Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
161.6 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
6
Modified dose descriptor starting point:
NOAEC
Value:
969.7 mg/m³
Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
327.4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
24
Modified dose descriptor starting point:
NOAEL
Value:
7 857.1 mg/kg bw/day
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 950 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
10
Dose descriptor starting point:
other: 29525 µg/cm2

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

General considerations:

In a 90 day feeding study in rats with an equal mixture of citronellol and linalool (100 mg/kg bw/d nominal test substance, resulting in 51 or 56 mg/kg bw/d citronellol in males or females, respectively), food intake and body weight gain was reduced in males due to limited palatability (Trubek 1958). No effects were observed in urine analysis, haematology, gross examinations and in liver and kidney weights.

In a 112 day feeding study in rats with mixture of structurally similar substances, i. e. geraniol and the isomer 3,7-dimethyl-1,6-octadienol, no clinical signs, no effects on body weight as well as no histopathological changes up to a dose of 10000 ppm (550 mg/kg bw/d) have been observed (Hagan,1967).

In a 90 day gavage study in rats with a mixture of structurally similar and metabolically related substances, i. e. citronellyl acetate and geranyl acetate (CAS 150-84-5, CAS 105-87-3), no adverse effects were observed at the limit dose (NOAEL = 2000 mg/kg bw/d, corresponding to 580 mg/kg bw/d citronellyl acetate; NTP, 1987). Administration of excessive doses (4000 mg/kg bw/d) resulted in a slight increase in the mortality rate and decreases in mean body weights. In a follow-up carcinogenicity study in rats (103 weeks) an evident increase in mortality rates and body weights was noted at 2000 mg/kg bw/d and the NOAEL has been set at 1000 mg/kg bw/d (corresponding to 290 mg/kg bw/d citronellyl acetate).

In a 90 day gavage study in mice (NTP, 1987) with a mixture of structurally similar substances, i. e. citronellyl acetate and geranyl acetate, no adverse effects were observed up to the limit dose (NOAEL = 1000 mg/kg bw/d; corresponding to 290 mg/kg bw/d citronellyl acetate). Administration of excessive doses (2000 mg/kg bw/d) resulted in increases in the mortality rate and decreases in mean body weights. Furthermore, lipid inclusion and vacuolisation in liver, kidney myocard and stomach lesions were observed. 

Developmental toxicity was evaluated in a study performed according to OECD Guideline 414 (BASF SE, 2015). Citronellol was administered as a solution in corn oil to 25 "time-mated" female Wistar rats/group by stomach tube at doses of 75, 25 and 750 mg/kg bw on day 6 through day 19 post coitum (p. c.). The dosage of 750 mg/kg bw/day resulted in some substance-related findings (i. e. temporary salivation, marginally increased liver weights), which are not considered to be adverse, but mirror some adaptive responses of the animals. The test substance had no influence on gestational parameters and did not induce adverse signs of developmental toxicity or teratogenic effects at all dose levels. The NOAEL for maternal and developmental toxicity has been set at ≥ 750 mg/kg bw/day. 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.

The respective NOAEL of 550 mg/kg bw/day has been taken as point of departure for the systemic DNELs derived. It needs to be pointed out, that the multiplicatory principle of AF has been maintained, although there were no substantial adverse effects up to the limit dose. Taken together with the conservative choice of the NOAEL as point of departure, it is assumed that the derivation of DNELs, as performed further below, provides a sufficient degree of conservatism.

Route to route extrapolation:

Experimental data on absorption of citronellol are available. Based on the physicochemical properties citronellol is considered to show good bioavailability via the oral route. On the basis of the physicochemical properties and the dermal penetration data available (Gilpin 2010) an absorption of 7% via the dermal route and an absorption of 100% via the oral route has been taken for route to route extrapolation.

Citronellol would be available as a vapour only to a limited extent on the basis of its intrisic physico-chemical parameters, i. e. a low vapour pressure (8.6 Pa). This forms the rationale for a comparable or higher oral bioavailability when compared to the inhalative route. Furthermore, the moderate water solubility of citronellol (307 mg/L) bears a certain potential for retention in the mucus of the airways, whereas absorption via the gastrointestinal tract would be favoured. Overall, an equal bioavailability via the oral and inhalative route is considered appropriate and the assumption of a factor of 1 is considered valid.

