Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.7 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor starting point:

NOAEL

Value:

492 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

433.7 mg/m³

AF for dose response relationship:

1

AF for differences in duration of exposure:

4

AF for interspecies differences (allometric scaling):

1

AF for other interspecies differences:

2.5

AF for intraspecies differences:

5

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.9 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

492 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

984 mg/kg bw/day

AF for dose response relationship:

1

AF for differences in duration of exposure:

4

AF for interspecies differences (allometric scaling):

4

AF for other interspecies differences:

2.5

AF for intraspecies differences:

5

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

500 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

Overall assessment factor (AF):

10

Dose descriptor:

other: 5000 µg/cm²

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

medium hazard (no threshold derived)

An OECD 422 is available as key study on oral repeated dose toxicity for hydroxycitronellal. Hydroxycitronellal was administered via the drinking water to groups of 10 male and 10 female Wistar rats (F0 animals) at dose levels of 0 ppm (test group 0), 1500 ppm (test group 1), 5000 ppm (test group 2) and 15000 ppm (test group 3). The duration of treatment covered a 2-week premating period and mating in both sexes (mating pairs were from the same test group), the entire gestation period (about 22 days) as well as 13 days of lactation period in females up to the day of scheduled sacrifice of the animals. Under the conditions of this Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, the oral administration via the drinking water of Hydroxycitronellal to male and female Wistar rats revealed signs of systemic toxicity, impairments of reproductive performance and developmental toxicity at a concentration of 15000 ppm. Thus, the no observed adverse effect level (NOAEL) for general systemic toxicity was 5000 ppm for male for female Wistar rats (770 mg/kg bw/d and 492 mg/kg bw/d, respectively). The NOAEL for reproductive performance and fertility was also set to 5000 ppm for male and female Wistar rats (770 mg/kg bw/d and 492 mg/kg bw/d, respectively). The NOAEL for developmental toxicity was 5000 ppm (492 mg/kg bw/d).

Therefore, the respective oral NOAEL of 492 mg/kg bw/day for female rats has been taken as conservative point of departure for the respective systemic DNELs derived, which covers findings observed for general systemic, reproduction and developmental toxicity.

In a subacute inhalation study rats were 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 adverse effects (incl. parameters for respiratory tract irritation) were observed up to the highest concentration tested, leading to a NOAEC of 70 mg/m3. Based on this study results, the true NOAEC cannot be determined. The inhalative repeated dose toxicity study was not taken as a basis for the derivation of inhalative DNELs. Using 70 mg/m3 as a starting point for the derivation of the long-term systemic inhalative DNEL would result in a much too low and conservative value. Therefore, the respective oral NOAEL of 492 mg/kg bw/day for female rats in the OECD 422 has been taken as conservative point of departure for the inhalative DNEL derived.

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, for females the oral NOAEL of 492 mg/kg bw/d and for males the oral NOAEL of 770 mg/kg bw/d from the OECD 422 was taken as a basis and converted into a corrected inhalative NOAEC according to the procedure, recommended in the current guidance document (R8, ECHA 2012). After applying all assessment factors, the more conservative derived DNEL for females was taken for risk assessment. The inhalative long-term systemic DNEL was set at 8.7 mg/m³for the worker.

Long-term – inhalation, systemic effects:

Females

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 492 mg/kg bw/day
Step 2) Modification of starting point	50%/100% 0.38 m3/kg bw 6.7 m3/10 m3	Ratio of oral (rat) to inhalation (human) absorption (default value, as proposed in the REACH guidance (R.8.4.2) Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance (R.8.4.2) Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3)
Modified dose-descriptor	NOAEC corrected inhalative = 492 * (50/100) * (1/0.38) * (6.7/10) = 433.7 mg/m3
Step 3) Assessment factors
Allometric scaling	1	No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation according to R8 ECHA
Remaining differences	2.5	Default assessment factor according to R8 ECHA
Intraspecies	5	Default assessment factor according to R8 ECHA
Exposure duration	4	OECD 422 with 62-day exposure of female rats as starting point for long-term systemic DNEL derivation
Dose response	1	Default assessment factor according to R8 ECHA
Quality of database	1	Default assessment factor according to R8 ECHA (GLP guideline study)
DNEL	Value
	433.7 / (1 x 2.5 x 5 x 4 x 1 x 1) = 8.7 mg/m3

