/10 m³).
Modified dose-descriptor	NOAEC corrected inhalative = 316 * (50/100) * (1/0.38) * (6.7/10) = 278.6 mg/m³
Step 3) Assessment factors
Allometric scaling	1	No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation according to R8 ECHA 2008.
Remaining differences	2.5	according to R8 ECHA 2008
Intraspecies	5	according to R8 ECHA 2008
Exposure duration	2	Use of a subchronic study as starting point for a long-term systemic DNEL derivation (default assessment factor according to R8 ECHA 2008)
Dose response	1	according to R8 ECHA 2008
Quality of database	1	according to R8 ECHA 2008 (GLP guideline Study)
DNEL	Value
	278.6 / (1 x 2.5 x 5 x 2 x 1 x 1) = 11.14 mg/m³

For comparison, the pregnancy-specific long-term systemic inhalative DNEL based on the rabbit teratogenicity study is higher (i.e. 33.5 mg/m³) demonstrating, that the derived DNEL is sufficiently conservative to cover potential effects during pregnancy.

The starting point for DNEL calculations for pregnant individuals is derived from a study in rabbits, the standard respiratory volume of rabbits of 1440 L/day^# was used. Using average rabbit body weights of 4 kg^# (acceptable for pregnant and non-pregnant animals and comparable to body weights of study animals used), a standard respiratory volume for rabbits of 0.12 m³/kg bw/8 hours was determined for route-to-route extrapolation:

NOAEC corrected inhalative = 150 * (50/100) * (1/0.12) * (6.7/10) = 418.8 mg/m³

DNEL = 418.8 / (1^a x 2.5^a x 5^a x 1^b x 1^a x 1^a) = 33.5 mg/m³

^aAllometry, remaining differences, intraspecies variation, dose response, quality of database according to R8 ECHA 2012

^bSince the complete pregnancy was covered in the study, an assessment factor for exposure duration of 1 is acceptable.

Acute/short term, systemic and acute/short term and long term, local inhalation DNEL

The substance Tetrahydrolinalool is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral and dermal toxicity. Thus, no DNEL for systemic effects after acute inhalation exposure is required. Furthermore, the DNEL derived for systemic effects after long term inhalation exposure is considered sufficiently conservative to cover potential acute systemic and general local inhalation effects.

Workers - Hazard via dermal route

Long term, systemic dermal DNEL

For derivation of the long-term systemic dermal DNEL for Tetrahydrolinalool, the oral systemic no adverse effect level of the subchronic repeated dose toxicity study (316 mg/kg bw/d) was taken as a basis (= corrected dermal NOAEL) according to the procedure, recommended in the current guidance document (R8, ECHA 2008). This point of departure is supported by the dermal systemic effects of the structurally similar substance Linalool, i.e. decreases in body weights, occurring at and above limit dose only, in a subchronic dermal repeated dose toxicity study in rats.

Applying all assessment factors, the dermal long-term systemic DNEL derived was 3.16 mg/kg bw/d for the worker.

Long-term – dermal, systemic effects

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 316 mg/kg bw/day	Subchronic repeated dose toxicity study in rats, oral (OECD 408)
Step 2) Modification of starting point	Oral absorption rat = 100% Dermal absorption human = 100%	Absence of experimental data for dermal penetration of tetrahydrolinalool according to R8 ECHA 2008
Modified Dose descriptor Step 3) Assessment factors	NOAEL: 316 mg/kg bw/day	NOAEL corrected dermal = 316 * (100/100) = 316 mg/kg bw/d
Allometric scaling	4	Assessment factor for allometric scaling according to R8 ECHA 2008
Remaining differences	2.5	according to R8 ECHA 2008
Intraspecies	5	according to R8 ECHA 2008
Exposure duration	2	Use of a subchronic study as starting point for long-term systemic DNEL derivation (default assessment factor according to R8 ECHA 2008)
Dose response	1	according to R8 ECHA 2008
Quality of database	1	according to R8 ECHA 2008
DNEL	Value
	316 / (4 x 2.5 x 5 x 2 x 1 x 1) = 3.16 mg/kg bw/day

For comparison, the pregnancy-specific long-term systemic dermal DNEL based on the rabbit teratogenicity study is higher (i.e 6.00 mg/kg bw/d), demonstrating, that the derived DNEL is sufficiently conservative to cover potential effects during pregnancy.