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:

Feeding of citronellol/ linalool in the subchronic feeding study did not result in any test substance related adverse effects besides palatability triggered effects. Feeding of the structurally similar substances, i. e. geraniol and the isomer 3,7-dimethyl-1,6-octadienol in the subchronic feeding study did not result in any test substance related adverse effects. Subchronic administration of the respective esters resulted in no adverse effects up to the limit doses. Findings above the limit doses represent unspecific adverse systemic effects. In a gavage developmental toxicity study in rats with Citronellol (acc. to OECD TG 414) substance-related findings (i. e. temporary salivation, marginally increased liver weights), which are not considered to be adverse, but mirror some adaptive responses of the animals were observed in the high dosage group of 750 mg/kg bw/day. The test substance administration had no influence on gestational parameters and induced no adverse signs of developmental toxicity; especially, no indications of teratogenic effects occurred which could be causally related to the test substance administration.

In the key studies given above, the nature of effects observed are mainly based on either adaptive or unspecific systemic adverse effects such as temporary salivation and marginally increased liver weights. 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:

Feeding of citronellol/ linalool in the subchronic feeding study did not result in any test substance related adverse effects besides palatability triggered effects. Feeding of the structurally similar substances, i. e. geraniol and the isomer 3,7-dimethyl-1,6-octadienol in the subchronic feeding study did not result in any test substance related adverse effects. Subchronic administration of the respective esters resulted in no adverse effects up to the limit doses. Findings above the limit doses represent unspecific adverse systemic effects. In a gavage developmental toxicity study in rats with Citronellol (acc. to OECD TG 414) substance-related findings (i. e. temporary salivation, marginally increased liver weights), which are not considered to be adverse, but mirror some adaptive responses of the animals were observed in the high dosage group of 750 mg/kg bw/day. The test substance administration had no influence on gestational parameters and induced no adverse signs of developmental toxicity; especially, no indications of teratogenic effects occurred which could be causally related to the test substance administration.

In the key studies given above, the nature of effects observed are mainly based on either adaptive, rat specific 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 citronellol, the oral NOAEL of 550 mg/kg bw/d was taken as a basis and converted into a corrected inhalative NOAEC of 969.7 mg/m3. Applying all assessment factors, the inhalative long-term systemic DNEL was set at 161.6 mg/m3 for the worker.

 

Long-term – inhalation, systemic effects

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 550 mg/kg bw/day

 

Step 2) Modification of starting point

100%/100%

 

 

0.38 m3/kg bw

 

 

6.7 m3/10 m3

 

Ratio of oral (rat) to inhalation (human) absorption (see discussion)

 

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 = 550 * (100/100) * (1/0.38) * (6.7/10) = 969.7 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 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 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

DNEL

Value

 

969.7 / (1 x 1 x 3 x 2 x 1 x 1) = 161.6 mg/m3

 

 

For derivation of the long-term systemic dermal DNEL of citronellol, the oral NOAEL of 550 mg/kg bw/d was taken as a basis and was converted into a corrected dermal NOAEL of 7857.1 mg/kg bw/d. Applying all assessment factors, the dermal long-term systemic DNEL derived was 327.4mg/kg bw/d for the worker.

 

Long-term – dermal, systemic effects 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 550 mg/kg bw/day

 

Step 2) Modification of starting point

100%/7%

Ratio of oral (rat) to dermal (human) absorption (see discussion)

Modified dose-descriptor

NOAEL corrected dermal = 550 * (100/7) = 7857.1 mg/kg bw/d

Step 3) Assessment factors

 

 

Allometric scaling

4

Default assessment factor 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 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

DNEL

Value

 

7857.1 / (4 x 1 x 3 x 2 x 1 x 1) = 327.4 mg/kg bw/day

 

Short term / long term local dermal DNEL

Citronellol is irritating to skin and eyes and is a skin sensitizer. Data on skin sensitization were taken as leading toxic effect for the derivation of the short term local dermal DNEL, since skin irritation would be expected to occur at higher concentrations compared to concentrations initiating skin sensitization. The eye irritating properties of citronellol are addressed qualitatively in terms of suitable risk management measures (see further below).

Animal and human data on skin sensitization are available. In a skin sensitization study in mice (LLNA) citronellol is considered to be a weak skin sensitizer. The respective EC3 value was set to be 43.5%.

