Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
9 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
12
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

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

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.7 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
63
Modified dose descriptor starting point:
LOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

No DNELs were derived for systemic effects after short term dermal exposure, as the substance exhibits no hazardous potential in terms of these endpoints, and the respective long term systemic DNELs are considered sufficient. 

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
140 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
10
Dose descriptor:
other: NOAEL
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

The 2-year feeding study in mice has been chosen (NTP 2003d) for the derivation of DNELs for systemic dermal effects after long term exposure by route to route extrapolation. A LOAEL of 60 mg/kg bw/ day on the basis of impaired body weight gains has been observed representing the point of departure. This point of departure is valid to cover all adverse effects observed in different species and different studies available.

For the derivation of DNELs for systemic inhalative effects after long term exposure, the available inhalation studies, i. e. a 21-day and 13-week inhalation toxicity study (6h/day) in rats (Gaworski 1993) and a developmental toxicity study in rats (Gaworski 1992), have been chosen. The observed NOAEC of 34 ppm or 215 mg/m3on the basis of evident local irritation and impaired body weight gains serves as point of departure. 

On the basis of the toxicokinetic data, a high rate of oral absorption in rats has been observed and a 90% bioavailability has been set for the oral route. On the basis of the data available for dermal absorption, a dermal penetration rate of 50% has been set for route to route extrapolation. Based on the availability of a sufficient toxicity dataset, the default assessment factors (acc. to ECHA GD R8) have been modified into substance specific assessment factors (AF), considering the intrinsic hazard properties of the registered substance.

 

The values used as point of departure for the respective systemic DNELs were based on general systemic effects of Citral such as impaired body weight gains and local irritation of the respiratory tract. On the basis of the nature of these general adverse systemic effects observed after Citral administration no difference in sensitivity (toxicodynamic and/or additional toxicokinetic differences) between test animals and humans is to be expected at these Citral dose levels besides aspects covered by allometric scaling.This substance specific argumentation is supported by a probabilistic approach for interspecies extrapolation using the RepDose database (Escher et al. 2013), supporting that species are on average equally sensitive to equipotent doses, if doses are related to energy turnover (uptake via inhalation, drinking water or food). The remaining uncertainties observed in this study were rather low considering the included differences in study design and intraspecies variability. These findings are found to hold true for systemic as well as for local effects after inhalation (as seen in repeated dose toxicity studies with Citral). Based on this assessment, a default interspecies extrapolation distribution between animals and humans according to the respective allometric scaling factor for body doses (e.g. gavage studies) and a factor of 1 for doses in ppm or mg/m3 (e.g. uptake via food, drinking water or inhalation) is proposed.

Furthermore, due to the general systemic effects observed for Citral in different repeated dose toxicity studies, such as impaired body weight gains and local irritation of the respiratory tract, the default assessment factors for intraspecies variability for systemic toxicity incl. local inhalative toxicity after repeated dosing have been amended to less conservative values. These findings are not considered to have a very high variation within the human population (referring to local respiratory tract irritation) or do not represent severe specific organ toxicity (referring to body weight changes). The derivation of these Citral specific assessment factors are guided by the following information. In an attempt to evaluate the intraspecies variability within the human population, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined (Hattis et al 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998; see ECETOC TR No.86, 2003). These evaluations included data from ‘healthy adults’ of both sexes, as well as limited data from the young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The data of Renwick and Lazarus (1998) and Hattis et al. (1999) were based exclusively on human data and similar values were obtained within each percentile. Considering that the data analysed by these authors included both sexes, a variety of disease states and ages, the use of the 95th percentile is considered sufficiently conservative to account for intraspecies variability in the general population. Thus, a default assessment factor of 5 was taken for the general population with a lower factor of 3 (i. e. closer to the 90th percentile) for the more homogenous worker population.

Overall, it needs to be pointed out, that several factors of conservatism have been applied to the systemic DNEL derivation made. Next to the use of the 90-95th percentile concerning intraspecies variability, the multiplicatory principle of AF together with an conservative choice of the NOAEL, i. e. conversion of LOAEL to NOAEL by factor 3 on the basis of the minor effects on body weight gain after oral application of Citral as point of departure provide a sufficient degree of conservatism.

