Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.3 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Value:
132.2 mg/m³
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:
1.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
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

The key study considered for DNEL derivation of tetrahydrogeraniol is a subchronic oral toxicity study (OECD 408) in rats with the structural analogue 2-propyl-1-heptanol (doses: 0, 30, 150 and 600 mg/kg bw/d; BASF 1996; 51C0279/94026).

Clinical signs (salivation, urine-smeared fur in the anogenital region) was observed. Salivation was seen as being the consequence of local effects of the test substance on the upper digestive tract, rather than being a systemic effect on the autonomic nervous system. Reduced food consumption and impairment of body weight change and the final body weight of the males was observed. Increased mean absolute and relative liver weights and diffuse hypertrophy and loss of fatty infiltration of the liver cells was observed. Corresponding, an increase in cyanide-insensitive palmitoyl-CoA-oxidation in the serum was found, which is probably caused by hepatic peroxisome proliferation accompanied by induction of peroxisomal enzymes involved in oxidation of fatty acids. The thyroid follicular epithelium was found to be hypertrophic and the thyrotrophic basophilic cells of the anterior (glandular) part of the pituitary gland were vacuolated. This effect is considered to be a rat specific adaption of the hypothalamic-pituitary axis as a consequence of a higher rate or an accelerated metabolic degradation of T3 and/or T4 in the liver. Treatment-related decreases in platelet counts were seen although the underlying mechanism of this isolated finding remains unclear. Additionally, increases in albumin and the decreases in globulins indicative for a disturbance in protein metabolism were considered to be test substance-related. Decrease in urinary specific gravity, an increase in urinary volume and transitional epithelial cells and an increase in squamous epithelial cells in the urine was observed. Together, the changes seen are indicative signs of a mild nephrotoxic potential of the test compound at the high dose level.

Test substance-related effects were seen at 600 mg/kg bw/d in both sexes and at 150 mg/kg in females only. Considering the rodent specific effects observed in the mid dose, i.e. peroxisomal proliferation, the NOAEL relevant for human hazard is set at 150 mg/kg bw. This NOAEL has been taken as point of departure for the respective DNELs. 

Route to route extrapolation:

No experimental data on absorption of tetrahydrogeraniol are available. Based on its physicochemical properties, tetrahydrogeraniol is considered to become readily bioavailable via the dermal and oral route. On the basis of the low vapour pressure, the exposure of tetrahydrogeraniol via inalation 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 of 2 in the case of oral-to-inhalation extrapolation. For dermal absorption, the default ratio of 1 for oral to dermal extrapolation is used for the DNEL derivation. 

 

For the worker, the following DNELs were derived:

For derivation of the long-term systemic inhalative DNELfor tetrahydrogeraniol, the oral NOAEL from 2-propyl-1-heptanol was taken as a basis and converted into a corrected inhalative NOAEC of 132.2 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 5.3 mg/m3 for the worker.

 

Long-term –inhalation, systemic effects

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 150 mg/kg bw/day

Step 2) Modification of starting point

2

 

 

0.38 m3/kg bw

 

 

 

6.7 m3/10 m3

Ratio of inhalation to oral 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 = 150*(1/0.38)*(50/100)*(6.7/10)

= 132.2 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 toR8 ECHA 2008.

Remaining differences

2.5

Default assessment factor according to R8 ECHA 2008 was used as worst case to cover uncertainties due to the read across made.

Intraspecies

5

Default assessment factor according to R8 ECHA 2008 was used as worst case to cover uncertainties due to the read across made.

Exposure duration

2

Subchronic to chronic extrapolation

Dose response

1

according to R8 ECHA 2008

Quality of database

1

based on validity of studies performed

DNEL

Value

 

176.3 / (1 x 2.5 x 5 x 2 x 1 x 1) = 5.3mg/m3

 

 

For derivation of the long-term systemic dermal DNELof tetrahydrogeraniol, the oral NOAEL from 2-propyl-1-heptanol was taken as a basis and was converted into a corrected dermal NOAEL of 150 mg/kg bw/d according to the procedure, recommended in the current guidance document (R8, ECHA 2008).Applying all assessment factors, the dermal long-term systemic DNEL derived was 1.5 mg/kg bw/d for the worker.