The EC3 [%] can be converted to EC3 [µg/cm2]:

EC3 [%] * 250 [µg/cm2/%] = EC3 [µg/cm2] = 43.5 * 250 = 10875 µg/cm2

In a human repeat insult patch test (HRIPT) 101 subjects (29 male and 72 female) received nine occlusive dermal applications of 25% dl-citronellol in 3:1 DEP: EtOH for induction (determined by the RIFM expert panel to be 29525 µg/cm2). Approximately 2 weeks after the last induction application, a 24 h challenge application with 25% citronellol in 3:1 DEP: EtOH was made to a naive site. In this HRIPT citronellol did not induce dermal sensitization in human subjects under the chosen testing conditions.

The Expert Panel of the Research Institute for Fragrance Materials, i. e. an independent panel of academic dermatologists, toxicologists and environmental scientists, reviewed the critical effect data for dl-citronellol and, based on the weight of evidence, established the No Expected Sensitization Induction Level (NESIL) as 29500μg/cm2 (see attachment “RIFM evaluation NESIL”). This represents an integral part of the exposure-based quantitative risk assessment approach for fragrance ingredients (detailed in the QRA Expert Group Technical Dossier of June 22, 2006). A NOEL from a well performed HRIPT will (even if higher) have precedence over all other NOELs (including LLNA EC3 values). The HRIPT used for the NESIL derivation represents such a well performed study. It needs to be noted, that the concentration reported here represent the highest concentration tested, not necessarily the highest achievable NOEL.

It is recognized that a general DNEL must take into account that the threshold for skin sensitisation 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). 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 refer mostly to individuals who have previously been sensitized to other substances which may increase the susceptibility to further sensitisers (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. Therefore a DNEL for local effects after short-term dermal exposure covering skin sensitization was set at 2950 µg/cm2. This DNEL is valid to cover also for putative local effects after long-term dermal exposure. However, to account for the skin sensitizing and skin/eye irritating properties of citronellol, dermal and eye protection as risk management measure, i. e. use of suitable gloves and goggles, is recommended for all types of worker scenarios handling high concentrations of the substance.

Short term / long term local inhalative DNEL

No valid data on local effects of citronellol after short/long-term inhalation exposure are available. The available inhalation studies with citronellol have methodological deficiencies and do therefore not allow a robust basis as point of departure for the derivation of a long term worker inhalation DNEL.

For the considered use scenarios, the amount of substance which will enter the respiratory tract is considered to be very low due to the low vapour pressure (8.6 Pa).

A toxicological working group within the German Chemical Industry Association (VCI) assessed the relationship between established occupational exposure limit (OEL) values and the classification for local irritation and corrosion of particularly industrial chemicals, ensuring the adequate applicability domain for the scope of REACH. It was aimed to assess the hypothesis that it would be possible to define pragmatic, but sufficiently reliable and safe upper cut-off limits without further animal testing. It has been shown, that the applicability domain for this approach does not cover heavy metals, sensitizers, CMR and acutely very toxic substances, as well as substances that hydrolyze to form strong acids or bases or do vigorously react with water. As a result, it was shown that the OEL for irritating substances in this dataset is not lower than 10 mg/m3 and for corrosives not lower than 1 mg/m3 (publication in preparation).

Furthermore, subacute repeated dose inhalation studies in rats from fragrance materials, with irritating properties, i. e. linalool (CAS 78-70-6), or skin sensitizing properties, i. e. hydroxycitronellal (CAS 107-75-5) are available supporting the derivation of the respective DNELs.

The structurally similar compound linalool was administered as a 6-hour, nose-only inhalation exposure to Crl: CD(SD) rats (Wil 2012). Exposures were conducted on a 5-day per week basis for a period of 2 weeks (10 total exposures for each animal). The target exposure concentrations were 0.63, 6.3 and 63 mg/m3 (equivalent to 0.1, 1, and 10 ppm, respectively) and the overall mean exposure concentrations were 0.76, 6.6, 56 mg/m3. There were no test substance-related effects on survival, clinical observations, body and organ weights, food consumption, hematology, coagulation, serum chemistry, BALF clinical chemistry, BALF cytology parameters, BALF cytokine levels, or macroscopic findings in any of the test substance-treated groups.

