Reaction mass of 2,6-Octadien-1-ol, 3,7-dimethyl-, (E) and 2,6-Octadien-1-ol, 3,7-dimethyl-, (Z)-

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

14.7 mg/m³

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

Overall assessment factor (AF):

6

Modified dose descriptor starting point:

NOAEC

Value:

88.2 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:

8.3 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

Overall assessment factor (AF):

24

Modified dose descriptor starting point:

NOAEL

Value:

200 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:

DNEL (Derived No Effect Level)

Value:

11 800 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

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

No data concerning the repeated dose toxicity of the reaction mass of geraniol and nerol is available. However, the 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.

 

An oral study according to OECD 421 was performed with the reaction mass of geraniol and nerol (E- and Z-isomer, 60:40 -mixture) in Wistar rats (BASF SE, 2010). The dose levels were 0, 100, 300 and 1000 mg/kg body weight/day in corn oil as vehicle.

All mid- and high-dose as well as some low-dose animals of both sex showed transient salivation for a few minutes immediately after each treatment. This was likely to be induced by the unpleasant taste of the test substance or by local irritation of the upper digestive tract. It is neither considered to be a sign of systemic toxicity nor as adverse. Clinical observations indicated distinct toxicity in the exposed parental animals of the high dose group (1000 mg/kg bw/d) but not in the animals of the mid- and low-dose group. A reduction of food consumption and decreased body weight in males had been determined during treatment weeks 2-4. A similar pattern as for clinical observations was noted for body weight and body weight change of the parental animals.

The test compound did not adversely affect fertility of the F0 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.

Pregnancy was unaffected at the low-dose. However, there is an alert for a dose-dependent adverse effect of the test substance on pre-/postnatal development of the F1 offspring at mid and high-dose level (300 and 1000 mg/kg bw/d). Overall, maternal toxicity as evidence by lack of care of the pups, significantly reduced feed consumption in the dams and empty stomachs in the pups appears to be responsible for the findings seen at the top and mid dose groups. Effects are mainly due to one animal each at either dose group. The observed findings show a questionable correlation between the effects seen on maternal toxicity and effects seen on the offspring. Hence, their relevance based only on this screening study is doubtful and more complete studies at tolerated doses are required.

Based on the present data, the NOAEL for fertility was set to 1000 mg/kg bw/day and for developmental toxicity to 100 mg/kg bw/day.

 

Apart from studies with the registered substance reaction mass of geraniol and nerol (E- and Z-isomer, 60:40 -mixture), studies using the pure test substance geraniol were taken into account to address the endpoint of toxicity to reproduction.

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 anddevelopmental toxicityfor geraniol is shown to be >300 mg/kg bw/day via the dermal route, respectively.

 

Developmental toxicity was evaluated in a study performed according to OECD Guideline 414 (BASF AG, 2015). Geraniol 60 was administered as a solution in olive oil to 25 "time-mated" female Wistar rats/group by stomach tube at doses of 100, 300 and 1000 mg/kg bw on day 6 through day 19 post coitum (p.c.).As a result, administration of 1000 mg/kg bw elicited substance-induced effects on the dams including signs of maternal toxicity like reduced body weight gain, resulting in about 10% less weight gain during treatment period and a reduced corrected (net) body weight gain was (about -14%). The dosage of 300 mg/kg bw/day resulted in reduced body weight gain and reduced corrected (net) body weight gain (about -13%). At the low dose (100 mg/kg bw/day) no substance-induced effects on dams occurred. The test substance had no influence on gestational parameters. Fetal examinations revealed that there is no effect of the compound on the respective morphological structures up to the highest dose tested (1000 mg/kg bw/d). Incidences of dilated renal pelvis and incomplete ossifications of various skeletal elements represent temporary delays in development which have no permanent effect on morphology and function of the affected organs or structures.The NOAEL for maternal toxicity has been set at 100 mg/kg bw/day and at 300 mg/kg bw/day for developmental toxicity.

As the experimental exposure of a study according to Guideline OECD 414 adequately covered the pregnancy of the species under investigation an AF for exposure duration is not necessary.

