Registration Dossier

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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
11.8 mg/m³
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
15
Dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
176.3
Explanation for the modification of the dose descriptor starting point:

Please refer to "Discussion"

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:
4.2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
Overall assessment factor (AF):
72
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Please refer to "Discussion"

Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
11 800 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
1
Dose descriptor:
other: NOAEL
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

Oral repeated dose toxicity was evaluated in a study (Hagan, 1967) with a mixture of 3,7-dimethyl-2,6-octadienol and 3,7-dimethyl-1,6-octadienol (named "Geraniol extra" by the authors).


The test substance was feed to five male and five female individually housed Osborne-Mendel rats per dose group. Thereby, a concentration of 1000 ppm (= ca. 55 mg/kg bw/day) was administered for 189-169 days and a concentration of 10000 ppm (= ca. 550 mg/kg bw/day) was given for 112 days. Since no clinical signs, no effects on body weight as well as no histopathological changes were observed, the NOEL could be estimated as 10000 ppm. Thus, the NOAEL would be > 550 mg/kg bw/day.


 


A dermal reproduction/developmental toxicity screening test according to OECD 421 has been performed with purified geraniol in wistar rats (BASF SE, 2010).


Doses of 0, 50, 150 and 450 mg/kg bw/day were chosen for the reproduction screening study. The test substance was administered to male and female young Wistar rats dissolved in corn oil. After removal of the dressing, the application area was washed with lukewarm water. Application was daily for at least six hours.


During the course of the study the initial high dose (450 mg/kg bw/day) turned out to be intolerable for the rat skin (strong irritation reactions), so that from day 10 onwards the high dose had to be reduced to 300 mg/kg bw/day. Regarding clinical examinations, only signs of local dermal toxicity were observed for males and females at all dose levels. No changes in food consumption and body weight data were seen at any dose level. Fertility indices for male and female animals were not impaired by test-substance administration. Regarding pathology, there were no treatment-related necropsies or histological findings in ovaries, testes or epididymides associated with dermal administration of the test substance. The live birth indices as well as the rate of stillborn pups was comparable between all test groups and the control and reflected the normal range of biological variation inherent in this strain. None of the pups died during lactation in the control group and in all test groups. F1 pups did not show adverse clinical signs up to scheduled sacrifice. Systemic exposure to geraniol is limited by the strong local irritation effects. Therefore, the NOAEL for fertility and developmental toxicity for geraniol is shown to be >300 mg/kg bw/day via the dermal route, respectively.


 


The potential toxicity of Geraniol when given by oral gavage to adult rats and their offspring. Dosing of animals was 50, 200 and 800 mg/kg bw/d for low, mid and high dose. The study design included the administration of F0 animals for 10 weeks prior to mating, Cohort 1A and 1B with the extension of Cohort 1B to mate the F1 animals to produce the F2 Generation, as well as Cohort 2A, 2B and 3.


In the study it was concluded that administration of Geraniol by daily oral gavage administration was not initially tolerated by F1 weanling rats at dose levels of greater than 400 mg/kg/day, being associated with mortality at 600 and 800 mg/kg/day. Target organ effects were primarily adaptive in nature, affecting liver, thyroid and spleen at dose levels of 800 mg/kg/day (F0 generation) and from 50 mg/kg/day (F1 generation). However, the olfactory epithelium degeneration at 800 mg/kg/day was an adverse change because it involved a neural tissue that does not regenerate. Based on the results, the following no-observed-adverse-effect levels (NOAELs) were assigned:


Adult rats = 200 mg/kg/day (based on olfactory epithelium degeneration)


Offspring viability, neonatal health, developmental status at birth = 200 mg/kg/day (F0 litters, based on pup survival) and 800 mg/kg/day (F1 litters)


Physical development until adulthood = 200 mg/kg/day (based on early mortality)


Pre and postnatal functional development until adulthood = 800 mg/kg/day


Nervous system and immune system development = 800 mg/kg/day.


Integrity and performance of adult reproductive systems = 800 mg/kg/day.


