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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.078 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
225
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.28 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
Overall assessment factor (AF):
225
Dose descriptor starting point:
LOAEC

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
18.2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
300
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
525 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
45
Dose descriptor:
other: NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
525 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
45
Dose descriptor starting point:
other: NOAEL

Workers - Hazard for the eyes

Additional information - workers

1. Introduction:

In this chapter, all the endpoints from α-Hexyl Cinnamic Aldehyde (HCA) are re-examined and analyzed in order to establish a DNEL (s)/DMEL (s) for each one of them if possible. The followed method is that proposed in the guidance for the implementation of Reach (Chapter R.8: Characterisation of dose (concentration)-response for human health, December 2010)

 

2. Classification according to the Directive 67/548/EEC and to the CLP Regulation (Regulation (EC) No. 1272/2008)

A self-classification is proposed for HCA:

- May cause sensitization by skin contact: Xn; R43 / Category 1 (H317)

- Irritating to the skin (Xi; R38)

 

According to the CLP Regulation, the major criterion for the irritant category is that at least 2 of 3 tested animals have a mean individual erythema or edema score of ≥ 2,3 - ≤ 4,0. Under the test conditions, HCA is classified as “Xi; R38, Irritating to skin” according to the criteria of Annex VI to the Directive 67/548/EEC but it is not classified according to the CLP Regulation, as the mean individual score for erythema and edema was 2 in all animals.

 

3. DNELs derivation according to the toxicological profile of HCA

Neither indications of carcinogenic nor reprotoxic potential were observed or expected. Tests assessing the mutagenic potential of HCA in vitro and in vivo provided no evidence of genotoxic activity (mutagenicity and cytogenicity).

 

3.1 Inhalation

 

3.1.1 Worker-DNEL acute for inhalation route – local effects:

An acute inhalation study (Breckenridge, 1980) was conducted with HCA according to a limit test using a droplet aerosol. Clinical signs of toxicity included enlarged bronchial lymph nodes at the terminal kill, multiple grey-green foci on the lungs and occasional pulmonary congestion at the measured concentration of 2120 mg/m3. These effects are likely to be the consequence of a local irritation induced by HCA. These local respiratory effects are consistent with the HCA classification as a skin irritant. The concentration of 2120 mg/m3is therefore considered as the LOAEC for local effect.

According to the physico-chemical (log Kow = 5.3 at 24°C; water solubility = 1.62 mg/L at 20°C and pH 4-5; molecular mass= 216.3 g/mol) and the toxicological properties, HCA is not likely to be systemically absorbed by inhalation at a significant rate during acute exposure (15-minute exposure period at peak concentration during the workplace).Extrapolation of the DNEL for systemic effects is not relevant and route to route extrapolation cannot be used in any case considering the local effects.

Taking into account the irritant potential ofHCA, time scaling is not appropriate as the adverse effects are mainly driven by the exposure concentration.

Hence, the dose descriptor is not modified for the 15-minute worker exposure and the LOAEC of 2120 mg/m3 is considered as the dose descriptor for DNEL derivation.

 

The following Table 3.1/1 indicates the calculation of acute DNELby inhalation for local effects.

 

Table3.1/1: Calculation of the acute DNEL by inhalation for local effects for HCA

Worker

Acute DNEL / inhalation / Local effects

Step a : Determination of the critical dose

Key study

Breckenridge, 1980/ similar to OECD 403, K2

Relevant dose descriptor

LOAEC = 2120 mg/m3(foci on the lungs and lung congestion)

Step b : Correction for uncertainty factors

Differences in absorption depending on route of exposure (route-route extrapolation, human/animal)

-

(same route of exposure rat/human)

Modification for exposure

(experiment in animal and human)

-

(adverse effects mainly driven by exposure concentration)

Modification for the respiratory volume

0.210 / 0.315

(respiratory rate difference under standard conditions and under conditions of light activity for 15 minutes)

Correct starting point = relevant dose descriptor / overall factor for uncertainties

1413 mg/m3

Step c : Correction for assessment factors

Interspecies differences 

-      Differences in metabolic rate per b.w. (allometric scaling)

-      Remaining differences(toxicokinetics and toxicodynamics) 

  

-

(local effects)

 

2.5

Intraspecies differences

5

(worker)

Duration extrapolation

(sub-acute/sub-chronic/chronic)

-

(acute DNEL from acute toxicity study)

Issues related to dose-response

6

(Extrapolation of the LOAEC from a limit test to the No Adverse Effect Concentration (NAEC))

Quality of the whole database

3

(Incomplete database)

Overall assessment factor

225

DNEL calculation

6.28 mg/m3

 (6.28 * 0.315 / 70 = 0.03 mg/kg bw/d)

The acute DNEL by inhalation for local effects by inhalation is 6.28 mg/m3 for workers.