Test substance-related microscopic findings (inflammation and epithelial squamous and transitional hyperplasia) were noted in the nasal cavity of males and females exposed to 0.63, 6.3, and 63 mg/m3of the test substance. These findings were considered exacerbated background lesions as they were also observed in control group males and females, and were not considered adverse. Therefore, the no-observed-adverse-effect concentration was considered to be 63 mg/m3(equivalent to 10 ppm), the highest exposure concentration tested.

In a study with hydroxycitronellal, the test substance was administered as a 6-hour, nose-only inhalation exposure to Crl: CD(SD) rats (Wil 2013). Exposures were conducted on a 5-day per week basis for a period of 2 weeks (10 total exposures for each animal). The target exposure concentrations were 0.70, 7.0, and 70 mg/m3(equivalent to 0.1, 1, and 10 ppm, respectively) and the overall mean exposure concentrations were 0.84, 6.4, and 73 mg/m3. Exposure was well tolerated at all exposure levels. Test substance-related effects were limited to nonadverse clinical observations in the 70 mg/m3group females. Therefore, the no-observed-adverse-effect concentration was considered to be 70 mg/m3(equivalent to 10 ppm), the highest exposure concentration tested.

Overall, the generic DNEL of 10 mg/m3, would be adequate based on the information given in the assessment mentioned above. A comparable value would be obtained by using the systemic DNEL and applying an additional database uncertainty factor of 10 because repeated exposure studies evaluating local effects on the respiratory tract are not available. Although substances with skin sensitizing properties were outside the applicability domain for the generic assessment described above, the derived DNELs can be supported by inhalation data of a structurally similar irritating (linalool) and a skin sensitizing (hydroxycitronellal) fragrance compound. The proposed risk management measures are considered adequate and sufficient to ensure safe use of the substance in this respect.

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.

·          Cadby et al., Consumer Exposure to Fragrance Ingredients: Providing Estimates for Safety Evaluation; Regulatory Toxicology and Pharmacology 36, 246–252 (2002)

·          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.

·          ECETOC (2003). Contact Sensitization: classification according to potency.Technical Report No. 87, April 2003.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
47.8 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC
Value:
478.3 mg/m³
Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
196.4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
Value:
7 857.1 mg/kg bw/day
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 950 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
10
Dose descriptor starting point:
other: 29500 μg/cm2

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
13.8 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
Value:
550 mg/kg bw/day
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

General considerations:

In a 90 day feeding study in rats with an equal mixture of citronellol and linalool (100 mg/kg bw/d nominal test substance, resulting in 51 or 56 mg/kg bw/d citronellol in males or females, respectively), food intake and body weight gain was reduced in males due to limited palatability (Trubek 1958). No effects were observed in urine analysis, haematology, gross examinations and in liver and kidney weights.

In a 112 day feeding study in rats with mixture of structurally similar substances, i. e. geraniol and the isomer 3,7-dimethyl-1,6-octadienol, no clinical signs, no effects on body weight as well as no histopathological changes up to a dose of 10000 ppm (550 mg/kg bw/d) have been observed (Hagan,1967).

In a 90 day gavage study in rats with a mixture of structurally similar and metabolically related substances, i. e. citronellyl acetate and geranyl acetate (CAS 150-84-5, CAS 105-87-3), no adverse effects were observed at the limit dose (NOAEL = 2000 mg/kg bw/d, corresponding to 580 mg/kg bw/d citronellyl acetate; NTP, 1987). Administration of excessive doses (4000 mg/kg bw/d) resulted in a slight increase in the mortality rate and decreases in mean body weights. In a follow-up carcinogenicity study in rats (103 weeks) an evident increase in mortality rates and body weights was noted at 2000 mg/kg bw/d and the NOAEL has been set at 1000 mg/kg bw/d (corresponding to 290 mg/kg bw/d citronellyl acetate).

In a 90 day gavage study in mice (NTP, 1987) with a mixture of structurally similar substances, i. e. citronellyl acetate and geranyl acetate, no adverse effects were observed up to the limit dose (NOAEL = 1000 mg/kg bw/d; corresponding to 290 mg/kg bw/d citronellyl acetate). Administration of excessive doses (2000 mg/kg bw/d) resulted in increases in the mortality rate and decreases in mean body weights. Furthermore, lipid inclusion and vacuolisation in liver, kidney myocard and stomach lesions were observed. 