 

Therefore, the respective NOAEL of 100 mg/kg bw/day for male and female rats in thescreening study to reproduction and development(OECD 421, BASF SE, 2010) 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.

 

Route to route extrapolation:

On the basis of the low vapour pressure (0.01 hPa), the exposure with Geraniol 60 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.

 

No experimental data on dermal absorption of Geraniol 60 is available. However, data from the single component Geraniol (CAS 106-24-1) can be used for read-across.

A dermal absorption study was conducted with 230 male mice, using an area on the shaved abdominal skin measuring 2.2 cm²(Meyer, 1959). Absorption was noted over a period of up to 2 hours, and Eserine (0.23%) was used as an indicator as it has a characteristic and easily recorded effect on striated muscles. Geraniol was used as a carrier for Eserine, and the latency period between the application to the skin and the appearance of Eserine's effect in the periodically stimulated masticatory muscles was used as a measure of the absorption time. The time to absorption was recorded, and experiments were conducted 3 - 6 times. As result, no absorption was noted. 

 

Van Ravenzwaay and Leibold (2004) have compared the differences in absorption for a large number of chemicals and found the dermal absorption through rat skin is generally at least 2.3 times greater than through human skin. Taking this information together with the observation of no absorption in an in vivo dermal absorption study in mice, a very low penetration through the skin might be assumed. A worst case of 50% penetration through human skin is assumed for Geraniol 60, although realistic values may be considerably much lower. Hence, an assessment factor of 2 (Ratio of oral (rat) to dermal (human) absorption, 100%/50%) was chosen.

 

Substance specific assessment factor for remaining differences

Although ‘residual’ interspecies variability may remain following allometric scaling, this is largely accounted for in the assessment factors proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies assessment factors (Calabrese and Gilbert, 1993).

Furthermore, within the ERASM project, it was suggested that a factor of 2.5 for ‘remaining‘ interspecies differences may be questionable as a standard procedure (Escher and Mangelsdorf, 2009; Batkeet al, 2010; Bitsch et al, 2006). The comparison of rats and mice indicated an interspecies difference of 1.4 for these two species. This corresponds closely to an interspecies AF solely explained by allometry (7:4 = 1.75) without an additional factor of 2.5 for putative toxicodynamic differences.

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.

In thereproduction/developmental toxicity screening test according to OECD 421,areduction of food consumption, decreased body weights, decreased body weight changesand clinical observations, i.e. temporary salivationwere observed in parental animals. The test compound did not adversely affect fertility of the F0 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.Pregnancy was unaffected at the low-dose. However, maternal toxicity as evidence by lack of care of the pups, significantly reduced feed consumption in the dams and empty stomachs in the pups appears to be responsible for the findings seen at the top and mid dose groups. Effects are mainly due to one animal each at either dose group. The observed findings show a questionable correlation between the effects seen on maternal toxicity and effects seen on the offspring.

In a gavage developmental toxicity study in rats (acc. to OECD TG 414) adverse effects have been observed consisting of decreased body weight gain and clinical observations, i.e. temporary salivation. The test substance administration had no influence on gestational parameters. Incidences of dilated renal pelvis and incomplete ossifications of various skeletal elements represent temporary delays in development which have no permanent effect on morphology and function of the affected organs or structures.

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. In order to add sufficient conservatism into the DNEL derivation, namely to cover for the uncertainty of an putative systemically toxic parent compound/metabolite being excreted dependent on the caloric demand, an AF of 4 for allometric scaling is included for oral/ dermal systemic long term DNELs.

Since only rat specific but no human relevant organ specific toxicity has been observed, no additional AF covering toxicodynamic differences between rats and humans are considered necessary. In fact, an underestimation of interspecies differences between rats and humans beyond allometric scaling is unlikely due to the favorable toxicological profile of the registered substance.

It needs further to be pointed out, that the multiplicatory principle of different AFs 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 67/548/EEC and regulation (EU) 1272/2008.

 

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 67/548/EEC and 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.