 

3.1.2 Worker-DNEL long-term for inhalation route – systemic effects:

For potential systemic effects during inhalation exposure, route-to-route extrapolation from the oral NOAEL value was performed.

A reproduction/development toxicity screening test (Lewis, 2010) was conducted with HCA according to the OECD guideline No. 421 and in compliance with GLP. The only effects observed were a slight transient reduction of maternal body weight gain and food consumption in the 100mg/kg bw/day group on days 1 and 5 of lactation in comparison to the vehicle control group. Under the conditions of this study a NOAEL of 100 mg/kg bw/day is determined. This value is considered as the dose-descriptor for route-to-route extrapolation.

 

Using available data (Yuan, 1993), it was assumed that 10% absorption occurs by the oral route. To secure a conservative external NOAEL, a maximum absorption should be assumed for the inhalation route (i.e.; 100%) (see Guidance Document, Chapter R.8, pp 25). To convert the oral NOAEL into inhalatory NOAEC, a rat default respiratory volume was used corresponding to the daily duration of worker exposure (sRVrat: 0.38 m3/kg bw/8 h).

For workers a correction was added for the difference between respiratory rates under standard conditions (sRVhuman: 6.7 m3 for an 8-h exposure period) and under conditions of light activity (wRV: 10 m3 for an 8-h exposure period).

 

Thus, the corrected dose descriptor for inhalation is 17.6 mg/m3 for workers.

 

 

The following Table 3.1/2 indicates the calculation of long-term DNEL by inhalation for systemic effects.

 

Table3.1/2: Calculation of the long-term DNEL by inhalation for systemic effects for HCA

Worker

Systemic long-term DNEL / inhalation

Step a: Determination of the critical dose

Key study

Lewis, 2010/ OECD 421, K1

Relevant dose descriptor

NOAEL = 100 mg/kg bw/d

Step b: Correction for uncertainty factors

Differences in absorption depending on route of exposure (route-route extrapolation, human/animal)

10/100

Modification for exposure

(experiment and human)

(1/0.38)*(6.7/10)

Correct starting point

17.6 mg/m3

Step c: Correction for assessment factors

Interspecies differences

 

-      Differences in metabolic rate per b.w. (allometric scaling)

 

-      Remaining differences (toxicokinetics and toxicodynamics)

 

 

-

 

 

2.5

 

Intraspecies differences

5

(worker)

Duration extrapolation

(sub-acute/sub-chronic/chronic)

6

(sub-acute to chronic extrapolation)

Issues related to dose-response

1

(NOAEL)

Quality of whole database

3

Overall assessment factor

225

DNEL calculation

0.078 mg/m3

0.01 mg/kg bw/d*

*10 m3respiratory volume during 8h/ 70 kg bw

 

The long-term DNEL by inhalation for systemic effects is 0.078 mg/m3 for workers.

 

Conclusion on inhalation:

The acute DNEL by inhalation for local effects is 6.28 mg/m3 for workers.

The long-term DNEL by inhalation for systemic effects is 0.078 mg/m3 for workers.

 

 

3.2 Dermal route

 

3.2.1 Worker – DNEL long term for dermal route –systemic effects:

Based on the observed effects in the sub-chronic dermal toxicity study (Lough, 1980), a relevant NOAEL for systemic effects cannot be determined for dermal-only exposure since the animals were exposed both by dermal and oral route. However, as no systemic effect was observed at 125 mg/kg bw/d (as routes were confused), it is assumed that the NOAEL for systemic effect by dermal route is likely much higher than this dose for dermal-only exposure.

 

As the above study is not considered as adequate for dermal-only exposure and on a worst-case assumption, route-to-route extrapolation from the oral NOAEL value was preferred to evaluate the potential effect during long-term dermal exposure.

Under the conditions of the screening reproductive oral study (see §3.2) a NOAEL of 100 mg/kg bw/day is concluded based on a slight and transient reduction of maternal body weight gain and food consumption at this dose level. This value is considered as the dose-descriptor for route-to-route extrapolation.

Using available data (Yuan, 1993), it was assumed that 10%absorption occurs by the oral route and only 0.183% by dermal route (see §7.1).

Thus, the corrected dose descriptor for dermal route is 5465 mg/kg bw/d for worker.

The following Table 3.2/1 indicates the calculation of the long term DNEL by dermal route for systemic effects of HCA.