 


Developmental toxicity was evaluated in a study performed according to OECD Guideline 414 (BASF SE, 2016). The test substance Geraniol Extra was administered as a solution in corn oil to 25 "time-mated" (mated by breeder) female Wistar rats/group by stomach tube at doses of 30, 100 and 300 mg/kg bw on day 6 through day 19 post coitum (p.c.). On day 20 p.c., all females were sacrificed and assessed. Under the conditions of this prenatal developmental toxicity study, the oral administration of Geraniol Extra to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) at doses as high as 300 mg/kg bw/d caused neither evidence of maternal nor developmental toxicity. In conclusion, the no observed adverse effect level (NOAEL) for maternal and prenatal developmental toxicity is 300 mg/kg bw/d.


 


Therefore, the respective oral NOAEL of 200 mg/kg bw/day for male and female rats in the EOGRTS (OECD 443) has been taken as conservative point of departure for the respective systemic DNELs derived, which covers findings observed in the subchronic repeated dose and reproduction/developmental toxicity studies.


The respective dermal NOAEL of 300 mg/kg bw/day for male and female rats in the OECD 421 has been taken as conservative point of departure for the respective systemic dermal DNEL derived.


 


Route to route extrapolation:


On the basis of the low vapour pressure (0.0001 hPa), the exposure with Geraniol 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.


 


Substance specific assessment factor for intraspecies extrapolation


Studies on the distribution of human data for various toxicokinetic and toxicodynamic parameters were taken into account, including ‘healthy adults’ of both sexes, young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. (Hattis 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998). Using the 95th percentile of the combined distribution of the toxicokinetic and -dynamic variability of datasets is a statistical approach to account for intraspecies variability based on toxicological datasets. On the basis of the above mentioned assessments and statistical approach, an AF of 5 for the general population and AF factor of 3 for the more homogenous worker population can be estimated to account for intraspecies variability.


It needs further to be pointed out, that the multiplicatory principle of AF used further adds to conservatism in the derivation of the respective DNELs, especially for the registered substance, which contains a toxicological profile, justifying a non-classification according to regulation (EU) 1272/2008.


Based on the availability of a sufficient toxicity dataset, the default assessment factors (acc. to ECHA GD R8) can be modified into substance specific assessment factors (AF) considering the intrinsic hazard properties of the registered substance. The following findings form the basis of the rationale for the substance specific AF:


In a subchronic feeding study in rats, no clinical signs, no effects on body weight as well as no histopathological changes were observed.


During the course of the dermal reproduction/developmental toxicity screening test according to OECD 421 the initial high dose (450 mg/kg bw/day) turned out to be intolerable for the rat skin (strong irritation reactions), so that from day 10 onwards the high dose had to be reduced to 300 mg/kg bw/day. Regarding clinical examinations, only signs of local dermal toxicity were observed for males and females at all dose levels. No effects further effects on orang toxicity, fertility or developmental toxicity were observed. Systemic exposure to geraniol is limited by the strong local irritation effects. Therefore, the NOAEL for general systemic fertility and developmental toxicity for geraniol is shown to be >300 mg/kg bw/day via the dermal route.


Target organ effects observed in the OECD 443 were primarily adaptive in nature, affecting liver, thyroid and spleen at dose levels of 800 mg/kg/day (F0 generation) and from 50 mg/kg/day (F1 generation). The olfactory epithelium degeneration at 800 mg/kg/day was an adverse change. The test compound did not adversely affect fertility of the F0 and F1 generation parental animals at all dose levels as there were no changes of male/female mating and fertility indices, time until successful copulation, duration of pregnancy and mean number of implantations. Maternal toxicity as evidence by lack of care of the pups, significantly reduced feed consumption in the dams during lactation and empty stomachs in the pups appears to be responsible for the findings seen at the top dose group.


In a gavage developmental toxicity study in rats (acc. to OECD TG 414) no adverse effects have been observed up to 300 mg/kg bw/day.


In the key studies given above, the nature of effects observed are mainly based on either adaptive or unspecific systemic adverse effects such as reduced food consumption and body weight changes. No human relevant organ specific toxicity is identified for the registered substance, which would justify a conservative default assessment factor for intraspecies variations in toxicokinetics or toxicodynamics. However, an AF of 3 or 5 has been included to cover for remaining uncertainties within a controlled subpopulation, i.e. healthy workers or the general population, respectively.