In thereproduction/developmental toxicity screening test according to OECD 421,areduction of food consumption, decreased body weights, decreased body weight changesand clinical observations, i.e. temporary salivationwere observed in parental animals. The test compound did not adversely affect fertility of the F0 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.Pregnancy was unaffected at the low-dose. However, maternal toxicity as evidence by lack of care of the pups, significantly reduced feed consumption in the dams and empty stomachs in the pups appears to be responsible for the findings seen at the top and mid dose groups. Effects are mainly due to one animal each at either dose group. The observed findings show a questionable correlation between the effects seen on maternal toxicity and effects seen on the offspring.

In a gavage developmental toxicity study in rats (acc. to OECD TG 414) adverse effects have been observed consisting of decreased body weight gain and clinical observations, i.e. temporary salivation. The test substance administration had no influence on gestational parameters. Incidences of dilated renal pelvis and incomplete ossifications of various skeletal elements represent temporary delays in development which have no permanent effect on morphology and function of the affected organs or structures.

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 60, the oral NOAEL of 100 mg/kg bw/d was taken as a basis and converted into a corrected inhalative NOAEC of 88.2 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 14.7mg/m³ for the worker.

 

Long-term – inhalation, systemic effects

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 100 mg/kg bw/day
Step 2) Modification of starting point	50%/100%       0.38 m^3/kg bw     6.7 m^3/10 m^3	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 m^3/10 m^3)
Modified dose-descriptor	NOAEC corrected inhalative = 100 * (50/100) * (1/0.38) * (6.7/10) = 88.2 mg/m^3
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 2012.
Remaining differences	1	Substance specific assessment factor (see justification above)
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 2012).
Dose response	1	according to R8 ECHA 2012
Quality of database	1	according to R8 ECHA 2012 (GLP guideline Study)
DNEL	Value
	88.2 / (1 x 1 x 3 x 2 x 1 x 1) = 14.7 mg/m^3

 

For derivation of the long-term systemic dermal DNEL for Geraniol 60, the oral NOAEL of 100 mg/kg bw/d was taken as a basis. Applying all assessment factors, the dermal long-term systemic DNEL derived was 8.3 mg/kg bw/d for the worker.

 

Long-term – dermal, systemic effects 

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 100 mg/kg bw/day
Step 2) Modification of starting point	100%/50%	Substance specific assessment factor for oral to dermal extrapolation based onin vivodermal absorption study (see justification above)
Modified dose-descriptor	NOAEL corrected dermal = 100 * (100/50) = 200 mg/kg bw/d
Step 3) Assessment factors
Allometric scaling	4	Assessment factor for allometric scaling according to R8 ECHA 2012
Remaining differences	1	Substance specific assessment factor: (see justification above)
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 2012).
Dose response	1	according to R8 ECHA 2012
Quality of database	1	according to R8 ECHA 2012 (GLP guideline Study)
DNEL	Value
	200 / (4 x 1 x 3 x 2 x 1 x 1) = 8.3 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 60 is not subject to classification and labelling and consequently the establishment of DNELs for acute/short-term exposure - systemic effects is not required.

 

Geraniol 60 is a skin and eye irritant and hence subjected to classification as R38 and R41 according to Directive 67/548/EEC and skin irritation and eye damage Cat 2 / H 315 and Cat 1/ H 318 (Causes skin irritation and Causes serious eye damage), respectively, according to Regulation 1272/2008/EC. No experimental data are available addressing local effects in the respiratory tract. Furthermore, Geraniol 60 is a skin sensitiser and hence subjected to classification as R43 according to Directive 67/548/EEC and skin sens. Cat 1B / H317 (May cause an allergic skin reaction) according to Regulation 1272/2008/EC. 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:

4.3 mg/m³

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

Overall assessment factor (AF):

10

Modified dose descriptor starting point:

NOAEC

Value:

43.5 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:

5 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

Overall assessment factor (AF):

40

Modified dose descriptor starting point:

NOAEL

Value:

200 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:

DNEL (Derived No Effect Level)

Value:

11 800 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

Dose descriptor:

other: NOAEL

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:

2.5 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

Overall assessment factor (AF):

40

Modified dose descriptor starting point:

NOAEL

Value:

100 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:

medium hazard (no threshold derived)

Additional information - General Population

No data concerning the repeated dose toxicity of the reaction mass of geraniol and nerol is available. However, the 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.