NOAEL corrected dermal = 150 * (100/100) = 150 mg/kg bw/d

DNEL = 150 / (2^b x 2.5^a x 5^a x 1^c x 1^a x 1^a) = 6.00 mg/kg bw/d

^aRemaining differences, intraspecies variation, dose response, quality of database according to R8 ECHA 2012

^b4 kg^# rabbit bw was applied and acceptable for pregnant and non-pregnant animals and comparable to body weights of study animals used. Allometric scaling factor was calculated for rabbits based on R8 ECHA 2012: AS factor = (bw human/bw animal)^0.25 = (70 kg /4 kg)^0.25 = 2

^cSince the complete pregnancy was covered in the study, an assessment factor for exposure duration of 1 is acceptable.

Acute/short-term systemic dermal DNEL

The substance Tetrahydrolinalool is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral and dermal toxicity. Thus, no DNEL for sytemic effects after acute dermal exposure is required. Furthermore, the DNEL derived for systemic effects after long term dermal exposure is considered sufficiently conservative to cover potential acute systemic dermal effects.

Acute/short-term and Long term local dermal DNEL

To assess the DNEL for local effects after long term dermal exposure, data for skin sensitization were considered.

In the chosen key study, i.e. a murine LLNA according to OECD TG 429 and GLP, (BASF SE;58V0267/10A539), an EC3 for 3H-thymidine incorporation was determined to be 7.6%. According to the ECHA guidance document R8, this EC3 is converted as follows:

EC3 [μg/cm2] = EC3 [%]*250 [μg/cm2/% ] = 7.6 * 250 = 1900 µg/cm2

Furthermore, human data for Tetrahydrolinalool need to be taken into account, such as a human maximization test conducted on 32 healthy volunteers, showing no dermal effects at a concentration of 4 % (2760 µg/cm2) tetrahydrolinalool (Epstein 1976) and a human repeated patch test using concentrations up to 0.5%, showing any skin findings in 46 patients (Takenaka 1986).

The human data available for Tetrahydrolinalool, i.e. HRIPT, indicate the absences of a skin sensitization potential at a concentration above the EC3 (µg/cm2) determined in the murine LLNA determined (2760 µg/cm2 versus 1900 µg/cm2, respectively). Since no evident species specific differences in potencies in terms of a higher human susceptibility are indicated between the murine test and human subjects, the use of an additional interspecies assessment factor is not plausible. Although the human data are considered reliable, the point of departure for the local long term dermal DNEL is based on the murine LLNA EC3 as a conservative approach, due to limitations in study design of the available HRIPT, such as the number of participants.

It is recognized that a general DNEL must take into account that the threshold for skin sensitization varies 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 tetrahydrolinalool 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; Dermal Sensitization Quantitative Risk Assessment (QRA) for fragrance ingredients - Technical dossier or Api et al. 2008; Reg Toxicol Pharmacol 52: 3-23). 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 190 µg/cm2/day. 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.

· 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.

· ECETOC (2003). Contact Sensitization: classification according to potency. Technical Report No. 87, April 2003.

· Escher S, Batke M, Hoffmann-Doerr S, Messinger H, Mangelsdorf I (2013). Interspecies extrapolation based on the RepDose database—A probabilistic approach.Toxicology Letters 218: 159– 165

Worker - Hazard for the eyes

Tetrahydrolinalool 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 a no effect level for eye irritation. However, a qualitative risk characterization including the implementation of suitable risk management measures is performed in the CSR.

^#International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline Impurities: Guideline For Residual Solvents. (2011).

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.75 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

Overall assessment factor (AF):

50

Dose descriptor starting point:

NOAEL

Value:

316 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

137.4 mg/m³

Explanation for the modification of the dose descriptor starting point:

See additional information.

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:

1.58 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

316 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

316 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

See additional information.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

190 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

Overall assessment factor (AF):

10

Hazard assessment conclusion:

low hazard (no threshold derived)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.58 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

316 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

316 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

See additional information.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

low hazard (no threshold derived)

Selection of the relevant dose descriptor (starting point):

The available key study for repeated dose toxicity, i.e. an oral (feeding) subchronic repeated dose toxicity study in rats, has been identified as suitable basis for the derivation of the systemic DNELs of Tetrahydrolinalool (OECD TG 408, GLP, BASF 2019; 50C0267/10C194).