 


 


For the worker, the following DNELs were derived:


 


For derivation of the long-term systemic inhalative DNEL for Geraniol, the oral NOAEL of 200 mg/kg bw/d from the OECD 443 was taken as a basis and converted into a corrected inhalative NOAEC of 176.3 mg/m3. Applying all assessment factors, the inhalative long-term systemic DNEL was set at 11.8 mg/m3 for the worker.


 


Long-term – inhalation, systemic effects




































































Description



Value



Remark



Step 1) Relevant dose-descriptor



NOAEL: 200 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 = 200 * (50/100) * (1/0.38) * (6.7/10) = 176.3 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



Remaining differences



2.5



according to R8 ECHA



Intraspecies



3



Substance specific assessment factor (see justification above)



Exposure duration



2



Use of a subchronic study as starting point for long-term systemic DNEL derivation (default assessment factor according to R8 ECHA)



Dose response



1



according to R8 ECHA



Quality of database



1



according to R8 ECHA (GLP guideline study)



DNEL



Value



 



176.3 / (1 x 2.5 x 3 x 2 x 1 x 1) = 11.8 mg/m3



 


 


For derivation of the long-term systemic dermal DNEL for Geraniol, the dermal NOAEL of 300 mg/kg bw/d (highest dose tested due to local dermal effects) from the OECD 421 was taken as a basis. Applying all assessment factors, the dermal long-term systemic DNEL derived was 4.2 mg/kg bw/d for the worker.


 


Long-term – dermal, systemic effects 
































































Description



Value



Remark



Step 1) Relevant dose-descriptor



NOAEL: 300 mg/kg bw/day



The NOAE of 300 mg/kg bw/day represents a very conservative starting point for the DNEL derivation, as the dermal dose in study was limited by local irritating effects. It can be assumed that the actual NOAEL for systemic effects is much higher.



Step 2) Modification of starting point



-



-



Step 3) Assessment factors



 



 



Allometric scaling



4



Assessment factor for allometric scaling according to R8 ECHA



Remaining differences



1



As no general adverse systemic effects were observed in the dermal OECD 421 up the highest dose tested (dermal dose was limited by local dermal irritation), no difference in sensitivity (toxicodynamic and/or additional toxicokinetic differences) between test animals and humans is to be expected.



Intraspecies



3



Substance specific assessment factor (see justification above)



Exposure duration



6



Use of a subacute study as starting point for long-term systemic DNEL derivation (default assessment factor according to R8 ECHA)



Dose response



1



according to R8 ECHA



Quality of database



1



according to R8 ECHA (GLP guideline study)



DNEL



Value



 



300 / (4 x 1 x 3 x 6 x 1 x 1) = 4.2 mg/kg bw/day



 


 


According to ECHA Guidance on information requirements and CSR, chapter R8, a DNEL for acute systemic toxicity should be derived only if an acute systemic toxicity hazard leading to C&L has been identified. Geraniol Extra is not subject to classification and labelling and consequently the establishment of DNELs for acute/short-term exposure - systemic effects is not required.


 


Geraniol is classified as Skin Irrit. Cat 2 / H315 and Eye Damage Cat 1/ H318 (Causes skin irritation and Causes serious eye damage) according to Regulation 1272/2008/EC. No experimental data are available addressing local effects in the respiratory tract. Furthermore, Geraniol is a skin sensitiser and hence subjected to classification as and Skin Sens. Cat 1 / H317 (May cause an allergic skin reaction) according to Regulation 1272/2008/EC Annex VI. Since sensitising reactions occur also at not irritating concentrations, this endpoint was chosen as most sensitive. The RIFM Expert Panel reviewed the critical effect data for geraniol and, based on the weight of evidence, established the No Expected Sensitization Induction Level (NESIL) as 11800 μg/cm². This concentration protects also against (skin) irritation, meaning the NESIL covers both, short and long term local effects.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.5 mg/m³
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
25
Dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
87 mg/m³
Explanation for the modification of the dose descriptor starting point:

Please refer to "Discussion"

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:
2.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
Overall assessment factor (AF):
120
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Please refer to "Discussion"

Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 180 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
10
Dose descriptor:
other: NESIL
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:
2 mg/kg bw/day
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
100
Dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Please refer to "Discussion"

Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

Oral repeated dose toxicity was evaluated in a study (Hagan, 1967) with a mixture of 3,7-dimethyl-2,6-octadienol and 3,7-dimethyl-1,6-octadienol (named "Geraniol extra" by the authors).


