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EC number: 201-133-9 | CAS number: 78-69-3
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data

Toxicological Summary
- Administrative data
- Workers - Hazard via inhalation route
- Workers - Hazard via dermal route
- Workers - Hazard for the eyes
- Additional information - workers
- General Population - Hazard via inhalation route
- General Population - Hazard via dermal route
- General Population - Hazard via oral route
- General Population - Hazard for the eyes
- Additional information - General Population
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 11.14 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- 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.
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
- Explanation for the modification of the dose descriptor starting point:
See additional 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:
- 3.16 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- 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.
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
- Explanation for the modification of the dose descriptor starting point:
See additional information.
Local effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 190 µg/cm²
- Most sensitive endpoint:
- sensitisation (skin)
DNEL related information
- Overall assessment factor (AF):
- 10
Acute/short term exposure
- Hazard assessment conclusion:
- low hazard (no threshold derived)
Workers - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- low hazard (no threshold derived)
Additional information - workers
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-2µ-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). The lowest NOAEL for males (316 mg/kg bw/d) was used as a point of departure for the derivation of the respective 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 |
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 = 100 * (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 |
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.
General Population - 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
- Route of original study:
- Oral
DNEL related information
- 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.
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
- Explanation for the modification of the dose descriptor starting point:
See additional 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:
- 1.58 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- 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.
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
- Explanation for the modification of the dose descriptor starting point:
See additional information.
Local effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 190 µg/cm²
- Most sensitive endpoint:
- sensitisation (skin)
DNEL related information
- Overall assessment factor (AF):
- 10
Acute/short term exposure
- Hazard assessment conclusion:
- low hazard (no threshold derived)
General Population - Hazard via oral route
Systemic effects
Long term exposure
- 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
DNEL related information
- 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.
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
- Explanation for the modification of the dose descriptor starting point:
See additional information.
General Population - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- low hazard (no threshold derived)
Additional information - General Population
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-2µ-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). The lowest NOAEL for males (316 mg/kg bw/d) was used as a point of departure for the derivation of the respective 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 |
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 |
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 |
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.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.

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