Males

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 770 mg/kg bw/day
Step 2) Modification of starting point	50%/100% 0.38 m3/kg bw 6.7 m3/10 m3	Ratio of oral (rat) to inhalation (human) absorption (default value, as proposed in the REACH guidance (R.8.4.2) Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance (R.8.4.2) Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3)
Modified dose-descriptor	NOAEC corrected inhalative = 770 * (50/100) * (1/0.38) * (6.7/10) = 678.8 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
Remaining differences	2.5	Default assessment factor according to R8 ECHA
Intraspecies	5	Default assessment factor according to R8 ECHA
Exposure duration	6	OECD 422 with 31-day exposure of male rats as starting point for long-term systemic DNEL derivation (default assessment factor for subacute exposure duration according to R8 ECHA)
Dose response	1	Default assessment factor according to R8 ECHA
Quality of database	1	Default assessment factor according to R8 ECHA (GLP guideline study)
DNEL	Value
	678.8/ (1 x 2.5 x 5 x 6 x 1 x 1) = 9.1 mg/m3

For derivation of the long-term systemic dermal DNEL for hydroxycitronellal, for females the oral NOAEL of 492 mg/kg bw/d and for males the oral NOAEL of 770 mg/kg bw/d from the OECD 422 was taken as a basis and converted into a corrected dermal NOAEL according to the procedure, recommended in the current guidance document (R8, ECHA 2012). After applying all assessment factors, the more conservative derived DNEL for females was taken for risk assessment. The dermal long-term systemic DNEL was set at 4.9 mg/kg bw/d for the worker.

Long-term – dermal, systemic effects:

Females

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 492 mg/kg bw/d
Step 2) Modification of starting point	100%/50%	experimental data on dermal penetration rate
Modified dose-descriptor	NOAEL corrected dermal = 492 * (100/50) = 984 mg/kg bw/d
Step 3) Assessment factors
Allometric scaling	4	Assessment factor for allometric scaling according to R8 ECHA (data from rat study)
Remaining differences	2.5	Default assessment factor according to R8 ECHA
Intraspecies	5	Default assessment factor according to R8 ECHA
Exposure duration	4	OECD 442 with 62-day exposure of female rats as starting point for long-term systemic DNEL derivation
Dose response	1	Default assessment factor according to R8 ECHA
Quality of database	1	Default assessment factor according to R8 ECHA (GLP guideline study)
DNEL	Value
	984 / (4 x 2.5 x 5 x 4 x 1 x 1) = 4.9 mg/kg bw/d

Males

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 770 mg/kg bw/d
Step 2) Modification of starting point	100%/50%	experimental data on dermal penetration rate
Modified dose-descriptor	NOAEL corrected dermal = 770 * (100/50) = 1540 mg/kg bw/d
Step 3) Assessment factors
Allometric scaling	4	Assessment factor for allometric scaling according to R8 ECHA (data from rat study)
Remaining differences	2.5	Default assessment factor according to R8 ECHA
Intraspecies	5	Default assessment factor according to R8 ECHA
Exposure duration	6	OECD 422 with 31-day exposure of male rats as starting point for long-term systemic DNEL derivation (default assessment factor for subacute exposure duration according to R8 ECHA)
Dose response	1	Default assessment factor according to R8 ECHA
Quality of database	1	Default assessment factor according to R8 ECHA (GLP guideline study)
DNEL	Value
	1540 / (4 x 2.5 x 5 x 6 x 1 x 1) = 5.1 mg/kg bw/d

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, hydroxycitronellal is 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 long term local dermal DNEL.