 

For the worker, the following DNELs were derived:

The LOAEL of the chronic oral study was set at 60 mg/kg bw/d citral covering males and females. For derivation of the long-term systemic dermal DNEL, the oral LOAEL was converted into a corrected dermal LOAEL of 108 mg/kg bw/d according to the procedure recommended in the current guidance document (R8, ECHA 2008).

LOAEL corrected dermal = 60*(90/50) = 108 mg/kg bw/d

The following assessment factors (AF) were applied:

-     allometric scaling = 7 (according to R8 ECHA 2008)

-     remaining differences = 1 (On the basis of the general adverse systemic effects observed at the LOAEL of Citral, i. e. body weight changes, no difference in sensitivity (toxicodynamic and/or additional toxicokinetic differences) between test animals and humans is to be expected besides aspects already covered by allometric scaling).

-     intraspecies = 3 (based on the main substance related adverse effects observed at the LOAEL of Citral, i. e. body weight changes and the reasoning given above. )

-     exposure duration = 1 (chronic);

-     dose response = 3 (conversion of LOAEL to NOAEL on the basis of the minor effects on body weight gain);

-     quality of whole database = 1 (based on validity of studies performed).

AF = 7 x 1 x 3 x 1 x 3 x 1 = 63. Consequently, the dermal long-term systemic DNEL derived was 1.7 mg/kg bw/d for the worker.

 

For derivation of the of the long-term systemic inhalative DNEL, the available NOAEC of 215 mg/m3has been converted into a corrected inhalative NOAEC of 108 mg/m3according to the procedure, recommended in the current guidance document (R8, ECHA 2008).

NOAECinhal corrected= 215*(6/8) *(6.7/10) = 108 mg/m3

 

The following assessment factors (AF) were applied:

-     allometric scaling = 1 (not applicable according toR8 ECHA 2008)

-     remaining differences = 1 (On the basis of the general adverse systemic effects observed after Citral administration, i. e. body weight changes and local irritation, no difference in sensitivity (toxicodynamic and/or additional toxicokinetic differences) between test animals and humans is to be expected besides aspects already covered in the conversion performed above).

-     intraspecies = 3 (based on the main substance related adverse effects observed after Citral administration, i. e. body weight changes/ local irritation and the reasoning given above.)

-     exposure duration = 2 (subchronic to chronic);

-     quality of whole database = 2 (based on the lack of detailed documentation of test results).

AF = 1 x 1 x 3 x 2 x 2 = 12. Consequently, the inhalative long-term systemic DNEL was set at 9 mg/m3for the worker.

 

To assess the DNEL for local effects after long term dermal exposure, data for skin sensitization were considered. The critical skin sensitization data for citral were reviewed by the Expert Panel of the Research Institute for Fragrance Materials, i. e. an independent panel of academic dermatologists, toxicologists and environmental scientists, and based on the weight of evidence a No Expected Sensitization Induction Level (NESIL) of 1400μg/cm2 was established. 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). As outlined in this Technical Dossier, a NOEL from a well performed HRIPT will (even if higher) have precedence over all other NOELs (including LLNA EC3 value of 5.7% w/v (1414µg/cm²)). The HRIPT used for the NESIL derivation represents such a well performed study. 101 subjects (30 males, 71 females) received 9 applications of 0.3 ml aliquot of 1.2% citral in 3:1 DEP: EtOH for 24 hours in 3 successive weeks. Approximately 2 weeks after the last induction application, a 24 h challenge application with 1.2% citral (determined by the RIFM expert panel to be 1400 µg/cm2) in 3:1 DEP: EtOH was made to a naive site.

When reactions to challenge were read 24 h, 48 h, 72 h and 96 h after patch removal, no skin sensitizing effects were observed.

