Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
18 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
Overall assessment factor (AF):
6
Modified dose descriptor starting point:
NOAEC
Value:
108 mg/m³
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.9 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
63
Modified dose descriptor starting point:
LOAEL
Value:
120 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:
500 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
10
Dose descriptor starting point:
other: 5000 µg/cm2

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

No key study on oral repeated dose toxicity is available for hydroxycitronellal. The most relevant oral repeated dose toxicity studies were performed with the structural similar terpene aldehyde citral (CAS 5392-40-5). These studies are taken into account for assessment via read across. The respective unsaturated aldehyde differs due to the presence of double bonds and lack of an additional hydroxyl residue but contain a terpenoid structure of comparable chain length such as hydroxycitronellal. Physicochemical parameters relevant for oral uptake show comparability in molecular weight and water solubility between hydroxycitronellal and citral (molecular weight of 172.3 and 152.2; log POWat 1.68 and 2.76; water solubility of 35 and 0.420 g/L respectively). Furthermore, due to the additional hydroxyl residue, hydroxycitronellal is likely to be faster and more efficiently conjugated and eliminated than citral. Therefore citral is considered to represent a worst case.

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.

In a reproduction toxicity screening test in Sprague Dawley rats (Yoshimura, 2002), hydroxycitronellal was administered oral (gavage) in concentrations of 0, 40, 200, and 1000 mg/kg bw/day in corn oil as vehicle. In the dose group, receiving 1000 mg/kg bw/day, parental toxicity was found in terms of decreased body weights (significant for body weight changes), temporarily decreased food consumption and histological changes in the forestomach, indicating an irritative potential of the test substance in the GI tract. No test substance related effects were detected in terms of reproductive performance, parental organ weights or histopathology of the reproductive organs. The test substance administration evoked no signs of reproductive toxicity. The NOAEL for developmental toxicity and parental toxicity has been set at 200 mg/kg bw/day and at 1000 mg/kg bw/day (the highest dose tested) for reproductive toxicity.

The respective LOAEL of 60 mg/kg bw/day has been taken as conservative point of departure for systemic DNELs derived, which covers findings observed in the subchronic repeated dose study and reproduction toxicity tests.

 

Inhalative repeated dose toxicity studies of hydroxycitronellal and citral were taken as a basis for the derivation of inhalative DNELs.

Although very low, a higher vapour pressure of citral vs hydroxycitronellal (4.6 vs 0.54 Pa respectively) indicates that citral data represent a worst case concerning adverse effects by vapour inhalation when compared to hydroxycitronellal.

For the derivation of DNELs for systemic inhalative effects after long term exposure, the available inhalation studies with citral, i.e. a 21-day and 13-week inhalation toxicity study (6 h/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. These data are supported by the subacute inhalation study in rats, treated with aerosolized hydroxycitronellal (CAS 107-75-5) by nose-only inhalation 6 hours per day on a 5 day per week basis for a period of 2 weeks (WIL Research 2013). No test substance related effects (incl. parameters for respiratory tract irritation) were observed up to the highest concentration tested, leading to a NOAEC of 70 mg/m3.

Experimental data on dermal absorption of hydroxycitronellal was evaluated using [14C]-labeled hydroxycitronellal and full-thickness dorsal rat skin in an in vitro flow-through diffusion cell system (Tonge 1995). Application of neat HC and HC in different vehicles resulted in calculated sums (% dose of receptor fluid + intact skin) between 60% and 64%. No determination of HC levels in the stratum corneum was performed in this experimental setup, however, considering the ratio of HC found in the skin layer distribution study, the bioavailable amount of HC, i.e. levels in receptor fluid, dermis and epidermis was estimated to be approx. 50% of the applied dose or lower. Although human skin is described to result in lower skin penetration levels than rat skin, the estimated 50% bioavailability via the dermal route has been taken for the respective DNEL derivation as a worst case.

For the worker, the following DNELs were derived:

For derivation of the long-term systemic inhalative DNEL for hydroxycitronellal, the NOAEC of 215.0 mg/m3 was taken as a basis and converted into a corrected inhalativeNOAEC of 108.0 mg/m3 according to the procedure, recommended in the current guidance document (R8, ECHA 2008). Applying all assessment factors, the inhalative long-term systemic DNEL was set at 18mg/m3 for the worker.