It is recognized that a general DNEL must take into account that the threshold for skin sensitisation varies between individuals. This may be due to differences in parameters such as genetic effects, sensitive subpopulations, inherent barrier function, age, gender, and ethnicity (Api et al., 2008). The barrier function of the skin may be compromised which in turn may lead to a greater susceptibility of the individual. At the same time the barrier function is thought to be very similar from infancy to adulthood. The influence of the genetic setting is not well understood, however, may be plausible in the light of the immunological effect under consideration. The term sensitive subpopulations refer mostly to individuals who have previously been sensitized to other substances which may increase the susceptibility to further 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 long term local dermal effects was set at 500 µg/cm². The derived DNEL of 500 µg/cm²is considered adequate to cover also for short term local dermal effects, e.g. putative irritant effects after single 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. 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 characterization 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

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.1 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

NOAEL

Value:

492 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

213.9 mg/m³

AF for dose response relationship:

1

AF for differences in duration of exposure:

4

AF for interspecies differences (allometric scaling):

1

AF for other interspecies differences:

2.5

AF for intraspecies differences:

10

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

400

Dose descriptor starting point:

NOAEL

Value:

492 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

984 mg/kg bw/day

AF for dose response relationship:

1

AF for differences in duration of exposure:

4

AF for interspecies differences (allometric scaling):

4

AF for other interspecies differences:

2.5

AF for intraspecies differences:

10

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

500 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

Overall assessment factor (AF):

10

Dose descriptor:

other: 5000 µg/m²

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.2 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

NOAEL

Value:

492 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

492 mg/kg bw/day

AF for dose response relationship:

1

AF for differences in duration of exposure:

4

AF for interspecies differences (allometric scaling):

4

AF for other interspecies differences:

2.5

AF for intraspecies differences:

10

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

medium hazard (no threshold derived)

An OECD 422 is available as key study on oral repeated dose toxicity for hydroxycitronellal. Hydroxycitronellal was administered via the drinking water to groups of 10 male and 10 female Wistar rats (F0 animals) at dose levels of 0 ppm (test group 0), 1500 ppm (test group 1), 5000 ppm (test group 2) and 15000 ppm (test group 3). The duration of treatment covered a 2-week premating period and mating in both sexes (mating pairs were from the same test group), the entire gestation period (about 22 days) as well as 13 days of lactation period in females up to the day of scheduled sacrifice of the animals. Under the conditions of this Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, the oral administration via the drinking water of Hydroxycitronellal to male and female Wistar rats revealed signs of systemic toxicity, impairments of reproductive performance and developmental toxicity at a concentration of 15000 ppm. Thus, the no observed adverse effect level (NOAEL) for general systemic toxicity was 5000 ppm for male for female Wistar rats (770 mg/kg bw/d and 492 mg/kg bw/d, respectively). The NOAEL for reproductive performance and fertility was also set to 5000 ppm for male and female Wistar rats (770 mg/kg bw/d and 492 mg/kg bw/d, respectively). The NOAEL for developmental toxicity was 5000 ppm (492 mg/kg bw/d).

Therefore, the respective oral NOAEL of 492 mg/kg bw/day for female rats has been taken as conservative point of departure for the respective systemic DNELs derived, which covers findings observed for general systemic, reproduction and developmental toxicity.

In a subacute inhalation study rats were 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 adverse effects (incl. parameters for respiratory tract irritation) were observed up to the highest concentration tested, leading to a NOAEC of 70 mg/m3. Based on this study results, the true NOAEC cannot be determined. The inhalative repeated dose toxicity study was not taken as a basis for the derivation of inhalative DNELs. Using 70 mg/m3 as a starting point for the derivation of the long-term systemic inhalative DNEL would result in a much too low and conservative value. Therefore, the respective oral NOAEL of 492 mg/kg bw/day for female rats in the OECD 422 has been taken as conservative point of departure for the inhalative DNEL derived.