In this study, decreased body weight changes, shortened prothrombin time, changed energy metabolism and alpha-2u-globulinuria were observed at a dose level of 15000 ppm (982 mg/kg bw/d males, 1118 mg/kg bw/d females), i.e. the highest dose tested. Thus, the oral administration of Tetrahydrolinalool via diet over a period of 3 months revealed adverse effects and the no observed adverse effect level (NOAEL) was 5000 ppm in males (316 mg/kg bw/d) and females (384 mg/kg bw/d). In the EOGRTS available (OECD TG 443, GLP, BASF 2022; 91R0267/10S213), NOAELs for systemic toxicty of the parental F0 and offspring F1 generation (4000 ppm resulting in mean doses of 278/ ~340 mg/kg bw/d in F0/F1 males and 345/ ~360 mg/kg bw/d in F0/F1 females) as well as the NOAEL for developmental toxicity (4000 ppm resulting in 431 mg/kg bw/d) were comparable to the NOAELs derived in the subchronic repeated dose toxicity study. No effects on fertility was observed up to the highest dose tested. In a developmental toxicity study in rabbits (acc. to OECD 414,GLP), the NOAEL derived for maternal toxicity was determined at 150 mg/kg bw/d based on clinical toxic signs (incl. mortality), decreased body weights and food consumption at 500 mg/kg bw/d (BASF 2022; 40R0267/10R214). No evidence for toxicologically relevant adverse effects on the offspring (especially fetal morphology) was observed in this study.

Thus the NOAEL for males (316 mg/kg bw/d) from the subchronic repeated dose toxicity study was used as a suitable point of departure for the derivation of the respective DNELs, covering also maternal and offspring effects observed in the EOGRTS.

Additionally, pregnancy-specific DNELs are derived, using the maternal NOAEL determined in the rabbit teratogenicity study, to compare if this point of departure results in lower/more conservative DNELs.

Route to route extrapolation:

No valid experimental data on absorption of Tetrahydrolinalool are available. However, for the structurally related Linalool, a rapid and complete uptake in rats after oral administration was described. Considering molecular weight and Po/w of Tetrahydrolinalool, a certain rate of dermal penetration is to be expected, however, this uptake is assumed to be significantly lower than via the oral route. On the basis of the low vapour pressure, the exposure with Tetrahydrolinalool via inhalation as a vapour is low. According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information to include a default factor in the case of inhalation-to-oral extrapolation, assuming 50% oral and 100% inhalation absorption. Based on the absence of experimental data for the dermal penetration of Tetrahydrolinalool, a default factor of 1 for oral-to-dermal extrapolation is used for the DNEL derivation, assuming a comparable oral and dermal absorption as a worst case.

General population – Hazard via inhalation route

Long term, systemic inhalation DNEL

For derivation of the long-term systemic inhalative DNEL for Tetrahydrolinalool, the oral systemic no adverse effect level of the subchronic repeated dose toxicity study (316 mg/kg bw/d) was taken as a basis and converted into a corrected inhalative NOAEC of 137.4 mg/m3 according to the procedure, recommended in the current guidance document (R8, ECHA 2008). Applying all assessment factors, the inhalative long-term systemic DNEL was set at 2.75 mg/m3 for the general population.

Long-term – inhalation, systemic effects

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 316 mg/kg bw/day	Subchronic repeated dose toxicity study in rats, oral (OECD 408)
Step 2) Modification of starting point	50%/100% 1.15 m³/kg bw	Ratio of oral (rat) to inhalation (human) absorption (default value, as proposed in the REACH guidance (R.8.4.2) Standard respiratory volume of a rat, corrected for 24 h exposure, as proposed in the REACH Guidance (R.8.4.2)
Modified dose-descriptor	NOEC corrected inhalative = 316 * (50/100) * (1/1.15) = 137.4 mg/m³
Step 3) Assessment factors
Allometric scaling	1	No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation according to R8 ECHA 2008.
Remaining differences	2.5	according to R8 ECHA 2008
Intraspecies	10	according to R8 ECHA 2008
Exposure duration	2	Use of a subchronic study as starting point for long-term systemic DNEL derivation (default assessment factor according to R8 ECHA 2008)
Dose response	1	according to R8 ECHA 2008
Quality of database	1	according to R8 ECHA 2008 (GLP guideline Study)
DNEL	Value
	137.4 / (1 x 2.5 x 10 x 2 x 1 x 1) = 2.75 mg/m³

For comparison, the pregnancy-specific long-term systemic inhalative DNEL based on the rabbit teratogenicity study is higher (i.e. 8.33 mg/m³), demonstrating, that the derived DNEL is sufficiently conservative to cover potential effects during pregnancy.