Both the LLNA and the HRIPT studies lead to similar dose descriptors showing a substance specific comparability of effect levels in the different test systems used. Since no species specific differences in potencies are indicated between the murine test and human subjects, the use of an additional interspecies assessment factor is not plausible. Furthermore, based on the ECHA guidance document (R8 p.23) no extrapolation and no assessment factor is necessary for interspecies differences in sensitivity, where human data are used as the starting point for risk characterization. It is recognized that a general DNEL must take into account that the threshold for skin sensitization varies between individuals. This may be due to differences in parameters such as genetic effects, sensitive subpopulations, inherent barrier function, age, gender, and ethnicity (Api et al., 2008). Whereas the latter three are recognized to have some effect on the sensitization threshold, it is generally recognized that genetic differences, the inherent barrier function and especially sensitive subpopulations play a major role (Api et al., 2008). The barrier function of the skin may be compromised which in turn may lead to a greater susceptibility of the individual. At the same time the barrier function is thought to be very similar from infancy to adulthood. The influence of the genetic setting is not well understood, however, may be plausible in the light of the immunological effect under consideration. The term sensitive subpopulations refers mostly to individuals who have previously been sensitized to other substances which may increase the susceptibility to further sensitizers (Api et al., 2006, Api et al., 2008). Overall, an assessment factor of 10 for intraspecies differences is applied to adequately address the combined influence of these effects. The underlying data are based on repeated dermal application of citral and the read out covers both, skin irritation and skin sensitization properties at the given concentration. The relevant parameters, i. e. induction of skin irritation and skin sensitization, are considered to depend on threshold concentrations and not on exposure duration. Therefore no assessment factor concerning exposure duration is deemed necessary for the derivation of the long term local dermal DNEL. The concept of threshold concentrations for the induction of these effects is generally well accepted (see e.g. Api et al. 2006; Dermal Sensitization Quantitative Risk Assessment (QRA) for fragrance ingredients - Technical dossier or Api et al. 2008; Reg Toxicol Pharmacol 52: 3-23). Furthermore, the ECHA guidance document does not indicate at all, that an assessment factor for exposure duration needs to be taken into account for the derivation of a DNEL for skin sensitization.

Therefore, a DNEL for skin sensitization was set at 140 µg/cm2/day. The derived DNEL on the basis of skin sensitization is considered sufficiently conservative to ensure the absence of skin irritation after short or long term exposure. Using this DNEL allows for a quantitative risk characterization for both hazards, i.e. skin irritation and skin sensitization.

Furthermore, citral is to be classified as eye irritant (category 2) according to 1272/2008/EEC. Since no quantitative data addressing the hazard of eye irritation are available, a respective no effect concentration cannot be derived and included in the derivation of the short term/long term local dermal DNEL. However, a qualitative risk characterisation including the implementation of suitable risk management measures is performed in the CSR.

Since data used for the derivation of the long-term systemic inhalative DNEL are sufficient to cover for local effects after short term or after long term inhalative exposure, no specific DNELs are derived.

Since data used for the derivation for the long term local dermal DNEL are sufficient to cover for local effects after short term dermal exposure, no specific DNEL is derived.

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 respective long term systemic DNELs are considered sufficient. 

 

·   Api AM, Basketter DA, Cadby PA, Cano M-F, Graham E, Gerberick F, Griem P, McNamee P, Ryan CA, Safford B (2006). Dermal Sensitization Quantitative Risk Assessment (QRA) for fragrance ingredients. Technical dossier. March 15, 2006 (revised May 2006).

·   Api AM, Basketter, DA, Cadby PA, Cano M-F, Ellis G, Gerberick GF, Griem P, McNamee PM, Ryan CA, Safford R (2008). Dermal sensitization quantitative risk assessment (QRA) for fragrance ingredients. Reg Toxicol Pharmacol 52: 3-23.

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

·   Escher S, Batke M, Hoffmann-Doerr S, Messinger H, Mangelsdorf I (2013). Interspecies extrapolation based on the RepDose database—A probabilistic approach. Toxicology Letters 218: 159– 165


General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.7 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

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

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
105
Modified dose descriptor starting point:
LOAEL
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:
140 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
10
Dose descriptor:
other: NOAEL
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.6 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
105
Modified dose descriptor starting point:
LOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

The 2-year feeding study in mice has been chosen (NTP 2003d) for the derivation of DNELs for systemic oral and dermal effects after long term exposure by route to route extrapolation. A LOAEL of 60 mg/kg bw/ day on the basis of impaired body weight gains has been observed representing the point of departure. This point of departure is valid to cover all adverse effects observed in different species and different studies available.