 

An oral study according to OECD 421 was performed with the reaction mass of geraniol and nerol (E- and Z-isomer, 60:40 -mixture) in Wistar rats (BASF SE, 2010). The dose levels were 0, 100, 300 and 1000 mg/kg body weight/day in corn oil as vehicle.

All mid- and high-dose as well as some low-dose animals of both sex showed transient salivation for a few minutes immediately after each treatment. This was likely to be induced by the unpleasant taste of the test substance or by local irritation of the upper digestive tract. It is neither considered to be a sign of systemic toxicity nor as adverse. Clinical observations indicated distinct toxicity in the exposed parental animals of the high dose group (1000 mg/kg bw/d) but not in the animals of the mid- and low-dose group. A reduction of food consumption and decreased body weight in males had been determined during treatment weeks 2-4. A similar pattern as for clinical observations was noted for body weight and body weight change of the parental animals.

The test compound did not adversely affect fertility of the F0 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.

Pregnancy was unaffected at the low-dose. However, there is an alert for a dose-dependent adverse effect of the test substance on pre-/postnatal development of the F1 offspring at mid and high-dose level (300 and 1000 mg/kg bw/d). Overall, maternal toxicity as evidence by lack of care of the pups, significantly reduced feed consumption in the dams and empty stomachs in the pups appears to be responsible for the findings seen at the top and mid dose groups. Effects are mainly due to one animal each at either dose group. The observed findings show a questionable correlation between the effects seen on maternal toxicity and effects seen on the offspring. Hence, their relevance based only on this screening study is doubtful and more complete studies at tolerated doses are required.

Based on the present data, the NOAEL for fertility was set to 1000 mg/kg bw/day and for developmental toxicity to 100 mg/kg bw/day.

 

Apart from studies with the registered substance reaction mass of geraniol and nerol (E- and Z-isomer, 60:40 -mixture), studies using the pure test substance geraniol were taken into account to address the endpoint of toxicity to reproduction.

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 anddevelopmental toxicityfor geraniol is shown to be >300 mg/kg bw/day via the dermal route, respectively.

 

Developmental toxicity was evaluated in a study performed according to OECD Guideline 414 (BASF AG, 2015). Geraniol 60 was administered as a solution in olive oil to 25 "time-mated" female Wistar rats/group by stomach tube at doses of 100, 300 and 1000 mg/kg bw on day 6 through day 19 post coitum (p.c.).As a result, administration of 1000 mg/kg bw elicited substance-induced effects on the dams including signs of maternal toxicity like reduced body weight gain, resulting in about 10% less weight gain during treatment period and a reduced corrected (net) body weight gain was (about -14%). The dosage of 300 mg/kg bw/day resulted in reduced body weight gain and reduced corrected (net) body weight gain (about -13%). At the low dose (100 mg/kg bw/day) no substance-induced effects on dams occurred. The test substance had no influence on gestational parameters. Fetal examinations revealed that there is no effect of the compound on the respective morphological structures up to the highest dose tested (1000 mg/kg bw/d). Incidences of dilated renal pelvis and incomplete ossifications of various skeletal elements represent temporary delays in development which have no permanent effect on morphology and function of the affected organs or structures.The NOAEL for maternal toxicity has been set at 100 mg/kg bw/day and at 300 mg/kg bw/day for developmental toxicity.

As the experimental exposure of a study according to Guideline OECD 414 adequately covered the pregnancy of the species under investigation an AF for exposure duration is not necessary.

 

Therefore, the respective NOAEL of 100 mg/kg bw/day for male and female rats in thescreening study to reproduction and development(OECD 421, BASF SE, 2010) 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.

 

Route to route extrapolation:

On the basis of the low vapour pressure (0.01 hPa), the exposure with Geraniol 60 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.

 

No experimental data on dermal absorption of Geraniol 60 is available. However, data from the single component Geraniol (CAS 106-24-1) can be used for read-across.