The test substance was feed to five male and five female individually housed Osborne-Mendel rats per dose group. Thereby, a concentration of 1000 ppm (= ca. 55 mg/kg bw/day) was administered for 189-169 days and a concentration of 10000 ppm (= ca. 550 mg/kg bw/day) was given for 112 days. Since no clinical signs, no effects on body weight as well as no histopathological changes were observed, the NOEL could be estimated as 10000 ppm. Thus, the NOAEL would be > 550 mg/kg bw/day.


 


A dermal reproduction/developmental toxicity screening test according to OECD 421 has been performed with purified geraniol in wistar rats (BASF SE, 2010).


Doses of 0, 50, 150 and 450 mg/kg bw/day were chosen for the reproduction screening study. The test substance was administered to male and female young Wistar rats dissolved in corn oil. After removal of the dressing, the application area was washed with lukewarm water. Application was daily for at least six hours.


During the course of the study the initial high dose (450 mg/kg bw/day) turned out to be intolerable for the rat skin (strong irritation reactions), so that from day 10 onwards the high dose had to be reduced to 300 mg/kg bw/day. Regarding clinical examinations, only signs of local dermal toxicity were observed for males and females at all dose levels. No changes in food consumption and body weight data were seen at any dose level. Fertility indices for male and female animals were not impaired by test-substance administration. Regarding pathology, there were no treatment-related necropsies or histological findings in ovaries, testes or epididymides associated with dermal administration of the test substance. The live birth indices as well as the rate of stillborn pups was comparable between all test groups and the control and reflected the normal range of biological variation inherent in this strain. None of the pups died during lactation in the control group and in all test groups. F1 pups did not show adverse clinical signs up to scheduled sacrifice. Systemic exposure to geraniol is limited by the strong local irritation effects. Therefore, the NOAEL for fertility and developmental toxicity for geraniol is shown to be >300 mg/kg bw/day via the dermal route, respectively.


 


The potential toxicity of Geraniol when given by oral gavage to adult rats and their offspring. Dosing of animals was 50, 200 and 800 mg/kg bw/d for low, mid and high dose. The study design included the administration of F0 animals for 10 weeks prior to mating, Cohort 1A and 1B with the extension of Cohort 1B to mate the F1 animals to produce the F2 Generation, as well as Cohort 2A, 2B and 3.


In the study it was concluded that administration of Geraniol by daily oral gavage administration was not initially tolerated by F1 weanling rats at dose levels of greater than 400 mg/kg/day, being associated with mortality at 600 and 800 mg/kg/day. Target organ effects were primarily adaptive in nature, affecting liver, thyroid and spleen at dose levels of 800 mg/kg/day (F0 generation) and from 50 mg/kg/day (F1 generation). However, the olfactory epithelium degeneration at 800 mg/kg/day was an adverse change because it involved a neural tissue that does not regenerate. Based on the results, the following no-observed-adverse-effect levels (NOAELs) were assigned:


Adult rats = 200 mg/kg/day (based on olfactory epithelium degeneration)


Offspring viability, neonatal health, developmental status at birth = 200 mg/kg/day (F0 litters, based on pup survival) and 800 mg/kg/day (F1 litters)


Physical development until adulthood = 200 mg/kg/day (based on early mortality)


Pre and postnatal functional development until adulthood = 800 mg/kg/day


Nervous system and immune system development = 800 mg/kg/day.


Integrity and performance of adult reproductive systems = 800 mg/kg/day.


 


Developmental toxicity was evaluated in a study performed according to OECD Guideline 414 (BASF SE, 2016). The test substance Geraniol Extra was administered as a solution in corn oil to 25 "time-mated" (mated by breeder) female Wistar rats/group by stomach tube at doses of 30, 100 and 300 mg/kg bw on day 6 through day 19 post coitum (p.c.). On day 20 p.c., all females were sacrificed and assessed. Under the conditions of this prenatal developmental toxicity study, the oral administration of Geraniol Extra to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) at doses as high as 300 mg/kg bw/d caused neither evidence of maternal nor developmental toxicity. In conclusion, the no observed adverse effect level (NOAEL) for maternal and prenatal developmental toxicity is 300 mg/kg bw/d.