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, for females the oral NOAEL of 492 mg/kg bw/d and for males the oral NOAEL of 770 mg/kg bw/d from the OECD 422 was taken as a basis and converted into a corrected inhalative NOAEC according to the procedure, recommended in the current guidance document (R8, ECHA 2012). After applying all assessment factors, the more conservative derived DNEL for females was taken for risk assessment. The inhalative long-term systemic DNEL was set at 2.1 mg/m³ for the general population.

Long-term – inhalation, systemic effects

Females

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 492 mg/kg bw/d
Step 2) Modification of starting point	50%/100% 1.15 m3/kg bw	Ratio of oral (rat) to inhalation (human) absorption (default value, as proposed in the REACH guidance (R.8.4.2) Standard respiratory volume of a rat, corrected for 24 h exposure, as proposed in the REACH Guidance (R.8.4.2)
Modified dose-descriptor	NOAEC corrected inhalative = 492 * (50/100) * (1/1.15) = 213.9 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
Remaining differences	2.5	Default assessment factor according to R8 ECHA
Intraspecies	10	Default assessment factor according to R8 ECHA
Exposure duration	4	OECD 422 with 62-day exposure of female rats as starting point for long-term systemic DNEL derivation
Dose response	1	Default assessment factor according to R8 ECHA
Quality of database	1	Default assessment factor according to R8 ECHA (GLP guideline study)
DNEL	Value
	213.9 / (1 x 2.5 x 10 x 4 x 1 x 1) = 2.1 mg/m3

Males

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 770 mg/kg bw/d
Step 2) Modification of starting point	50%/100% 1.15 m3/kg bw	Ratio of oral (rat) to inhalation (human) absorption (default value, as proposed in the REACH guidance (R.8.4.2) Standard respiratory volume of a rat, corrected for 24 h exposure, as proposed in the REACH Guidance (R.8.4.2)
Modified dose-descriptor	NOAEC corrected inhalative = 770 * (50/100) * (1/1.15) = 334.8 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
Remaining differences	2.5	Default assessment factor according to R8 ECHA
Intraspecies	10	Default assessment factor according to R8 ECHA
Exposure duration	6	OECD 422 with 31-day exposure of male rats as starting point for long-term systemic DNEL derivation
Dose response	1	Default assessment factor according to R8 ECHA
Quality of database	1	Default assessment factor according to R8 ECHA (GLP guideline study)
DNEL	Value
	334.89 / (1 x 2.5 x 10 x 6 x 1 x 1) = 2.2 mg/m3

For derivation of the long-term systemic dermal DNEL for hydroxycitronellal, for females the oral NOAEL of 492 mg/kg bw/d and for males the oral NOAEL of 770 mg/kg bw/d from the OECD 422 was taken as a basis and converted into a corrected dermal NOAEL according to the procedure, recommended in the current guidance document (R8, ECHA 2012). After applying all assessment factors, the more conservative derived DNEL for females was taken for risk assessment. The dermal long-term systemic DNEL was set at 2.5 mg/kg bw/d for the general population.

Long-term – dermal, systemic effects

Females

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 492 mg/kg bw/d
Step 2) Modification of starting point	100%/50%	experimental data on dermal penetration rate
Modified dose-descriptor	NOAEL corrected dermal = 492 * (100/50) = 984 mg/kg bw/d
Step 3) Assessment factors
Allometric scaling	4	Assessment factor for allometric scaling according to R8 ECHA (data from rat study)
Remaining differences	2.5	Default assessment factor according to R8 ECHA
Intraspecies	10	Default assessment factor according to R8 ECHA
Exposure duration	4	OECD 422 with 62-day exposure of female rats as starting point for long-term systemic DNEL derivation
Dose response	1	Default assessment factor according to R8 ECHA
Quality of database	1	Default assessment factor according to R8 ECHA (GLP guideline study)
DNEL	Value
	984 / (4 x 2.5 x 10 x 4 x 1 x 1) = 2.5 mg/kg bw/d