Developmental toxicity was evaluated in a study performed according to OECD Guideline 414 (BASF SE, 2015). Citronellol was administered as a solution in corn oil to 25 "time-mated" female Wistar rats/group by stomach tube at doses of 75, 25 and 750 mg/kg bw on day 6 through day 19 post coitum (p. c.). The dosage of 750 mg/kg bw/day resulted in some substance-related findings (i. e. temporary salivation, marginally increased liver weights), which are not considered to be adverse, but mirror some adaptive responses of the animals. The test substance had no influence on gestational parameters and did not induce adverse signs of developmental toxicity or teratogenic effects at all dose levels. The NOAEL for maternal and developmental toxicity has been set at ≥ 750 mg/kg bw/day. 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.

The respective NOAEL of 550 mg/kg bw/day has been taken as point of departure for the systemic DNELs derived. It needs to be pointed out, that the multiplicatory principle of AF has been maintained, although there were no substantial adverse effects up to the limit dose. Taken together with the conservative choice of the NOAEL as point of departure, it is assumed that the derivation of DNELs, as performed further below, provides a sufficient degree of conservatism.

Route to route extrapolation:

Experimental data on absorption of citronellol are available. Based on the physicochemical properties citronellol is considered to show good bioavailability via the oral route. On the basis of the physicochemical properties and the dermal penetration data available (Gilpin 2010) an absorption of 7% via the dermal route and an absorption of 100% via the oral route has been taken for route to route extrapolation.

Citronellol would be available as a vapour only to a limited extent on the basis of its intrisic physico-chemical parameters, i. e. a low vapour pressure (8.6 Pa). This forms the rationale for a comparable or higher oral bioavailability when compared to the inhalative route. Furthermore, the moderate water solubility of citronellol (307 mg/L) bears a certain potential for retention in the mucus of the airways, whereas absorption via the gastrointestinal tract would be favoured. Overall, an equal bioavailability via the oral and inhalative route is considered appropriate and the assumption of a factor of 1 is considered valid.

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:

Feeding of citronellol/ linalool in the subchronic feeding study did not result in any test substance related adverse effects besides palatability triggered effects. Feeding of the structurally similar substances, i. e. geraniol and the isomer 3,7-dimethyl-1,6-octadienol in the subchronic feeding study did not result in any test substance related adverse effects. Subchronic administration of the respective esters resulted in no adverse effects up to the limit doses. Findings above the limit doses represent unspecific adverse systemic effects. In a gavage developmental toxicity study in rats with Citronellol (acc. to OECD TG 414) substance-related findings (i. e. temporary salivation, marginally increased liver weights), which are not considered to be adverse, but mirror some adaptive responses of the animals were observed in the high dosage group of 750 mg/kg bw/day. The test substance administration had no influence on gestational parameters and induced no adverse signs of developmental toxicity; especially, no indications of teratogenic effects occurred which could be causally related to the test substance administration.

In the key studies given above, the nature of effects observed are mainly based on either adaptive or unspecific systemic adverse effects such as temporary salivation and marginally increased liver weights. 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:

Feeding of citronellol/ linalool in the subchronic feeding study did not result in any test substance related adverse effects besides palatability triggered effects. Feeding of the structurally similar substances, i. e. geraniol and the isomer 3,7-dimethyl-1,6-octadienol in the subchronic feeding study did not result in any test substance related adverse effects. Subchronic administration of the respective esters resulted in no adverse effects up to the limit doses. Findings above the limit doses represent unspecific adverse systemic effects. In a gavage developmental toxicity study in rats with Citronellol (acc. to OECD TG 414) substance-related findings (i. e. temporary salivation, marginally increased liver weights), which are not considered to be adverse, but mirror some adaptive responses of the animals were observed in the high dosage group of 750 mg/kg bw/day. The test substance administration had no influence on gestational parameters and induced no adverse signs of developmental toxicity; especially, no indications of teratogenic effects occurred which could be causally related to the test substance administration.

In the key studies given above, the nature of effects observed are mainly based on either adaptive, rat specific 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 citronellol, the oral NOAEL of 550 mg/kg bw/d was taken as a basis and converted into a corrected inhalative NOAEC of 478.3 mg/m3. Applying all assessment factors, the inhalative long-term systemic DNEL was set at 47.8 mg/m3 for the general population.

