Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
62.59 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC
DNEL value:
625.9 mg/m³
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
35.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
DNEL value:
1 420 mg/kg bw/day
Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

The basis of the derived systemic DNELs for geranyl acetate formed the available repeated dose toxicity studies with food-grade geranyl acetate (71% geranyl acetate (CAS 105-87-3) and 29% citronellyl acetate (CAS 150-84-5)) in a weight of evidence performed by the National Toxicity Program of the US National Institutes of Health (NTP, 1987).

In an oral 90 day repeated dose toxicity study in Fischer 344 rats, mortality and depressed mean body weights were the major adverse test substance related effects and a NOAEL of 2000 mg/kg bw/d of food-grade geranyl acetate has been set, corresponding to 1420 mg/kg bw/d geranyl acetate.

In a related oral 2 year repeated dose toxicity study in Fischer 344 rats, mortality, reduced body weights and an increased incidence of nephropathy with questionable relationship to test substance administration was found as major findings and a NOAEL is to be set at 1000 mg/kg bw/d, corresponding to 710 mg/kg bw/d geranyl acetate.

In an oral 90 day repeated dose toxicity study in B6C3F1 mice, mortalities, delays in body weight gain, cytoplasmic vacuolization with lipid inclusions indicative of fatty degeneration in liver, kidney and myocardium and stomach lesions including inflammation and edema were reported. The NOAEL was set at 1000 mg/kg bw/d food-grade geranyl acetate corresponding to 710 mg/kg bw/d geranyl acetate.

In a related oral 2 year repeated dose toxicity study in B6C3F1 mice, findings were confirmed but the respective study had limitations in study execution (e.g. dosage errors, test substance independent mortality and infections) and does not form a valid basis for the derivation of a NOAEL.

Therefore a NOAEL of 710 mg/kg bw/d from the 90 day study in mice and the 2 year study in rats has been taken as point of departure for the respective DNELs. 

Route to route extrapolation:

Indications for a moderate dermal penetration potential (limited penetration into corium and subcutis) of geranyl acetate are available from non-guideline studies. No further experimental data on absorption of geranyl acetate are available. Based on the physicochemical properties geranyl acetate is considered to become readily bioavailable via the dermal and oral route. On the basis of the low vapour pressure, the exposure with geranyl acetate 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. For oral-to-dermal extrapolation, a twofold higher oral absorption compared to dermal absorption is used for the DNEL derivation based on the indications from the data cited above.

 

For the worker, the following DNELs were derived:

For derivation of the long-term systemic inhalative DNEL for geranyl acetate, the oral NOAEL of 710 mg/kg bw/d was taken as a basis and converted into a corrected inhalative NOAEC of 625.9 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 62.59 mg/m3 for the worker.

 

Long-term –inhalation, systemic effects

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 710 mg/kg bw/day

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 = 710*(1/0.38)*(50/100)*(6.7/10)

= 625.9 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

1

Substance specific assessment factor: Major adverse effects observed were predominantly general systemic toxicity.

On the basis of these findings, no toxicodynamic and/or additional toxicokinetic differences between test animals and humans is to be expected besides aspects already covered by allometric scaling (not relevant, see above).

Some organ specific adverse effects (e.g. lipidosis) were found to be species specific. However, the chosen NOAEL as point of departure also includes these species specific effects. Overall, no additional AF for remaining differences is considered mandatory.

Intraspecies

5

Default assessment factor according to R8 ECHA 2008 was used as worst case.

Exposure duration

1

Data from chronic study was taken into account

Dose response

1

according to R8 ECHA 2008

Quality of database

2

Studies used as point of departure tested a mixture of geranyl acetate and citronellyl acetate, which limits the conclusion on single component.

DNEL

Value

 

625.9 / (1 x 1 x 5 x 1 x 1 x 2) = 62.59 mg/m3

 

 

For derivation of the long-term systemic dermal DNEL of geranyl acetate, the oral NOAEL of 710 mg/kg bw/d was taken as a basis and was converted into a corrected dermal NOAEL of 1420 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 35.5 mg/kg bw/d for the worker.