 


Therefore, the respective oral NOAEL of 200 mg/kg bw/day for male and female rats in the EOGRTS (OECD 443) has been taken as conservative point of departure for the respective systemic DNELs derived, which covers findings observed in the subchronic repeated dose and reproduction/developmental toxicity studies.


The respective dermal NOAEL of 300 mg/kg bw/day for male and female rats in the OECD 421 has been taken as conservative point of departure for the respective systemic dermal DNEL derived.


 


Route to route extrapolation:


On the basis of the low vapour pressure (0.0001 hPa), the exposure with Geraniol 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.


 


Substance specific assessment factor for intraspecies extrapolation:


Studies on the distribution of human data for various toxicokinetic and toxicodynamic parameters were taken into account, including ‘healthy adults’ of both sexes, young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. (Hattis 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998). Using the 95th percentile of the combined distribution of the toxicokinetic and -dynamic variability of datasets is a statistical approach to account for intraspecies variability based on toxicological datasets. On the basis of the above-mentioned assessments and statistical approach, an AF of 5 for the general population and AF factor of 3 for the more homogenous worker population can be estimated to account for intraspecies variability.


It needs further to be pointed out, that the multiplicatory principle of AF used further adds to conservatism in the derivation of the respective DNELs, especially for the registered substance, which contains a toxicological profile, justifying a non-classification according to regulation (EU) 1272/2008.


Based on the availability of a sufficient toxicity dataset, the default assessment factors (acc. to ECHA GD R8) can be modified into substance specific assessment factors (AF) considering the intrinsic hazard properties of the registered substance. The following findings form the basis of the rationale for the substance specific AF:


In a subchronic feeding study in rats, no clinical signs, no effects on body weight as well as no histopathological changes were observed.


During the course of the dermal reproduction/developmental toxicity screening test according to OECD 421 the initial high dose (450 mg/kg bw/day) turned out to be intolerable for the rat skin (strong irritation reactions), so that from day 10 onwards the high dose had to be reduced to 300 mg/kg bw/day. Regarding clinical examinations, only signs of local dermal toxicity were observed for males and females at all dose levels. No effects further effects on orang toxicity, fertility or developmental toxicity were observed. Systemic exposure to geraniol is limited by the strong local irritation effects. Therefore, the NOAEL for general systemic fertility and developmental toxicity for geraniol is shown to be >300 mg/kg bw/day via the dermal route.


Target organ effects observed in the OECD 443 were primarily adaptive in nature, affecting liver, thyroid and spleen at dose levels of 800 mg/kg/day (F0 generation) and from 50 mg/kg/day (F1 generation). The olfactory epithelium degeneration at 800 mg/kg/day was an adverse change. The test compound did not adversely affect fertility of the F0 and F1 generation parental animals at all dose levels as there were no changes of male/female mating and fertility indices, time until successful copulation, duration of pregnancy and mean number of implantations. Maternal toxicity as evidence by lack of care of the pups, significantly reduced feed consumption in the dams during lactation and empty stomachs in the pups appears to be responsible for the findings seen at the top dose group.


In a gavage developmental toxicity study in rats (acc. to OECD TG 414) no adverse effects have been observed up to 300 mg/kg bw/day.


In the key studies given above, the nature of effects observed are mainly based on either adaptive or unspecific systemic adverse effects such as reduced food consumption and body weight changes. No human relevant organ specific toxicity is identified for the registered substance, which would justify a conservative default assessment factor for intraspecies variations in toxicokinetics or toxicodynamics. However, an AF of 3 or 5 has been included to cover for remaining uncertainties within a controlled subpopulation, i.e. healthy workers or the general population, respectively.


 


 


For the general population, the following DNELs were derived:


 


For derivation of the long-term systemic inhalative DNEL for Geraniol, the oral NOAEL of 200 mg/kg bw/day from the OECD 443 was taken as a basis and converted into a corrected inhalative NOAEC of 176.3 mg/m3. Applying all assessment factors, the inhalative long-term systemic DNEL was set at 3.5 mg/m3 for the general population.