Males

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 770 mg/kg bw/d
Step 2) Modification of starting point	100%/50%	experimental data on dermal penetration rate
Modified dose-descriptor	NOAEL corrected dermal = 770 * (100/50) = 1540 mg/kg bw/d
Step 3) Assessment factors
Allometric scaling	4	Assessment factor for allometric scaling according to R8 ECHA (data from rat study)
Remaining differences	2.5	Default assessment factor according to R8 ECHA
Intraspecies	10	Default assessment factor according to R8 ECHA
Exposure duration	4	OECD 422 with 31-day exposure of male rats as starting point for long-term systemic DNEL derivation
Dose response	1	Default assessment factor according to R8 ECHA
Quality of database	1	Default assessment factor according to R8 ECHA (GLP guideline study)
DNEL	Value
	1540 / (4 x 2.5 x 10 x 6 x 1 x 1) = 2.6 mg/kg bw/d

For derivation of the long-term systemic oral DNEL for hydroxycitronellal, for females the oral NOAEL of 492 mg/kg bw/d and for males the oral NOAEL of 770 mg/kg bw/d from the OECD 422 was used. After applying all assessment factors, the more conservative derived DNEL for females was taken for risk assessment. The oral long-term systemic DNEL was set at 1.2 mg/kg bw/d for the general population.

Long-term – oral, systemic effects

Females

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 492 mg/kg bw/d
Step 2) Modification of starting point	-	-
Step 3) Assessment factors
Allometric scaling	4	Assessment factor for allometric scaling according to R8 ECHA (data from rat study)
Remaining differences	2.5	Default assessment factor according to R8 ECHA
Intraspecies	10	Default assessment factor according to R8 ECHA
Exposure duration	4	OECD 422 with 62-day exposure of female rats as starting point for long-term systemic DNEL derivation
Dose response	1	Default assessment factor according to R8 ECHA
Quality of database	1	Default assessment factor according to R8 ECHA (GLP guideline study)
DNEL	Value
	492 / (4 x 2.5 x 10 x 4 x 1 x 1) = 1.2 mg/kg bw/d

Males

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 700 mg/kg bw/d
Step 2) Modification of starting point	-	-
Step 3) Assessment factors
Allometric scaling	4	Assessment factor for allometric scaling according to R8 ECHA (data from rat study)
Remaining differences	2.5	Default assessment factor according to R8 ECHA
Intraspecies	10	Default assessment factor according to R8 ECHA
Exposure duration	6	OECD 422 with 31-day exposure of male rats as starting point for long-term systemic DNEL derivation
Dose response	1	Default assessment factor according to R8 ECHA
Quality of database	1	Default assessment factor according to R8 ECHA (GLP guideline study)
DNEL	Value
	700 / (4 x 2.5 x 10 x 6 x 1 x 1) = 1.2 mg/kg bw/d

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, hydroxycitronellal is 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 long term local dermal DNEL.

It is recognized that a general DNEL must take into account that the threshold for skin sensitisation varies between individuals. This may be due to differences in parameters such as genetic effects, sensitive subpopulations, inherent barrier function, age, gender, and ethnicity (Api et al., 2008). The barrier function of the skin may be compromised which in turn may lead to a greater susceptibility of the individual. At the same time the barrier function is thought to be very similar from infancy to adulthood. The influence of the genetic setting is not well understood, however, may be plausible in the light of the immunological effect under consideration. The term sensitive subpopulations refer mostly to individuals who have previously been sensitized to other substances which may increase the susceptibility to further sensitisers (Api et al., 2006, Api et al., 2008). Overall, an assessment factor of 10 for intraspecies differences is applied to adequately address the combined influence of these effects.

Therefore, a DNEL for local effects for skin sensitization was set at 500 µg/cm². The derived DNEL of 500 µg/cm²is considered adequate to cover also for short term local dermal effects e.g. putative irritant effects after single application.

Hydroxycitronellal is to be classified as “eye irritant” (category 2) according to 1272/2008/EEC. However, the eye irritating properties of hydroxycitronellal 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

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7-hydroxycitronellal

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