The starting point for DNEL calculations for pregnant individuals is derived from a study in rabbits, the standard respiratory volume of rabbits of 1440 L/day^# was used. Using average rabbit body weights of 4 kg^# (acceptable for pregnant and non-pregnant animals and comparable to body weights of study animals used), a standard respiratory volume for rabbits of 0.36 m³/kg bw/8 hours was determined for route-to-route extrapolation:

NOAEC corrected inhalative = 150 * (50/100) * (1/0.36) = 208.3 mg/m³

DNEL = 208.3 / (1^a x 2.5^a x 10^a x 1^b x 1^a x 1^a) = 8.33 mg/m³

^aAllometry, remaining differences, intraspecies variation, dose response, quality of database according to R8 ECHA 2012

^bSince the complete pregnancy was covered in the study, an assessment factor for exposure duration of 1 is acceptable.

Acute/short term, systemic and acute/short term and long term, local inhalation DNEL

The substance Tetrahydrolinalool is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral and dermal toxicity. Thus, no DNEL for systemic effects after acute inhalation exposure is required. Furthermore, the DNEL derived for systemic effects after long term inhalation exposure is considered sufficiently conservative to cover potential acute systemic and general local inhalation effects.

General population - Hazard via dermal route

Long term, systemic dermal DNEL

For derivation of the long-term systemic dermal DNEL for Tetrahydrolinalool, the oral systemic no adverse effect level of the subchronic repeated dose toxicity study (316 mg/kg bw/d) was taken as a basis (= corrected dermal NOAEL) according to the procedure, recommended in the current guidance document (R8, ECHA 2008). This point of departure is supported by the dermal systemic effects of the structurally similar substance Linalool, i.e. decreases in body weights, occurring at and above limit dose only, in a subchronic dermal repeated dose toxicity study in rats.

Applying all assessment factors, the dermal long-term systemic DNEL derived was 1.58 mg/kg bw/d for the general population.

Long-term – dermal, systemic effects

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 316 mg/kg bw/day	Subchronic repeated dose toxicity study in rats, oral (OECD 408)
Step 2) Modification of starting point	Oral absorption rat = 100% Dermal absorption human = 100%	Absence of experimental data for dermal penetration of tetrahydrolinalool according to R8 ECHA 2008
Modified dose descriptor Step 3) Assessment factors	NOAEL: 316 mg/kg bw/day	NOAEL corrected dermal = 316 * (100/100) = 316 mg/kg bw/d
Allometric scaling	4	Assessment factor for allometric scaling according to R8 ECHA 2008
Remaining differences	2.5	according to R8 ECHA 2008
Intraspecies	10	according to R8 ECHA 2008
Exposure duration	2	Use of a subchronic study as starting point for long-term systemic DNEL derivation (default assessment factor according to R8 ECHA 2008)
Dose response	1	according to R8 ECHA 2008
Quality of database	1	according to R8 ECHA 2008 (GLP guideline Study)
DNEL	Value
	316 / (4 x 2.5 x 10 x 2 x 1 x 1) = 1.58 mg/kg bw/day

For comparison, the pregnancy-specific long-term systemic dermal DNEL based on the rabbit teratogenicity study is higher (i.e. 3.00 mg/kg bw/d), demonstrating, that the derived DNEL is sufficiently conservative to cover potential effects during pregnancy.

NOAEL corrected dermal = 150 * (100/100) = 150 mg/kg bw/d

DNEL = 150 / (2^b x 2.5^a x 10^a x 1^c x 1^a x 1^a) = 3.00 mg/kg bw/d

^aRemaining differences, intraspecies variation, dose response, quality of database according to R8 ECHA 2012

^b4 kg^# rabbit bw was applied and acceptable for pregnant and non-pregnant animals and comparable to body weights of study animals used. Allometric scaling factor was calculated for rabbits based on R8 ECHA 2012: AS factor = (bw human/bw animal)^0.25 = (70 kg /4 kg)^0.25 = 2

^cSince the complete pregnancy was covered in the study, an assessment factor for exposure duration of 1 is acceptable.

Acute/short-term systemic dermal DNEL

The substance Tetrahydrolinalool is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral and dermal toxicity. Thus, no DNEL for sytemic effects after acute dermal exposure is required. Furthermore, the DNEL derived for systemic effects after long term dermal exposure is considered sufficiently conservative to cover potential acute systemic dermal effects.

Acute/short-term and Long term local dermal DNEL

To assess the DNEL for local effects after long term dermal exposure, data for skin sensitization were considered.