A dermal absorption study was conducted with 230 male mice, using an area on the shaved abdominal skin measuring 2.2 cm²(Meyer, 1959). Absorption was noted over a period of up to 2 hours, and Eserine (0.23%) was used as an indicator as it has a characteristic and easily recorded effect on striated muscles. Geraniol was used as a carrier for Eserine, and the latency period between the application to the skin and the appearance of Eserine's effect in the periodically stimulated masticatory muscles was used as a measure of the absorption time. The time to absorption was recorded, and experiments were conducted 3 - 6 times. As result, no absorption was noted. 

 

Van Ravenzwaay and Leibold (2004) have compared the differences in absorption for a large number of chemicals and found the dermal absorption through rat skin is generally at least 2.3 times greater than through human skin. Taking this information together with the observation of no absorption in an in vivo dermal absorption study in mice, a very low penetration through the skin might be assumed. A worst case of 50% penetration through human skin is assumed for Geraniol 60, although realistic values may be considerably much lower. Hence, an assessment factor of 2 (Ratio of oral (rat) to dermal (human) absorption, 100%/50%) was chosen.

 

Substance specific assessment factor for remaining differences

Although ‘residual’ interspecies variability may remain following allometric scaling, this is largely accounted for in the assessment factors proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies assessment factors (Calabrese and Gilbert, 1993).

Furthermore, within the ERASM project, it was suggested that a factor of 2.5 for ‘remaining‘ interspecies differences may be questionable as a standard procedure (Escher and Mangelsdorf, 2009; Batkeet al, 2010; Bitsch et al, 2006). The comparison of rats and mice indicated an interspecies difference of 1.4 for these two species. This corresponds closely to an interspecies AF solely explained by allometry (7:4 = 1.75) without an additional factor of 2.5 for putative toxicodynamic differences.

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.

In thereproduction/developmental toxicity screening test according to OECD 421,areduction of food consumption, decreased body weights, decreased body weight changesand clinical observations, i.e. temporary salivationwere observed in parental animals. The test compound did not adversely affect fertility of the F0 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.Pregnancy was unaffected at the low-dose. However, maternal toxicity as evidence by lack of care of the pups, significantly reduced feed consumption in the dams and empty stomachs in the pups appears to be responsible for the findings seen at the top and mid dose groups. Effects are mainly due to one animal each at either dose group. The observed findings show a questionable correlation between the effects seen on maternal toxicity and effects seen on the offspring.

In a gavage developmental toxicity study in rats (acc. to OECD TG 414) adverse effects have been observed consisting of decreased body weight gain and clinical observations, i.e. temporary salivation. The test substance administration had no influence on gestational parameters. Incidences of dilated renal pelvis and incomplete ossifications of various skeletal elements represent temporary delays in development which have no permanent effect on morphology and function of the affected organs or structures.

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. In order to add sufficient conservatism into the DNEL derivation, namely to cover for the uncertainty of an putative systemically toxic parent compound/metabolite being excreted dependent on the caloric demand, an AF of 4 for allometric scaling is included for oral/ dermal systemic long term DNELs.

Since only rat specific but no human relevant organ specific toxicity has been observed, no additional AF covering toxicodynamic differences between rats and humans are considered necessary. In fact, an underestimation of interspecies differences between rats and humans beyond allometric scaling is unlikely due to the favorable toxicological profile of the registered substance.

It needs further to be pointed out, that the multiplicatory principle of different AFs 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 67/548/EEC and regulation (EU) 1272/2008.

 

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 67/548/EEC and 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.

In thereproduction/developmental toxicity screening test according to OECD 421,areduction of food consumption, decreased body weights, decreased body weight changesand clinical observations, i.e. temporary salivationwere observed in parental animals. The test compound did not adversely affect fertility of the F0 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.Pregnancy was unaffected at the low-dose. However, maternal toxicity as evidence by lack of care of the pups, significantly reduced feed consumption in the dams and empty stomachs in the pups appears to be responsible for the findings seen at the top and mid dose groups. Effects are mainly due to one animal each at either dose group. The observed findings show a questionable correlation between the effects seen on maternal toxicity and effects seen on the offspring.