 

Long-term – inhalation, systemic effects

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 550 mg/kg bw/day

 

Step 2) Modification of starting point

100%/100%

 

 

1.15 m3/kg bw

 

Ratio of oral (rat) to inhalation (human) absorption (see discussion)

 

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 = 550 * (100/100) * (1/1.15) = 478.3 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 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

DNEL

Value

 

478.3 / (1 x 1 x 5 x 2 x 1 x 1) = 47.8 mg/m3

  

For derivation of the long-term systemic dermal DNEL of citronellol, the oral NOAEL of 550 mg/kg bw/d was taken as a basis and was converted into a corrected dermal NOAEL of 7857.1 mg/kg bw/d. Applying all assessment factors, the dermal long-term systemic DNEL derived was 196.4 mg/kg bw/d for the general population.

 

Long-term – dermal, systemic effects 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 550 mg/kg bw/day

 

Step 2) Modification of starting point

100%/7%

Ratio of oral (rat) to dermal (human) absorption (see discussion)

Modified dose-descriptor

NOAEL corrected dermal = 550 * (100/7) = 7857.1 mg/kg bw/d

Step 3) Assessment factors

 

 

Allometric scaling

4

Default assessment factor 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

DNEL

Value

 

7857.1 / (4 x 1 x 5 x 2 x 1 x 1) = 196.4 mg/kg bw/day

  

For derivation of the long-term systemic oral DNEL of citronellol, the NOAEL 550 mg/kg bw/d was used. After applying the assessment factors, the oral long-term systemic DNEL was set at 13.8 mg/kg bw/day for the general population.

 

Long-term – oral, systemic effects

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 550 mg/kg bw/day

 

Step 2) Modification of starting point

-

-

Step 3) Assessment factors

 

 

Allometric scaling

4

Default assessment factor 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

DNEL

Value

 

550 / (4 x 1 x 5 x 2 x 1 x 1) = 13.8 mg/kg bw/day

 

Short term / long term local dermal DNEL

Citronellol is irritating to skin and eyes and is a skin sensitizer. Data on skin sensitization were taken as leading toxic effect for the derivation of the short term local dermal DNEL, since skin irritation would be expected to occur at higher concentrations compared to concentrations initiating skin sensitization. The eye irritating properties of citronellol are considered to be of no relevance for the general population based on the low final use levels in consumer products.

Animal and human data on skin sensitization are available. In a skin sensitization study in mice (LLNA) citronellol is considered to be a weak skin sensitizer. The respective EC3 value was set to be 43.5%. The EC3 [%] can be converted to EC3 [µg/cm2]:

EC3 [%] * 250 [µg/cm2/%] = EC3 [µg/cm2] = 43.5 * 250 = 10875 µg/cm2

In a human repeat insult patch test (HRIPT) 101 subjects (29 male and 72 female) received nine occlusive dermal applications of 25% dl-citronellol in 3:1 DEP: EtOH for induction (determined by the RIFM expert panel to be 29525 µg/cm2). Approximately 2 weeks after the last induction application, a 24 h challenge application with 25% citronellol in 3:1 DEP: EtOH was made to a naive site. In this HRIPT citronellol did not induce dermal sensitization in human subjects under the chosen testing conditions.

The Expert Panel of the Research Institute for Fragrance Materials, i. e. an independent panel of academic dermatologists, toxicologists and environmental scientists, reviewed the critical effect data for dl-citronellol and, based on the weight of evidence, established the No Expected Sensitization Induction Level (NESIL) as 29500μg/cm2(see attachment “RIFM evaluation NESIL”). This represents an integral part of the exposure-based quantitative risk assessment approach for fragrance ingredients (detailed in the QRA Expert Group Technical Dossier of June 22, 2006). A NOEL from a well performed HRIPT will (even if higher) have precedence over all other NOELs (including LLNA EC3 values). The HRIPT used for the NESIL derivation represents such a well performed study. It needs to be noted, that the concentration reported here represent the highest concentration tested, not necessarily the highest achievable NOEL.

It is recognized that a general DNEL must take into account that the threshold for skin sensitisation 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). 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 refer mostly to individuals who have previously been sensitized to other substances which may increase the susceptibility to further sensitisers (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. Therefore, a DNEL for local effects after short-term dermal exposure covering skin sensitization was set at 2950 µg/cm2. This DNEL is valid to cover also for putative local effects after long-term dermal exposure.