 

Long-term – dermal, systemic effects 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 150 mg/kg bw/day

 

Step 2) Modification of starting point

1

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral to dermal extrapolation.

Modified dose-descriptor

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

Step 3) Assessment factors

 

 

Allometric scaling

4

Assessment factor for allometric scaling according to R8 ECHA 2008

Remaining differences

2.5

Default assessment factor according to R8 ECHA 2008 was used as worst case to cover uncertainties due to the read across made.

Intraspecies

5

Default assessment factor according to R8 ECHA 2008 was used as worst case to cover uncertainties due to the read across made.

Exposure duration

2

Subchronic to chronic extrapolation

Dose response

1

 according to R8 ECHA 2008

Quality of database

1

 based on validity of studies performed

DNEL

Value

 

150 / (4 x 2.5 x 5 x 2 x 1 x 1) = 1.5 mg/kg bw/day

 

 

 

No DNELs were derived for local effects after short term or after long term inhalative exposure, since the conservatively derived long term inhalative DNEL for systemic effects covers putative local inhalative effects. No DNELs were derived for systemic effects after short term dermal or inhalative exposure, as the substance exhibits no hazardous potential in terms of these endpoints and the conservatively derived respective long term DNELS for systemic effects sufficiently covers such putative effects.

For derivation of the DNELs for local short-term and long-term dermal exposure, no reliable quantitative data addressing the hazard of skin and eye irritation is available. Therefore no DNELs were derived and a qualitative risk characterisation 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:
1.3 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEC
Value:
65.2 mg/m³
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:
0.75 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.75 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
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

The key study considered for DNEL derivation of tetrahydrogeraniol is a subchronic oral toxicity study (OECD 408) in rats with the structural analogue 2-propyl-1-heptanol (doses: 0, 30, 150 and 600 mg/kg bw/d; BASF 1996; 51C0279/94026).

Clinical signs (salivation, urine-smeared fur in the anogenital region) was observed. Salivation was seen as being the consequence of local effects of the test substance on the upper digestive tract, rather than being a systemic effect on the autonomic nervous system. Reduced food consumption and impairment of body weight change and the final body weight of the males was observed. Increased mean absolute and relative liver weights and diffuse hypertrophy and loss of fatty infiltration of the liver cells was observed. Corresponding, an increase in cyanide-insensitive palmitoyl-CoA-oxidation in the serum was found, which is probably caused by hepatic peroxisome proliferation accompanied by induction of peroxisomal enzymes involved in oxidation of fatty acids. The thyroid follicular epithelium was found to be hypertrophic and the thyrotrophic basophilic cells of the anterior (glandular) part of the pituitary gland were vacuolated. This effect is considered to be a rat specific adaption of the hypothalamic-pituitary axis as a consequence of a higher rate or an accelerated metabolic degradation of T3 and/or T4 in the liver. Treatment-related decreases in platelet counts were seen although the underlying mechanism of this isolated finding remains unclear. Additionally, increases in albumin and the decreases in globulins indicative for a disturbance in protein metabolism were considered to be test substance-related. Decrease in urinary specific gravity, an increase in urinary volume and transitional epithelial cells and an increase in squamous epithelial cells in the urine was observed. Together, the changes seen are indicative signs of a mild nephrotoxic potential of the test compound at the high dose level.

Test substance-related effects were seen at 600 mg/kg bw/d in both sexes and at 150 mg/kg in females only. Considering the rodent specific effects observed in the mid dose, i.e. peroxisomal proliferation, the NOAEL relevant for human hazard is set at 150 mg/kg bw. This NOAEL has been taken as point of departure for the respective DNELs. 

Route to route extrapolation:

No experimental data on absorption are available of tetrahydrogeraniol. Based on its physicochemical properties tetrahydrogeraniol is considered to become readily bioavailable via the dermal and oral route. On the basis of the low vapour pressure, the exposure of tetrahydrogeraniol via inalation 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 of 2 in the case of oral-to-inhalation extrapolation. For dermal absorption, the default ratio of 1 for oral to dermal extrapolation is used for the DNEL derivation. 

