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:
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:
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

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

For the derivation of systemic long term DNELs, no repeated dose toxicity studies available for (R)-3,7-dimethyloct-6-enal (CAS 2385 -77 -5) or the racemate citronellal (CAS 106 -23 -0) containing the respective R and S stereoisomer. However, on the basis of a structural similarity, comparable physico-chemical properties and expected similar metabolic profiles, repeated dose toxicity studies of the structural analogue citral (CAS 5392-40-5) have been used via read across. 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/m3 on the basis of evident local irritation and impaired body weight gains serves as point of departure. 

 

On the basis of the toxicokinetic data for citral, 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 of citral and the physico-chemical paramters of citronellal, a dermal penetation rate of 50% has been set for route to route extrapolation.

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 toR8 ECHA 2008)

·       remaining differences = 1 (On the basis of the general adverse systemic effects observed at the LOAEL, 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, i.e. body weight changes and ECETOC Technical Report No. 86)

·     exposure duration = 1 (chronic);

·     dose reponse = 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/m3 has been converted into a corrected inhalative NOAEC of 108 mg/m3 according 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, 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, i.e. body weight changes/ local irritation and ECETOC Technical Report No. 86)

·       exposure duration = 2 (subchronic to chronic);

·       quality of whole database = 2 (based on the lack ofdetailed 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/m3 for the worker.

 

To asses the DNEL for local effects after long term dermal exposure, data for skin sensitization were considered. Citronellal is considered to be a skin sensitizer. As the effect level described in a human repeated insult patch test (5000 µg/cm2) is of the same magnitude as the sensitization effect levels of the structurally related substance citral, i.e. 3900 µg/cm2 (Lalko and Api, 2008), a read-across with citral has been performed to derive a NOEL as starting point for local short/longterm dermal DNEL. However, dermal reactions upon application of citronellal at that dermal load is vehicle dependent. Furthermore, a higher potency of citral has been observed in local lymph node assays when compared to the LLNA using citronellal. A threshold for dermal sensitization induction by citral was derived by Lalko and Api (2008) based on a complete literature search in on-line databases and the toxicologic database of the Research Institute for Fragrance materials (RIFM). With a main focus on repeated insult patch tests in human volunteers (HRIPT) a NOEL of 1400 µg/cm2was derived. Overall, incorporation of the NOEL for citral (1400 µg/cm2 ) is considered to be a worst case assumption when used as a NOEL for sensitization for citronellal.

 

Intraspecies:

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.  

Therefore a DNEL for skin sensitization was set at 140 µg/cm2/day. The derived DNEL on the basis of skin sensitization is considered sufficient to ensure the absence of skin irritation after short or long term exposure. Furthermore, citronellal is to be classified as eye irritant (category 2) according to 1272/2008/EEC whereas no classification as eye irritant is warranted according to 67/548/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 dermalDNEL. However, a qualitative risk characterisation including the implementation of suitable risk management measures is performed in the CSR.

 

  • 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.

 

 

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. 

 

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:
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:
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

For the derivation of systemic long term DNELs, no repeated dose toxicity studies available for (R)-3,7-dimethyloct-6-enal (CAS 2385 -77 -5) or the racemate citronellal (CAS 106 -23 -0) containing the respective R and S stereoisomer. However, on the basis of a structural similarity, comparable physico-chemical properties and expected similar metabolic profiles, repeated dose toxicity studies of the structural analogue citral (CAS 5397-30-4) have been used via read across. 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/m3 on the basis of evident local irritation and impaired body weight gains serves as point of departure. 

 

On the basis of the toxicokinetic data for citral, 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 of citral and the physico-chemical properties of citronellal, a dermal penetation rate of 50% has been set for route to route extrapolation.

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, 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 ECETOC Technical Report No. 86)

·     exposure duration = 1 (chronic);

·  dose reponse = 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 toR8 ECHA 2008)

·     remaining differences = 1 (On the basis of the general adverse systemic effects observed at the LOAEL, 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 ECETOC Technical Report No. 86)

·     exposure duration = 1 (chronic);

·     dose reponse = 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/m3 has been converted into a corrected inhalative NOAEC of 54 mg/m3 according 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, 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, i.e. body weight changes/ local irritation and ECETOC Technical Report No. 86)

·     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 asses the DNEL for local effects after long term dermal exposure, data for skin sensitization were considered. Citronellal is considered to be a skin sensitizer. As the effect level described in a human repeated insult patch test (5000 µg/cm2) is of the same magnitude as the sensitization effect levels of the structurally related substance citral, i.e. 3900 µg/cm2 (Lalko and Api, 2008), a read-across with citral has been performed to derive a NOEL as starting point for local short/longterm dermal DNEL. However, dermal reactions upon application of citronellal at that dermal load is vehicle dependent. Furthermore, a higher potency of citral has been observed in local lymph node assays when compared to the LLNA using citronellal. A threshold for dermal sensitization induction by citral was derived by Lalko and Api (2008) based on a complete literature search in on-line databases and the toxicologic database of the Research Institute for Fragrance materials (RIFM). With a main focus on repeated insult patch tests in human volunteers (HRIPT) a NOEL of 1400 µg/cm2was derived. Overall, incorporation of the NOEL for citral (1400 µg/cm2 ) is considered to be a worst case assumption when used as a NOEL for sensitization for citronellal.

Intraspecies:

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.  

Therefore a DNEL for skin sensitization was set at 140 µg/cm2/day. The derived DNEL on the basis of skin sensitization is considered sufficient to ensure the absence of skin irritation after short or longterm exposure.

 

  • 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.

 

 

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.