 

Long-term – dermal, systemic effects 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 710 mg/kg bw/day

 

Step 2) Modification of starting point

2

Based on the limited data on dermal penetration no high dermal penetration potential is assumed and therefore a twofold higher oral absorption is considered appropriate.

Modified dose-descriptor

 NOAEL corrected dermal = 710*2 = 1420 mg/kg bw/d

Step 3) Assessment factors

 

 

Allometric scaling

4

Assessment factor for allometric scaling according to R8 ECHA 2008

Remaining differences

1

Substance specific assessment factor: Major adverse effects observed were predominantly general systemic toxicity.

On the basis of these findings, no toxicodynamic and/or additional toxicokinetic differences between test animals and humans is to be expected besides aspects already covered by allometric scaling.

Some organ specific adverse effects (e.g. lipidosis) were found to be species specific. However, the chosen NOAEL as point of departure also includes these species specific effects. Overall, no additional AF for remaining differences is considered mandatory.

Intraspecies

5

Default assessment factor according to R8 ECHA 2008 was used as worst case.

Exposure duration

1

Data from chronic study was taken into account

Dose response

1

according to R8 ECHA 2008

Quality of database

2

Studies used as point of departure tested a mixture of geranyl acetate and citronellyl acetate, which limits the conclusion on single component.

DNEL

Value

 

1420 / (4 x 1 x 5 x 1 x 1 x 2) = 35.5 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 irritation and skin sensitization are available. The present data currently do not allow a valid derivation of an EC3 value in the given LLNA, and supportive data in animals and humans do not allow the derivation of a DNEL in the given unit, i.e. µg/cm2. However, human data covered a test concentration range up to 10% geranyl acetate, and no evident skin sensitization was found:

In an repeated insult patch test with 4% geranyl acetate none of the 25 subjects showed sensitization reactions (Greif, 1967).

In a human maximization test with 25 male volunteers 10% neryl acetate (stereoisomer of geranyl acetate ) in petrolatum showed no skin reactivity on any subject during the study (Kligman 1972).

In a human maximization test (induction/challenge concentration = 4% geranyl acetate) no evidence of skin sensitization was reported (rate 0/25; Ishihara 1986).

In a patch test with 20 male and female perfume-sensitive patients, geranyl acetate at 2% in petrolatum did not produce any skin reactions (Larsen, 1970).

In a patch test, 0.05 - 0.5 % neryl acetate application resulted in sporadic skin reactions (3/187 erythema and 5/187 slight erythema) which were not found after application of 0.05 - 0.5 % geranyl acetate to 265 male and female Japanese patients (Takaneka, 1986).

In a patch test with 165 dermatoses patients, the application of 0.4% geranyl acetate did not result in any skin reactions (Fujji 1972).

 

Based on these results, geranyl acetate is considered to be a moderate skin sensitizer. Overall, a

qualitative risk characterisation including the implementation of suitable risk management measures to cover for skin irritating and moderate skin sensitizing properties of geranyl acetate 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:
15.4 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEC
DNEL value:
308.7 mg/m³
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
17.75 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
80
Modified dose descriptor starting point:
NOAEL
DNEL value:
1 420 mg/kg bw/day
Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.9 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
80
Modified dose descriptor starting point:
NOAEL
DNEL value:
710 mg/kg bw/day
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

The basis of the derived systemic DNELs for geranyl acetate formed the available repeated dose toxicity studies with food-grade geranyl acetate (71% geranyl acetate (CAS 105-87-3) and 29% citronellyl acetate (CAS 150-84-5)) in a weight of evidence performed by the National Toxicity Program of the US National Institutes of Health (NTP, 1987).