 

For the general population, the following DNELs were derived:

 

For derivation of the long-term systemic oral DNEL of tetrahydrogeraniol, the NOAEL from the repeated dose toxicity study (OECD 408) in rats with the structural analogue propyl-1-heptanol was used (150 mg/kg bw/day). After applying the assessment factors, the oral long-term systemic DNEL was set at 0.75 mg/ kg bw/day for the general population.

 

 

Long-term – oral, systemic effects

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 150 mg/kg bw/day

 

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

Default assessment factor according to R8 ECHA 2008 was used as worst case to cover uncertainties due to the read across made.

Intraspecies

10

Default assessment factor according to R8 ECHA 2008 was used as worst case to cover uncertainties due to the read across made.

Exposure duration

2

Subchronic to chronic extrapolation

Dose response

1

according to R8 ECHA 2008

Quality of database

1

based on validity of studies performed

DNEL

Value

 

150 / (4 x 2.5 x 10 x 2 x 1 x 1) = 0.75 mg/kg bw/day

 

 

For derivation of the long-term systemic inhalative DNELfor tetrahydrogeraniol, the oral NOAEL from 2-propyl-1-heptanol was taken as a basis and converted into a corrected inhalative NOAEC of 65.2 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 1.3 mg/m3 for the general population.

 

Long-term – inhalation, systemic effects

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 150 mg/kg bw/day

 

Step 2) Modification of starting point

2

 

 

1.15 m3/kg bw

 

 

 

 

Proportion inhalation 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

NOAECinhalcorrected= 150*(1/1.15)*(50/100)= 65.2 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 toR8 ECHA 2008.

Remaining differences

2.5

Default assessment factor according to R8 ECHA 2008 was used as worst case to cover uncertainties due to the read across made.

Intraspecies

10

Default assessment factor according to R8 ECHA 2008 was used as worst case to cover uncertainties due to the read across made.

Exposure duration

2

Subchronic to chronic extrapolation

Dose response

1

according to R8 ECHA 2008

Quality of database

1

based on validity of studies performed

DNEL

Value

 

65.2 / (1 x 2.5 x 10 x 2 x 1 x 1) = 1.3mg/m3

 

 

For derivation of the long-term systemic dermal DNELof tetrahydrogeraniol, the oral NOAELfrom 2-propyl-1-heptanol was taken as a basis andwas converted into a corrected dermal NOAEL of 150 mg/kg bw/day according to the procedure, recommended in the current guidance document (R8, ECHA 2008). Applying all assessment factors, the dermal long-term systemic DNEL derived was 0.75 mg/kg bw/d for the general population.

 

Long-term – dermal, systemic effects

Description

Value

Remark

Step 1) Relevantdose-descriptor

NOAEL: 150 mg/kg bw/day

 

Step 2) Modification of starting point

1

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral to dermal extrapolation.

Modified dose-descriptor

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

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling according to R8 ECHA 2008

Remaining differences

2.5

Default assessment factor according to R8 ECHA 2008 was used as worst case to cover uncertainties due to the read across made.

Intraspecies

10

Default assessment factor according to R8 ECHA 2008 was used as worst case to cover uncertainties due to the read across made.

Exposure duration

2

Subchronic to chronic extrapolation

Dose response

1

according to R8 ECHA 2008

Quality of database

1

based on validity of studies performed

DNEL

Value

 

150 / (4 x 2.5 x 10 x 2 x 1 x 1) = 0.75 mg/kg bw/day

 

 

No DNELs were derived for local effects after short term or after long term inhalative exposure, since the conservatively derived long term inhalative DNEL for systemic effects covers putative local inhalative effects. No DNELs were derived for systemic effects after short term oral, dermal or inhalative exposure, as the substance exhibits no hazardous potential in terms of these endpoints and the conservatively derived respective long term DNELS for systemic effects sufficiently covers such putative effects.

For derivation of the DNELs for local short-term and long-term dermal exposure, no reliable quantitative data addressing the hazard of skin and eye irritation is available. Therefore no DNELs were derived and a qualitative risk characterisation including the implementation of suitable risk management measures is performed in the CSR.