 

Long-term – inhalation, systemic effects

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEC: 215.0 mg/m3

 

Step 2) Modification of starting point

6 h/day/8 h/day

 

 

6.7 m3/10 m3

 

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 = 215.0 * (6/8) * (6.7/10) = 108.0 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 2008.

Remaining differences

1

Substance specific assessment factor:

Besides unspecific general systemic effects i.e. body weight changes and local irritation, no related organ toxicity has been observed in the available repeated dose inhalation studies. Therefore, 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).

Overall, no additional AF for remaining differences is considered mandatory.

Intraspecies

3

Substance specific assessment factor:

Test substance showed only low severity of adverse effects, i.e. body weight changes and local irritation.

However an AF of 3/5 has been included to cover for remaining uncertainties of putative subpopulations, based on the following assessment.

Additional generic argumentation:

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 95thpercentile 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 90thpercentile) for the more homogenous worker population.

Exposure duration

2

Use of a subchronic study as starting point forlong-term systemic DNEL derivation (default assessment factor according to R8 ECHA 2008)

Dose response

1

according to R8 ECHA 2008

Quality of database

1

according to R8 ECHA 2008

DNEL

Value

 

108.0 / (1 x 1 x 3 x 2 x 1 x 1) =18 mg/m3

For derivation of the long-term systemic dermal DNEL of hydroxycitronellal, the oral LOAEL of 60.0 mg/kg bw/d was taken as a basis and was converted into a corrected dermal LOAEL of 120.0 mg/kg bw/d according to the procedure, recommended in the current guidance document (R8, ECHA 2008). Applying all assessment factors, the dermal long-term systemic DNEL derived was 1.9 mg/kg bw/d for the worker.

 

Long-term – dermal, systemic effects 

Description

Value

Remark

Step 1) Relevant dose-descriptor

LOAEL: 60.0 mg/kg bw/day

 

Step 2) Modification of starting point

100%/50%

experimental data on dermal penetration rate

Modified dose-descriptor

LOAEL corrected dermal = 60.0 * (100/50) = 120.0 mg/kg bw/d

Step 3) Assessment factors

 

 

Allometric scaling

7

Assessment factor for allometric scaling according to R8 ECHA 2008 (data from mice study)

Remaining differences

1

Substance specific assessment factor:

Besides unspecific general systemic effects below the limit dose i.e. body weight changes, no evident test substance related organ toxicity has been observed in the oral repeated dose studies. Therefore, 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).

Overall, no additional AF for remaining differences is considered mandatory.

Intraspecies

3

Substance specific assessment factor:

Test substance showed only low severity of adverse effects, i.e. body weight changes.

However an AF of 3/5 has been included to cover for remaining uncertainties of putative subpopulations, based on the following assessment.

Additional generic argumentation:

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 95thpercentile 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 90thpercentile) for the more homogenous worker population.

Exposure duration

1

Use of a chronic study as starting point forlong-term systemic DNEL derivation (default assessment factor according to R8 ECHA 2008)

Dose response

3

conversion of LOAEL to NOAEL on the basis of the minor effects on body weight gain

Quality of database

1

based on the validity of study performed (similar to GLP guideline study)

DNEL

Value

 

120 / (7 x 1 x 3 x 1 x 3 x 1) = 1.9 mg/kg bw/day

 

Short term / long term local dermal DNEL

Hydroxycitronellal was found to be skin sensitizing in a broad variety of studies with animals and humans. A summary on the outcome of LLNAs performed with hydroxycitronellal is given in the HERA risk assessment (Human & Environmental Risk Assessment on ingredients of European household cleaning products - HYDROXYCITRONELLAL; 2005). There it is reported, that EC3 values in eight Local Lymph Node Assays varied with the vehicle between 19% and 33% with a mean around 22.8% (ca. 5.7 mg/cm2). Based on these results,hydroxycitronellalis considered to be a weak skin sensitizer.

The EC3 [%] is converted to EC3 [µg/cm2]:

EC3 [%] * 250 [µg/cm2/%] = EC3 [µg/cm2] = 22.8 * 250 = 5625 µg/cm2

This value can be considered as the LOAEL for induction

 

A No Expected Sensitization Level, i.e. a dose (expressed as quantities retained on unit areas of skin) that is not expected to give rise to sensitization of subjects under exaggerated test conditions, has been derived in the HERA risk assessment report. On the basis of a weight of evidence approach, the No Expected Sensitization Level for hydroxycitronellal has been set at 2.95 mg/cm2. A no expected sensitization induction level (NESIL) for hydroxycitronellal has been derived in 2008 by the expert panel of the Research Institute for Fragrance Materials (RIFM). The RIFM Expert Panel reviewed the critical effect data for hydroxycitronellal and, based on the weight of evidence, established the NESIL as 5000 μg/cm². The basis for this NESIL represents a newer HRIPT, not included in the former assessment by HERA. Therefore, the NESIL of 5000 μg/cm² has been taken as point of departure for the short term local dermal DNEL.