In a gavage developmental toxicity study in rats (acc. to OECD TG 414) adverse effects have been observed consisting of decreased body weight gain and clinical observations, i.e. temporary salivation. The test substance administration had no influence on gestational parameters. Incidences of dilated renal pelvis and incomplete ossifications of various skeletal elements represent temporary delays in development which have no permanent effect on morphology and function of the affected organs or structures.

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 60, the oral NOAEL of 100 mg/kg bw/d was taken as a basis and converted into a corrected inhalative NOAEC of 88.2 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 4.3mg/m³ for the general population.

 

Long-term – inhalation, systemic effects

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 100 mg/kg bw/day
Step 2) Modification of starting point	50%/100%       1.15 m^3/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 = 100 * (50/100) *(1/1.15)= 43.5 mg/m^3
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 2012.
Remaining differences	1	Substance specific assessment factor (see justification above)
Intraspecies	5	Substance specific assessment factor (see justification above)
Exposure duration	2	Use of a subchronic study as starting point forlong-term systemic DNEL derivation (default assessment factor according to R8 ECHA 2012).
Dose response	1	according to R8 ECHA 2012
Quality of database	1	according to R8 ECHA 2012 (GLP guideline Study)
DNEL	Value
	43.5 / (1 x 1 x 5 x 2 x 1 x 1) =4.3 mg/m^3

 

For derivation of the long-term systemic dermal DNEL for Geraniol 60, the oral NOAEL of 100 mg/kg bw/d was taken as a basis. Applying all assessment factors, the dermal long-term systemic DNEL derived was 5.0 mg/kg bw/d for thegeneral population.

 

Long-term – dermal, systemic effects 

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 100 mg/kg bw/day
Step 2) Modification of starting point	2	Substance specific assessment factor for oral to dermal extrapolation based onin vitrodermal penetration/permeability study (see justification above)
Modified dose-descriptor	NOAEL corrected dermal = 100 * 2 = 200 mg/kg bw/d
Step 3) Assessment factors
Allometric scaling	4	Assessment factor for allometric scaling according to R8 ECHA 2012
Remaining differences	1	Substance specific assessment factor: (see justification above)
Intraspecies	5	Substance specific assessment factor: (see justification above)
Exposure duration	2	Use of a subchronic study as starting point forlong-term systemic DNEL derivation (default assessment factor according to R8 ECHA 2012).
Dose response	1	according to R8 ECHA 2012
Quality of database	1	according to R8 ECHA 2012 (GLP guideline Study)
DNEL	Value
	200 / (4 x 1 x 5 x 2 x 1 x 1) = 5.0 mg/kg bw/day

 

For derivation of the long-term systemic oral DNEL for Geraniol 60, the oral NOAEL of 100 mg/kg bw/d was taken as a basis. Applying all assessment factors, the dermal long-term systemic DNEL derived was 2.5 mg/kg bw/d for the general population.

 

Long-term – oral, systemic effects

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 100 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 2012
Remaining differences	1	Substance specific assessment factor: (see justification above)
Intraspecies	5	Substance specific assessment factor: (see justification above)
Exposure duration	2	Use of a subchronic study as starting point forlong-term systemic DNEL derivation (default assessment factor according to R8 ECHA 2012).
Dose response	1	according to R8 ECHA 2012
Quality of database	1	according to R8 ECHA 2012 (GLP guideline Study)
DNEL	Value
	100 / (4 x 1 x 5 x 2 x 1 x 1) = 2.5 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 60 is not subject to classification and labelling and consequently the establishment of DNELs for acute/short-term exposure - systemic effects is not required.

 

Geraniol 60 is a skin and eye irritant and hence subjected to classification as R38 and R41 according to Directive 67/548/EEC and skin and eye damage Cat 2 / H 315 and Cat 1/ H 318 (Causes skin irritation and Causes serious eye damage), respectively, according to Regulation 1272/2008/EC. No experimental data are available addressing local effects in the repsiratory tract. Furthermore, Geraniol is a skin sensitiser and hence subjected to classification as R43 according to Directive 67/548/EEC and skin sens. Cat 1B / H317 (May cause an allergic skin reaction) according to Regulation 1272/2008/EC. 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 11800μg/cm². This concentration protects also against (skin) irritation, meaning the NESIL covers both, short and long term local effects.