For the derivation of DNELs for systemic inhalative effects after long term exposure, the available inhalation studies, i. e. a 21-day and 13-week inhalation toxicity study (6h/day) in rats (Gaworski 1993) and a developmental toxicity study in rats (Gaworski 1992), have been chosen. The observed NOAEC of 34 ppm or 215 mg/m3on the basis of evident local irritation and impaired body weight gains serves as point of departure. 

On the basis of the toxicokinetic data, a high rate of oral absorption in rats has been observed and a 90% bioavailability has been set for the oral route. On the basis of the data available for dermal absorption, a dermal penetration rate of 50% has been set for route to route extrapolation. Based on the availability of a sufficient toxicity dataset, the default assessment factors (acc. to ECHA GD R8) have been modified into substance specific assessment factors (AF), considering the intrinsic hazard properties of the registered substance.

 

The values used as point of departure for the respective systemic DNELs were based on general systemic effects of Citral, such as impaired body weight gains and local irritation of the respiratory tract. On the basis of the nature of these general adverse systemic effects observed after Citral administration no difference in sensitivity (toxicodynamic and/or additional toxicokinetic differences) between test animals and humans is to be expected at these Citral dose levels besides aspects covered by allometric scaling. This substance specific argumentation is supported by a probabilistic approach for interspecies extrapolation using the RepDose database (Escher et al. 2013), supporting that species are on average equally sensitive to equipotent doses, if doses are related to energy turnover (uptake via inhalation, drinking water or food). The remaining uncertainties observed in this study were rather low considering the included differences in study design and intraspecies variability. These findings are found to hold true for systemic as well as for local effects after inhalation (as seen in repeated dose toxicity studies with Citral). Based on this assessment, a default interspecies extrapolation distribution between animals and humans according to the respective allomatric scaling factor for body doses (e.g. gavage studies) and a factor of 1 for doses in ppm or mg/m3 (e.g. uptake via food, drinking water or inhalation) is proposed.

Furthermore, due to the general systemic effects observed for Citral in different repeated dose toxicity studies, such as impaired body weight gains and local irritation of the respiratory tract, the default assessment factors for intraspecies variability for systemic toxicity incl. local inhalative toxicity after repeated dosing have been amended to less conservative values. These findings are not considered to have a very high variation within the human population (referring to local respiratory tract irritation) or do not represent severe specific organ toxicity (referring to body weight changes). The derivation of these citral specific assessment factors are guided by the following information.

In an attempt to evaluate the intraspecies variability within the human population, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined (Hattis et al 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998; see ECETOC TR No.86, 2003). These evaluations included data from ‘healthy adults’ of both sexes, as well as limited data from the young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The data of Renwick and Lazarus (1998) and Hattis et al. (1999) were based exclusively on human data and similar values were obtained within each percentile. Considering that the data analysed by these authors included both sexes, a variety of disease states and ages, the use of the 95th percentile is considered sufficiently conservative to account for intraspecies variability in the general population. Thus, a default assessment factor of 5 was taken for the general population with a lower factor of 3 (i. e. closer to the 90th percentile) for the more homogenous worker population.

Overall, it needs to be pointed out, that several factors of conservatisms have been applied to the systemic DNEL derivation made. Next to the use of the 90-95th percentile concerning intraspecies variability, the multiplicatory principle of AF together with an conservative choice of the NOAEL, i. e. conversion of LOAEL to NOAEL by factor 3 on the basis of the minor effects on body weight gain after oral application of Citral as point of departure provide a sufficient degree of conservatism. The chosen approach is in line with other reference values for citral. The derived acceptable daily intake value (0-0.5 mg/kg bw/d) derived by the Joint FAO/WHO Expert Committee on Food Additives corresponds well with the respective long term systemic oral DNEL for the general population (0.6 mg/kg bw/d).