 

It is recognized that a general DNEL must take into account that the threshold for skin sensitisation varies betweenindividuals. 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 forshort term local dermal effectswas set at 500 µg/cm2. The derived DNEL of 500 µg/cm2 is considered adequate to cover also for longterm local dermal effects, e.g. putative irritant effects after repeated application.

However, to account for the skin sensitizing properties of hydroxycitronellal, dermal protection as risk management measure, i.e. use of suitable gloves, is recommended for all types of worker scenarios handling high concentrations of the substance.

Furthermore, hydroxycitronellal is to be classified as “eye irritant” (category 2) according to 1272/2008/EEC and “irritating to eye” (R36) 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 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.

 

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.

References:

- ECHA (2008). Guidance on information requirements and chemical safety assessment - Chapter R.8: Characterisation of dose [concentration]-response for human health.

- 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

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.4 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC
Value:
53.75 mg/m³
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.1 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
105
Modified dose descriptor starting point:
LOAEL
Value:
120 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:
500 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
10
Dose descriptor starting point:
other: 5000 µg/cm2

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
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
105
Modified dose descriptor starting point:
LOAEL
Value:
60 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

No key study on oral repeated dose toxicity is available for hydroxycitronellal. The most relevant oral repeated dose toxicity studies were performed with the structural similar terpene aldehyde citral (CAS 5392-40-5). These studies are taken into account for assessment via read across. The respective unsaturated aldehyde differs due to the presence of double bonds and lack of an additional hydroxyl residue but contain a terpenoid structure of comparable chain length such as hydroxycitronellal. Physicochemical parameters relevant for oral uptake show comparability in molecular weight and water solubility between hydroxycitronellal and citral (molecular weight of 172.3 and 152.2; log POWat 1.68 and 2.76; water solubility of 35 and 0.420 g/L respectively). Furthermore, due to the additional hydroxyl residue, hydroxycitronellal is likely to be faster and more efficiently conjugated and eliminated than citral. Therefore citral is considered to represent a worst case.

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.

In a reproduction toxicity screening test in Sprague Dawley rats (Yoshimura, 2002), hydroxycitronellal was administered oral (gavage) in concentrations of 0, 40, 200, and 1000 mg/kg bw/day in corn oil as vehicle. In the dose group, receiving 1000 mg/kg bw/day, parental toxicity was found in terms of decreased body weights (significant for body weight changes), temporarily decreased food consumption and histological changes in the forestomach, indicating an irritative potential of the test substance in the GI tract. No test substance related effects were detected in terms of reproductive performance, parental organ weights or histopathology of the reproductive organs. The test substance administration evoked no signs of reproductive toxicity. The NOAEL for developmental toxicity and parental toxicity has been set at 200 mg/kg bw/day and at 1000 mg/kg bw/day (the highest dose tested) for reproductive toxicity.

The respective LOAEL of 60 mg/kg bw/day has been taken as conservative point of departure for systemic DNELs derived, which covers findings observed in the subchronic repeated dose study and reproduction toxicity tests.

 

Inhalative repeated dose toxicity studies of hydroxycitronellal and citral were taken as a basis for the derivation of inhalative DNELs.

Although very low, a higher vapour pressure of citral vs hydroxycitronellal (4.6 vs 0.54 Pa respectively) indicates that citral data represent a worst case concerning adverse effects by vapour inhalation when compared to hydroxycitronellal.

For the derivation of DNELs for systemic inhalative effects after long term exposure, the available inhalation studies with citral, i.e. a 21-day and 13-week inhalation toxicity study (6 h/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. These data are supported by the subacute inhalation study in rats, treated with aerosolized hydroxycitronellal (CAS 107-75-5) by nose-only inhalation 6 hours per day on a 5 day per week basis for a period of 2 weeks (WIL Research 2013). No test substance related effects (incl. parameters for respiratory tract irritation) were observed up to the highest concentration tested, leading to a NOAEC of 70 mg/m3.