In an oral 90 day repeated dose toxicity study in Fischer 344 rats, mortality and depressed mean body weights were the major adverse test substance related effects and a NOAEL of 2000 mg/kg bw/d of food-grade geranyl-acetate has been set, corresponding to 1420 mg/kg bw/d geranyl acetate.

In a related oral 2 year repeated dose toxicity study in Fischer 344 rats, mortality, reduced body weights and an increased incidence of nephropathy with questionable relationship to test substance administration was found as major findings and a NOAEL is to be set at 1000 mg/kg bw/d, corresponding to 710 mg/kg bw/d geranyl acetate.

In an oral 90 day repeated dose toxicity study in B6C3F1 mice, mortalities, delays in body weight gain, cytoplasmic vacuolization with lipid inclusions indicative of fatty degeneration in liver, kidney and myocardium and stomach lesions including inflammation and edema were reported. The NOAEL was set at 1000 mg/kg bw/d food-grade geranyl acetate corresponding to 710 mg/kg bw/d geranyl acetate.

In a related oral 2 year repeated dose toxicity study in B6C3F1 mice, findings were confirmed but the respective study had limitations in study execution (e.g. dosage errors, test substance independent mortality and infections) and does not form a valid basis for the derivation of a NOAEL.

Therefore a NOAEL of 710 mg/kg bw/d from the 90 day study in mice and the 2 year study in rats has been been taken as point of departure for the respective DNELs. 

Route to route extrapolation:

Indications for a moderate dermal penetration potential (limited penetration into corium and subcutis) of geranyl acetate are available from non-guideline studies. No further experimental data on absorption of geranyl acetate are available. Based on the physicochemical properties geranyl acetate is considered to become readily bioavailable via the dermal and oral route. On the basis of the low vapour pressure, the exposure with geranyl acetate 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. For oral-to-dermal extrapolation, a twofold higher oral absorption compared to dermal absorption is used for the DNEL derivation based on the indications from the data cited above.

 

For the general population, the following DNELs were derived:

 

For derivation of the long-term systemic oral DNEL of geranyl acetate, the NOAEL 710 mg/kg bw/d was used. After applying the assessment factors, the oral long-term systemic DNEL was set at 8.9 mg/ kg bw/day for the general population.

 

Long-term – oral, systemic effects

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 710 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

1

Substance specific assessment factor: Major adverse effects observed were predominantly general systemic toxicity.

On the basis of these findings, no toxicodynamic and/or additional toxicokinetic differences between test animals and humans is to be expected besides aspects already covered by allometric scaling.

Some organ specific adverse effects (e.g. lipidosis) were found to be species specific. However, the chosen NOAEL as point of departure also includes these species specific effects. Overall, no additional AF for remaining differences is considered mandatory.

Intraspecies

10

Default assessment factor according to R8 ECHA 2008 was used as worst case.

Exposure duration

1

Data from chronic study was taken into account

Dose response

1

according to R8 ECHA 2008

Quality of database

2

Studies used as point of departure tested a mixture of geranyl acetate and citronellyl acetate, which limits the conclusion on single component.

DNEL

Value

 

710 / (4 x 1 x 10 x 1 x 1 x 2) = 8.9 mg/kg bw/day

 

 

For derivation of the long-term systemic inhalative DNEL for geranyl acetate, the oral NOAEL of 710 mg/kg bw/d was taken as a basis and converted into a corrected inhalative NOAEC of 308.7 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 15.4 mg/m3 for the general population.

 

Long-term – inhalation, systemic effects

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 710 mg/kg bw/day

 

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

NOAECinhalcorrected= 710*(1/1.15)*(50/100)= 308.7 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

1

Substance specific assessment factor: Major adverse effects observed were predominantly general systemic toxicity.

On the basis of these findings, no toxicodynamic and/or additional toxicokinetic differences between test animals and humans is to be expected besides aspects already covered by allometric scaling (not relevant, see above).