In the chosen key study, i.e. a murine LLNA according to OECD TG 429 and GLP, (BASF SE;58V0267/10A539), an EC3 for 3H-thymidine incorporation was determined to be 7.6%. According to the ECHA guidance document R8, this EC3 is converted as follows:

EC3 [μg/cm2] = EC3 [%]*250 [μg/cm2/% ] = 7.6 * 250 = 1900 µg/cm2

Furthermore, human data for Tetrahydrolinalool need to be taken into account, such as a human maximization test conducted on 32 healthy volunteers, showing no dermal effects at a concentration of 4 % (2760 µg/cm2) tetrahydrolinalool (Epstein 1976) and a human repeated patch test using concentrations up to 0.5%, showing any skin findings in 46 patients (Takenaka 1986).

The human data available for tetrahydrolinalool, i.e. HRIPT, indicate the absences of a skin sensitization potential at a concentration above the EC3 (µg/cm2) determined in the murine LLNA determined (2760 µg/cm2 versus 1900 µg/cm2, respectively). Since no evident species specific differences in potencies in terms of a higher human susceptibility are indicated between the murine test and human subjects, the use of an additional interspecies assessment factor is not plausible. Although the human data are considered reliable, the point of departure for the local long term dermal DNEL is based on the murine LLNA EC3 as a conservative approach, due to limitations in study design of the available HRIPT, such as the number of participants.

It is recognized that a general DNEL must take into account that the threshold for skin sensitization varies 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 tetrahydrolinalool 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; Dermal Sensitization Quantitative Risk Assessment (QRA) for fragrance ingredients - Technical dossier or Api et al. 2008; Reg Toxicol Pharmacol 52: 3-23). 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 190 µg/cm2/day. 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.

· 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.

· ECETOC (2003). Contact Sensitization: classification according to potency. Technical Report No. 87, April 2003.

· Escher S, Batke M, Hoffmann-Doerr S, Messinger H, Mangelsdorf I (2013). Interspecies extrapolation based on the RepDose database—A probabilistic approach.Toxicology Letters 218: 159– 165

General population - Hazard via oral route

Long term, systemic oral DNEL

For derivation of the long-term systemic oral DNEL of Tetrahydrolinalool, the oral systemic no adverse effect level of the subchronic repeated dose toxicity study (316 mg/kg bw/d) was used. After applying the assessment factors, the oral long-term systemic DNEL was set at 1.58 mg/ kg bw/day for the general population.

Long-term – oral, systemic effects

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 316 mg/kg bw/day	Subchronic repeated dose toxicity study in rats, oral (OECD 408)
Step 2) Modification of starting point	-	-
Step 3) Assessment factors
Allometric scaling	4	Assessment factor for allometric scaling according to R8 ECHA 2008
Remaining differences	2.5	according to R8 ECHA 2008
Intraspecies	10	according to R8 ECHA 2008
Exposure duration	2	Use of a subchronic study as starting point forlong-term systemic DNEL derivation (default assessment factor according to R8 ECHA 2008)
Dose response	1	according to R8 ECHA 2008
Quality of database	1	according to R8 ECHA 2008 (GLP guideline Study)
DNEL	Value
	316 / (4 x 2.5 x 10 x 2 x 1 x 1) = 1.58 mg/kg bw/day

For comparison, the pregnancy-specific long-term systemic oral DNEL based on the rabbit teratogenicity study is higher (i.e. 3.00 mg/kg bw/d), demonstrating, that the derived DNEL is sufficiently conservative to cover potential effects during pregnancy.

DNEL = 150 / (2^b x 2.5^a x 10^a x 1^c x 1^a x 1^a) = 3.00 mg/kg bw/d

^aRemaining differences, intraspecies variation, dose response, quality of database according to R8 ECHA 2012

^b4 kg^# rabbit bw was applied and acceptable for pregnant and non-pregnant animals and comparable to body weights of study animals used. Allometric scaling factor was calculated for rabbits based on R8 ECHA 2012: AS factor = (bw human/bw animal)^0.25 = (70 kg /4 kg)^0.25 = 2

^cSince the complete pregnancy was covered in the study, an assessment factor for exposure duration of 1 is acceptable.

Acute/short-term systemic oral DNEL

The substance Tetrahydrolinalool is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral and dermal toxicity. Thus, no DNEL for systemic effects after acute oral exposure is required. Furthermore, the DNEL derived for systemic effects after long term oral exposure is considered sufficiently conservative to cover potential acute systemic oral effects.

General population - Hazard for the eyes

Tetrahydrolinalool 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 a no effect level for eye irritation. However, due to the low final concentrations of tetrahydrolinalool in consumer products, the risk for eye irritation is considered to be low.

^#International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline Impurities: Guideline For Residual Solvents. (2011).