 

Experimental data on dermal absorption of hydroxycitronellal was evaluated using [14C]-labeled hydroxycitronellal and full-thickness dorsal rat skin in an in vitro flow-through diffusion cell system(Tonge 1995).Application of neat HC and HC in different vehicles resulted in calculated sums (% dose of receptor fluid + intact skin) between 60% and 64%. No determination of HC levels in the stratum corneum was performed in this experimental setup, however, considering the ratio of HC found in the skin layer distribution study, the bioavailable amount of HC, i.e. levels in receptor fluid, dermis and epidermis was estimated to be approx. 50% of the applied dose or lower. Although human skin is described to result in lower skin penetration levels than rat skin, the estimated 50% bioavailability via the dermal route has been taken for the respective DNEL derivation as a worst case.

 

For the general population, the following DNELs were derived:

For derivation of the long-term systemic inhalative DNEL for hydroxycitronellal, the NOAEC of 215.0 mg/m3 was taken as a basis and converted into a corrected inhalative NOAEC of 53.75 mg/m3 according to the procedure, recommended in the current guidance document (R8, ECHA 2008). Applying all assessment factors, the inhalative long-term systemic DNEL was set at 5.4 mg/m3 for the general population.

 

Long-term – inhalation, systemic effects

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEC: 215.0 mg/m3

 

Step 2) Modification of starting point

6 h/day/24 h/day

Corrected for 24 h exposure, as proposed in the REACH Guidance (R.8.4.2)

Modified dose-descriptor

NOAEC corrected inhalative = 215.0 * (6/24) = 53.75 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 2008.

Remaining differences

1

Substance specific assessment factor:

Besides unspecific general systemic effects i.e. body weight changes and local irritation, no related organ toxicity has been observed in the available repeated dose inhalation studies. Therefore, 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).

Overall, no additional AF for remaining differences is considered mandatory.

Intraspecies

5

Substance specific assessment factor:

Test substance showed only low severity of adverse effects, i.e. body weight changes and local irritation.

However an AF of 3/5 has been included to cover for remaining uncertainties of putative subpopulations, based on the following assessment.

Additional generic argumentation:

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 95thpercentile 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 90thpercentile) for the more homogenous worker population.

Exposure duration

2

Use of a subchronic study as starting point forlong-term systemic DNEL derivation (default assessment factor according to R8 ECHA 2008)

Dose response

1

according to R8 ECHA 2008

Quality of database

1

according to R8 ECHA 2008

DNEL

Value

 

53.75 / (1 x 1 x 5 x 2 x 1 x 1) = 5.4 mg/m3

For derivation of the long-term systemic dermal DNEL of hydroxycitronellal, the oral LOAEL of 60.0 mg/kg bw/d was taken as a basis and was converted into a corrected dermal LOAEL of 120.0 mg/kg bw/d according to the procedure, recommended in the current guidance document (R8, ECHA 2008). Applying all assessment factors, the dermal long-term systemic DNEL derived was 1.1 mg/kg bw/d for the general population.

 

Long-term – dermal, systemic effects 

Description

Value

Remark

Step 1) Relevant dose-descriptor

LOAEL: 60.0 mg/kg bw/day

 

Step 2) Modification of starting point

100%/50%

experimental data on dermal penetration rate

Modified dose-descriptor

LOAEL corrected dermal = 60.0 * (100/50) = 120.0 mg/kg bw/d

Step 3) Assessment factors

 

 

Allometric scaling

7

Assessment factor for allometric scaling according to R8 ECHA 2008 (data from mice study)

Remaining differences

1

Substance specific assessment factor:

Besides unspecific general systemic effects below the limit dose i.e. body weight changes, no evident test substance related organ toxicity has been observed in the oral repeated dose studies. Therefore, 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).

Overall, no additional AF for remaining differences is considered mandatory.

Intraspecies

5

Substance specific assessment factor:

Test substance showed only low severity of adverse effects, i.e. body weight changes.

However an AF of 3/5 has been included to cover for remaining uncertainties of putative subpopulations, based on the following assessment.

Additional generic argumentation:

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 95thpercentile 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 90thpercentile) for the more homogenous worker population..