 


Long-term – inhalation, systemic effects




































































Description



Value



Remark



Step 1) Relevant dose-descriptor



NOAEL: 200 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



NOAEC corrected inhalative = 200 * (50/100) * (1/1.15)  = 87 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



Remaining differences



2.5



according to R8 ECHA



Intraspecies



5



Substance specific assessment factor (see justification above)



Exposure duration



2



Use of a subchronic study as starting point for long-term systemic DNEL derivation (default assessment factor according to R8 ECHA)



Dose response



1



according to R8 ECHA



Quality of database



1



according to R8 ECHA (GLP guideline study)



DNEL



Value



 



87 / (1 x 2.5 x 5 x 2 x 1 x 1) = 3.5 mg/m3



 


 


For derivation of the long-term systemic dermal DNEL for Geraniol, the dermal NOAEL of 300 mg/kg bw/day from the OECD 421 (highest dose tested due to local dermal effects) was taken as a basis. Applying all assessment factors, the dermal long-term systemic DNEL derived was 2.5 mg/kg bw/day for the general population.


 


Long-term – dermal, systemic effects 
































































Description



Value



Remark



Step 1) Relevant dose-descriptor



NOAEL: 300 mg/kg bw/day



The NOAE of 300 mg/kg bw/day represents a very conservative starting point for the DNEL derivation, as the dermal dose in study was limited by local irritating effects. It can be assumed that the actual NOAEL for systemic effects is much higher.



Step 2) Modification of starting point



-



-



Step 3) Assessment factors



 



 



Allometric scaling



4



Assessment factor for allometric scaling according to R8 ECHA



Remaining differences



1



As no general adverse systemic effects were observed in the dermal OECD 421 up the highest dose tested (dermal dose was limited by local dermal irritation), no difference in sensitivity (toxicodynamic and/or additional toxicokinetic differences) between test animals and humans is to be expected.



Intraspecies



5



Substance specific assessment factor (see justification above)



Exposure duration



6



Use of a subacute study as starting point for long-term systemic DNEL derivation (default assessment factor according to R8 ECHA)



Dose response



1



according to R8 ECHA



Quality of database



1



according to R8 ECHA (GLP guideline study)



DNEL



Value



 



300 / (4 x 1 x 5 x 6 x 1 x 1) = 2.5 mg/kg bw/day



 


 


For derivation of the long-term systemic oral DNEL for Geraniol, the oral NOAEL of 200 mg/kg bw/day from the OECD 443 was used as stating point. Applying all assessment factors, the oral long-term systemic DNEL was set at 2 mg/kg bw/day mg/m3 for the general population.


 


Long-term – oral, systemic effects
































































Description



Value



Remark



Step 1) Relevant dose-descriptor



NOAEL: 200 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



Remaining differences



2.5



according to R8 ECHA



Intraspecies



5



Substance specific assessment factor (see justification above)



Exposure duration



2



Use of a subchronic study as starting point for long-term systemic DNEL derivation (default assessment factor according to R8 ECHA)



Dose response



1



according to R8 ECHA



Quality of database



1



according to R8 ECHA (GLP guideline study)



DNEL



Value



 



200 / (4 x 2.5 x 5 x 2 x 1 x 1) = 2 mg/kg bw/day



 


According to ECHA Guidance on information requirements and CSR, chapter R8, a DNEL for acute systemic toxicity should be derived only if an acute systemic toxicity hazard leading to C&L has been identified. Geraniol Extra is not subject to classification and labelling and consequently the establishment of DNELs for acute/short-term exposure - systemic effects is not required.


 


Geraniol is classified as Skin Irrit. Cat 2 / H315 and Eye Damage Cat 1/ H318 (Causes skin irritation and Causes serious eye damage) according to Regulation 1272/2008/EC. No experimental data are available addressing local effects in the respiratory tract. Furthermore, Geraniol is a skin sensitizer and hence subjected to classification as and Skin Sens. Cat 1 / H317 (May cause an allergic skin reaction) according to Regulation 1272/2008/EC Annex VI. Since sensitizing reactions occur also at not irritating concentrations, this endpoint was chosen as most sensitive. The RIFM Expert Panel reviewed the critical effect data for geraniol and, based on the weight of evidence, established the No Expected Sensitization Induction Level (NESIL) as 11800 μg/cm². This concentration protects also against (skin) irritation, meaning the NESIL covers both, short and long term local effects.


Furthermore, based on the ECHA guidance document (R8 p.23) no extrapolation and no assessment factor is necessary for interspecies differences in sensitivity, where human data are used as the starting point for risk characterization. It is recognized that a general DNEL must take into account 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 citral 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 1180 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