 


For the general population, the following DNELs were derived:

For derivation of the long-term systemic oral DNEL, the chosen LOAEL (60 mg/kg bw/d) was divided by the following assessment factors (AF):

-     allometric scaling = 7 (according toR8 ECHA 2008)

-     remaining differences = 1 (On the basis of the general adverse systemic effects observed at the LOAEL of Citral, i. e. body weight changes, no difference in sensitivity (toxicodynamic and/or additional toxicokinetic differences) between test animals and humans is to be expected besides aspects already covered by allometric scaling).

-     intraspecies = 5 (based on the main substance related adverse effects observed at the LOAEL of Citral, i. e. body weight changes and the reasoning given above.)

-     exposure duration = 1 (chronic);

-     dose response = 3 (conversion of LOAEL to NOAEL on the basis of the minor effects on body weight gain);

-     quality of whole database = 1 (based on validity of studies performed).

AF = 7 x 1 x 5 x 1 x 3 x 1 = 105. Consequently, the oral long-term systemic DNEL derived was 0.6 mg/kg bw/d.

 

The LOAEL of the chronic oral study was set at 60 mg/kg bw/d citral covering males and females. For derivation of the long-term systemic dermal DNEL, the oral LOAEL was converted into a corrected dermal LOAEL of 108 mg/kg bw/d according to the procedure, recommended in the current guidance document (R8, ECHA 2008).

LOAEL corrected dermal = 60*(90/50) = 108 mg/kg bw/d

 

The following assessment factors (AF) were applied:

-     allometric scaling = 7 (according to R8 ECHA 2008)

-     remaining differences = 1 (On the basis of the general adverse systemic effects observed at the LOAEL of Citral, i. e. body weight changes, no difference in sensitivity (toxicodynamic and/or additional toxicokinetic differences) between test animals and humans is to be expected besides aspects already covered by allometric scaling).

-     intraspecies = 5 (based on the main substance related adverse effects observed at the LOAEL, i. e. body weight changes and the reasoning given above.)

-     exposure duration = 1 (chronic);

-     dose response = 3 (conversion of LOAEL to NOAEL on the basis of the minor effects on body weight gain);

-     quality of whole database = 1 (based on validity of studies performed).

AF = 7 x 1 x 5 x 1 x 3 x 1 = 105. Consequently, the dermal long-term systemic DNEL derived was 1 mg/kg bw/d.

 

For derivation of the of the long-term systemic inhalative DNEL, the available NOAEC of 215 mg/m3has been converted into a corrected inhalative NOAEC of 54 mg/m3according to the procedure, recommended in the current guidance document (R8, ECHA 2008).

NOAECinhal corrected= 215*(6/24) = 54 mg/m3

 

The following assessment factors (AF) were applied:

-     ·  allometric scaling = 1 (not applicable according toR8 ECHA 2008)

-     ·  remaining differences = 1 (On the basis of the general adverse systemic effects observed after Citral administration, i. e. body weight changes and local irritation, no difference in sensitivity (toxicodynamic and/or additional toxicokinetic differences) between test animals and humans is to be expected besides aspects already covered in the conversion performed above).

-     ·  intraspecies = 5 (based on the main substance related adverse effects observed after Citral administration, i. e. body weight changes/ local irritation and the reasoning given above.)

-     ·  exposure duration = 2 (subchronic to chronic);

-     ·  quality of whole database = 2 (based on the lack of detailed documentation of test results).

AF = 1 x 1 x 5 x 2 x 2 = 20. Consequently, the inhalative long-term systemic DNEL was set at 2.7 mg/m3.

To assess the DNEL for local effects after long term dermal exposure, data for skin sensitization were considered. The critical skin sensitization data for citral were reviewed by the Expert Panel of the Research Institute for Fragrance Materials, i. e. an independent panel of academic dermatologists, toxicologists and environmental scientists, and based on the weight of evidence a No Expected Sensitization Induction Level (NESIL) of 1400μg/cm2 was established. 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). As outlined in this Technical Dossier, a NOEL from a well performed HRIPT will (even if higher) have precedence over all other NOELs (including LLNA EC3 value of 5.7% w/v (1414µg/cm²)). The HRIPT used for the NESIL derivation represents such a well performed study. 101 subjects (30 males, 71 females) received 9 applications of 0.3 ml aliquot of 1.2% citral in 3:1 DEP: EtOH for 24 hours in 3 successive weeks. Approximately 2 weeks after the last induction application, a 24 h challenge application with 1.2% citral (determined by the RIFM expert panel to be 1400 µg/cm2) in in 3:1 DEP: EtOH was made to a naive site.When reactions to challenge were read 24 h, 48 h, 72 h and 96 h after patch removal, no skin sensitizing effects were observed.