Exposure duration

1

Use of a chronic study as starting point forlong-term systemic DNEL derivation (default assessment factor according to R8 ECHA 2008)

Dose response

3

conversion of LOAEL to NOAEL on the basis of the minor effects on body weight gain

Quality of database

1

based on the validity of study performed (similar to GLP guideline study)

DNEL

Value

 

120 / (7 x 1 x 5 x 1 x 3 x 1) = 1.1 mg/kg bw/day

 

For derivation of the long-term systemic oral DNEL of hydroxycitronellal, the oral LOAEL 60.0 mg/kg bw/d was used. After applying the assessment factors, the oral long-term systemic DNEL was set at 0.6 mg/ kg bw/day for the general population.

Long-term – oral, systemic effects

Description

Value

Remark

Step 1) Relevant dose-descriptor

LOAEL: 60.0 mg/kg bw/day

 

Step 2) Modification of starting point

-

-

Step 3) Assessment factors

 

 

Allometric scaling

7

Assessment factor for allometric scaling according to R8 ECHA 2008 (data from mice study)

Remaining differences

1

Substance specific assessment factor:

Besides unspecific general systemic effects below the limit dose i.e. body weight changes, no evident test substance related organ toxicity has been observed in the oral repeated dose studies. Therefore, 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).

Overall, no additional AF for remaining differences is considered mandatory.

Intraspecies

5

Substance specific assessment factor:

Test substance showed only low severity of adverse effects, i.e. body weight changes.

However an AF of 3/5 has been included to cover for remaining uncertainties of putative subpopulations, based on the following assessment.

Additional generic argumentation:

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 95thpercentile 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 90thpercentile) for the more homogenous worker population.

Exposure duration

1

Use of a chronic study as starting point forlong-term systemic DNEL derivation (default assessment factor according to R8 ECHA 2008)

Dose response

3

conversion of LOAEL to NOAEL on the basis of the minor effects on body weight gain

Quality of database

1

based on the validity of study performed (similar to GLP guideline study)

DNEL

Value

 

60.0 / (7 x 1 x 5 x 1 x 3 x 1) = 0.6 mg/kg bw/day

Short term / long term local dermal DNEL

Hydroxycitronellal was found to be skin sensitizing in a broad variety of studies with animals and humans. A summary on the outcome of LLNAs performed with hydroxycitronellal is given in the HERA risk assessment (Human & Environmental Risk Assessment on ingredients of European household cleaning products - HYDROXYCITRONELLAL; 2005). There it is reported, that EC3 values in eight Local Lymph Node Assays varied with the vehicle between 19% and 33% with a mean around 22.8% (ca. 5.7 mg/cm2).Based on these results,hydroxycitronellalis considered to be a weak skin sensitizer.

The EC3 [%] is converted to EC3 [µg/cm2]:

EC3 [%] * 250 [µg/cm2/%] = EC3 [µg/cm2] = 22.8 * 250 = 5625 µg/cm2

This value can be considered as the LOAEL for induction.

 

A No Expected Sensitization Level, i.e. a dose (expressed as quantities retained on unit areas of skin) that is not expected to give rise to sensitization of subjects under exaggerated test conditions, has been derived in the HERA risk assessment report. On the basis of a weight of evidence approach, the No Expected Sensitization Level for hydroxycitronellal has been set at 2.95 mg/cm2. A no expected sensitization induction level (NESIL) for hydroxycitronellal has been derived in 2008 by the expert panel of the Research Institute for Fragrance Materials (RIFM). The RIFM Expert Panel reviewed the critical effect data for hydroxycitronellal and, based on the weight of evidence, established the NESIL as 5000 μg/cm². The basis for this NESIL represents a newer HRIPT, not included in the former assessment by HERA. Therefore, the NESIL of 5000 μg/cm² has been taken as point of departure for the short term local dermal DNEL.

 

It is recognized that a general DNEL must take into account that the threshold for skin sensitisation varies betweenindividuals. 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 forlocal effectsfor skin sensitization was set at 500 µg/cm2. The derived DNEL of 500 µg/cm2 is considered adequate to cover also for longterm local dermal effects e.g. putative irritant effects after repeated application.

 

Hydroxycitronellal is to be classified as “eye irritant” (category 2) according to 1272/2008/EEC and “irritating to eye” (R36) according to 67/548/EEC. However, theeye 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, as lined out in Chapter 9 of 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.

 

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.

References:

- ECHA (2008). Guidance on information requirements and chemical safety assessment - Chapter R.8: Characterisation of dose [concentration]-response for human health.

- 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