 

Short term / long term local inhalative DNEL

No valid data on local effects of citronellol after short/long-term inhalation exposure are available. The available inhalation studies with citronellol have methodological deficiencies and do therefore not allow a robust basis as point of departure for the derivation of a long term consumer inhalation DNEL.

For the considered use scenarios, the amount of substance which will enter the respiratory tract is considered to be very low due to the low vapour pressure (8.6 Pa).

A toxicological working group within the German Chemical Industry Association (VCI) assessed the relationship between established occupational exposure limit (OEL) values and the classification for local irritation and corrosion of particularly industrial chemicals, ensuring the adequate applicability domain for the scope of REACH. It was aimed to assess the hypothesis that it would be possible to define pragmatic, but sufficiently reliable and safe upper cut-off limits without further animal testing. It has been shown, that the applicability domain for this approach does not cover heavy metals, sensitizers, CMR and acutely very toxic substances, as well as substances that hydrolyze to form strong acids or bases or do vigorously react with water. As a result, it was shown that the OEL for irritating substances in this dataset is not lower than 10 mg/m3 and for corrosives not lower than 1 mg/m3 (publication in preparation).

Furthermore, subacute repeated dose inhalation studies in rats from fragrance materials, with irritating properties, i. e. linalool (CAS 78-70-6), or skin sensitizing properties, i. e. hydroxycitronellal (CAS 107-75-5) are available supporting the derivation of the respective DNELs.

The structurally similar compound linalool was administered as a 6-hour, nose-only inhalation exposure to Crl: CD(SD) rats (Wil 2012). Exposures were conducted on a 5-day per week basis for a period of 2 weeks (10 total exposures for each animal). The target exposure concentrations were 0.63, 6.3 and 63 mg/m3(equivalent to 0.1, 1, and 10 ppm, respectively) and the overall mean exposure concentrations were 0.76, 6.6, 56 mg/m3. There were no test substance-related effects on survival, clinical observations, body and organ weights, food consumption, hematology, coagulation, serum chemistry, BALF clinical chemistry, BALF cytology parameters, BALF cytokine levels, or macroscopic findings in any of the test substance-treated groups.

Test substance-related microscopic findings (inflammation and epithelial squamous and transitional hyperplasia) were noted in the nasal cavity of males and females exposed to 0.63, 6.3, and 63 mg/m3of the test substance. These findings were considered exacerbated background lesions as they were also observed in control group males and females, and were not considered adverse. Therefore, the no-observed-adverse-effect concentration was considered to be 63 mg/m3(equivalent to 10 ppm), the highest exposure concentration tested.

In a study with hydroxycitronellal, the substance was administered as a 6-hour, nose-only inhalation exposure to Crl: CD(SD) rats (Wil 2013). Exposures were conducted on a 5-day per week basis for a period of 2 weeks (10 total exposures for each animal). The target exposure concentrations were 0.70, 7.0, and 70 mg/m3(equivalent to 0.1, 1, and 10 ppm, respectively) and the overall mean exposure concentrations were 0.84, 6.4, and 73 mg/m3. Exposure was well tolerated at all exposure levels. Test substance-related effects were limited to nonadverse clinical observations in the 70 mg/m3group females. Therefore, the no-observed-adverse-effect concentration was considered to be 70 mg/m3(equivalent to 10 ppm), the highest exposure concentration tested.

Overall, the generic DNEL of 10 mg/m3would be adequate based on the information given in the assessment mentioned above. A comparable value would be obtained by using the systemic DNEL and applying an additional database uncertainty factor of 10 because repeated exposure studies evaluating local effects on the respiratory tract are not available. Although substances with skin sensitizing properties were outside the applicability domain for the generic assessment described above, the derived DNELs can be supported by inhalation data of a structurally similar irritating (linalool) and a skin sensitizing (hydroxycitronellal) fragrance compound. The proposed risk management measures are considered adequate and sufficient to ensure safe use of the substance in this respect.

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.

·          Cadby et al., Consumer Exposure to Fragrance Ingredients: Providing Estimates for Safety Evaluation; Regulatory Toxicology and Pharmacology 36, 246–252 (2002)

·          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.

·          ECETOC (2003). Contact Sensitization: classification according to potency.Technical Report No. 87, April 2003.