Both the LLNA and the HRIPT studies lead to similar dose descriptors showing a substance specific comparability of effect levels in the different test systems used. Since no species specific differences in potencies are indicated between the murine test and human subjects, the use of an additional interspecies assessment factor is not plausible. Furthermore, based on the ECHA guidance document (R8 p.23) no extrapolation and no assessment factor is necessary for interspecies differences in sensitivity, where human data are used as the starting point for risk characterization. It is recognized that a general DNEL must take into account that the threshold for skin sensitization varies between individuals. This may be due to differences in parameters such as genetic effects, sensitive subpopulations, inherent barrier function, age, gender, and ethnicity (Api et al., 2008). Whereas the latter three are recognized to have some effect on the sensitization threshold, it is generally recognized that genetic differences, the inherent barrier function and especially sensitive subpopulations play a major role (Api et al., 2008). The barrier function of the skin may be compromised which in turn may lead to a greater susceptibility of the individual. At the same time the barrier function is thought to be very similar from infancy to adulthood. The influence of the genetic setting is not well understood, however, may be plausible in the light of the immunological effect under consideration. The term sensitive subpopulations refers mostly to individuals who have previously been sensitized to other substances which may increase the susceptibility to further sensitizers (Api et al., 2006, Api et al., 2008). Overall, an assessment factor of 10 for intraspecies differences is applied to adequately address the combined influence of these effects. The underlying data are based on repeated dermal application of citral and the read out covers both, skin irritation and skin sensitization properties at the given concentration. The relevant parameters, i. e. induction of skin irritation and skin sensitization, are considered to depend on threshold concentrations and not on exposure duration. Therefore no assessment factor concerning exposure duration is deemed necessary for the derivation of the long term local dermal DNEL. The concept of threshold concentrations for the induction of these effects is generally well accepted (see e.g. Api et al. 2006; Dermal Sensitization Quantitative Risk Assessment (QRA) for fragrance ingredients - Technical dossier or Api et al. 2008; Reg Toxicol Pharmacol 52: 3-23). Furthermore, the ECHA guidance document does not indicate at all, that an assessment factor for exposure duration needs to be taken into account for the derivation of a DNEL for skin sensitization.

Therefore a DNEL for skin sensitization was set at 140 µg/cm2/day. The derived DNEL on the basis of skin sensitization is considered sufficiently conservative to ensure the absence of skin irritation after short or long-term exposure. Using this DNEL allows for a quantitative risk characterization for both hazards, i.e. skin irritation and skin sensitization.

Since data used for the derivation of the long-term systemic inhalative DNEL are sufficient to cover for local effects after short term or after long term inhalative exposure, no specific DNELs are derived.

Since data used for the derivation for the long term local dermal DNEL are sufficient to cover for local effects after short term dermal exposure, no specific DNEL is derived.

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 respective long term systemic DNELs are considered sufficient. 

 

·   Api AM, Basketter DA, Cadby PA, Cano M-F, Graham E, Gerberick F, Griem P, McNamee P, Ryan CA, Safford B (2006). Dermal Sensitization Quantitative Risk Assessment (QRA) for fragrance ingredients. Technical dossier. March 15, 2006 (revised May 2006).

·   Api AM, Basketter, DA, Cadby PA, Cano M-F, Ellis G, Gerberick GF, Griem P, McNamee PM, Ryan CA, Safford R (2008). Dermal sensitization quantitative risk assessment (QRA) for fragrance ingredients. Reg Toxicol Pharmacol 52: 3-23.

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

·   Escher S, Batke M, Hoffmann-Doerr S, Messinger H, Mangelsdorf I (2013). Interspecies extrapolation based on the RepDose database—A probabilistic approach. Toxicology Letters 218: 159– 165