Some organ specific adverse effects (e.g. lipidosis) were found to be species specific. However, the chosen NOAEL as point of departure also includes these species specific effects. Overall, no additional AF for remaining differences is considered mandatory.

Intraspecies

10

Default assessment factor according to R8 ECHA 2008 was used as worst case.

Exposure duration

1

Data from chronic study was taken into account

Dose response

1

according to R8 ECHA 2008

Quality of database

2

Studies used as point of departure tested a mixture of geranyl acetate and citronellyl acetate, which limits the conclusion on single component.

DNEL

Value

 

308.7/ (1 x 1 x 10 x 1 x 1 x 2) = 15.4 mg/m3

 

 

For derivation of the long-term systemic dermal DNEL of geranyl acetate, the oral NOAEL of 710 mg/kg bw/d was taken as a basis and was converted into a corrected dermal NOAEL of 1420 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 17.75 mg/kg bw/d for the general population.

 

Long-term – dermal, systemic effects

Description

Value

Remark

Step 1) Relevantdose-descriptor

NOAEL: 710 mg/kg bw/day

 

Step 2) Modification of starting point

2

Based on the limited data on dermal penetration no high dermal penetration potential is assumed and therefore a twofold higher oral absorption is considered appropriate.

Modified dose-descriptor

 NOAELcorrected dermal= 710*2= 1420 mg/kg bw/d

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling according to R8 ECHA 2008

Remaining differences

1

Substance specific assessment factor: Major adverse effects observed were predominantly general systemic toxicity.

On the basis of these findings, no toxicodynamic and/or additional toxicokinetic differences between test animals and humans is to be expected besides aspects already covered by allometric scaling.

Some organ specific adverse effects (e.g. lipidosis) were found to be species specific. However, the chosen NOAEL as point of departure also includes these species specific effects. Overall, no additional AF for remaining differences is considered mandatory.

Intraspecies

10

Default assessment factor according to R8 ECHA 2008 was used as worst case.

Exposure duration

1

Data from chronic study was taken into account

Dose response

1

according to R8 ECHA 2008

Quality of database

2

Studies used as point of departure tested a mixture of geranyl acetate and citronellyl acetate, which limits the conclusion on single component.

DNEL

Value

 

1420 / (4 x 1 x 10 x 1 x 1 x 2) = 17.75 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 irritation and skin sensitization are available. The present data currently do not allow a valid derivation of an EC3 value in the given LLNA, and supportive data in animals and humans do not allow the derivation of a DNEL in the given unit, i.e. µg/cm2. However, human data covered a test concentration range up to 10% geranyl acetate, and no evident skin sensitization was found:

In an repeated insult patch test with 4% geranyl acetate none of the 25 subjects showed sensitization reactions (Greif, 1967).

In a human maximization test with 25 male volunteers 10% neryl acetate (stereoisomer of geranyl acetate ) in petrolatum showed no skin reactivity on any subject during the study (Kligman 1972).

In a human maximization test (induction/challenge concentration = 4% geranyl acetate) no evidence of skin sensitization was reported (rate 0/25; Ishihara 1986).

In a patch test with 20 male and female perfume-sensitive patients, geranyl acetate at 2% in petrolatum did not produce any skin reactions (Larsen, 1970).

In a patch test, 0.05 - 0.5 % neryl acetate application resulted in sporadic skin reactions (3/187 erythema and 5/187 slight erythema) which were not found after application of 0.05 - 0.5 % geranyl acetate to 265 male and female Japanese patients (Takaneka, 1986).

In a patch test with 165 dermatoses patients, the application of 0.4% geranyl acetate did not result in any skin reactions (Fujji 1972).

 

Based on these results, geranyl acetate is considered to be a moderate skin sensitizer.

These findings given above provide evidence for the absence of an irritating and skin sensitization potential when exposed to products or articles with geranyl acetate concentrations <=10%. As lined out in Chapter 9 of the CSR, use levels of geranyl acetate are generally far below such concentrations.