Table3.2/1: Calculation of the long-term DNEL by dermal route for systemic effects for HCA

Worker

Systemic long-term DNEL / inhalation

Step a: Determination of the critical dose

Key study

Lewis, 2010/ OECD 421, K1

Relevant dose descriptor

NOAEL = 100 mg/kg bw/d

Step b: Correction for uncertainty factors

Differences in absorption depending on route of exposure (route-route extrapolation, human/animal)

10/0.183

Modification for exposure

(experiment and human)

-

Correct starting point

5465 mg/kg bw/d

Step c: Correction for assessment factors

Interspecies differences

 

-      Differences in metabolic rate per b.w. (allometric scaling)

 

-      Remaining differences (toxicokinetics and toxicodynamics)

 

 

4(rats)

 

 

2.5

 

Intraspecies differences

5

(worker)

Duration extrapolation

(sub-acute/sub-chronic/chronic)

2*

Issues related to dose-response

1

(NOAEL)

Quality of whole database

3

Overall assessment factor

300

DNEL calculation

18.2 mg/kg bw/d

*An assessment factor of 2 for duration extrapolation was used instead of 6 as no systemic effects were observed in the study of Lough (1980), following dermal/oral exposure to 125 mg HCA/kg bw/d for 90 days (see IUCLID §7.5.2).

The long-term DNEL by dermal routefor systemic effects is 18.2 mg/kg bw/d in the workers.

 

3.2.2 Worker - Induction specific DNEL:

According to the CLP criteria, HCA is classified as skin sensitizer but not as skin irritating. The general approach for sensitizers is a two-step procedure involving:

- a qualitative approach using potency categorization to define the risk management measure (RMMs) and operational conditions (OCs),

- and setting a DNEL to judge the remaining / residual likehood of risks after these RMMs and OCs are implemented.

 

Data obtained from both local lymph node assays (see §7.4.1) and historical predictive human test data (see §7.10.4) were used to provide information on the potency for induction, as well as on dose-response relationships of HCA.

 

HCA is recommended as positive control in skin sensitisation studies under OECD Guideline 406 and OECD Guideline 429. As such, it is recognised as a skin sensitiser and extensive data on its response in the LLNA are available. EC3 derived were in the range 6.6-11.5% (1650-2875 µg/cm2).

 

A NESIL or NOAEL of 23600 µg/cm2 (highest concentration tested showing no sensitisation in human), was obtained in the Human Repeated Insult Patch Test conducted by the RIFM (see section 7.10.4).

 

Although there is not a good agreement between LLNA EC3 and NOAEL derived from HRIPT studies, the HRIPT NOAEL was considered sufficiently robust and relevant as the study is conducted in human to override the EC3 value. Indeed the HRIPT was conducted according to Good Clinical Practice and following the RIFM standard test method.

 

Thus the dose descriptor for sensitisation is 23600 µg/cm2.

 

The following Table 3.2/2 indicates the calculation of the induction specific DNEL.

 

Table 3.2/2 Calculation of the induction specific DNEL for HCA

Worker

Induction specific DNEL

Step a: Determination of the critical dose

Key study

WoE

Relevant dose descriptor

NOAEL = 23600 µg/cm2

Step b: Correction for assessment factors

Interspecies differences

-      Differences in metabolic rate per b.w. (allometric scaling)

 

-      Remaining differences (toxicokinetics and toxicodynamics)

 

-

Intraspecies differences

5

(worker)

Issues related to dose-response

1

(NOAEL)

Quality of whole database

1

Vehicle or matrix effect

3

(Matrix for the product not the same as the experimental conditions and may be designed to enhance penetration)

Exposure considerations

3

(taking into potential whole body exposure, dermal integrity, effect of occlusion and environmental conditions)

Overall assessment factor

45

DNEL calculation

525 µg/cm2/d

 

The induction specific DNEL is 525 µg/cm2/d for the workers.

Considering an exposed skin for workers of 857.5 cm2(hands-only surface from ECETOC-TRA) and a weight of 70 kg, the induction specific DNEL is 6.43 mg/kg bw/d.

 

Conclusion on dermal route:

Comparing the long-term DNEL by dermal route for systemic effects and the induction specific DNEL which is lower, it can be concluded that the remaining/residual likelihood risks must be assess using the induction specific DNEL. Therefore, as a worst-case, the induction specific DNEL of 525 µg/cm2is used for the risk characterization for workers exposed by dermal route. This DNEL is compared with the remaining/residual likelihood of risks after the implementation of appropriate Risk Management Measures (RMMs) and Operational Conditions (OCs).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.019 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
450
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.71 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
Overall assessment factor (AF):
450
Dose descriptor starting point:
LOAEC

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
9.11 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
600
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
78.7 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
300
Dose descriptor:
other: NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
78.7 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
300
Dose descriptor starting point:
other: NOAEL

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.056 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
1 800
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

1. Introduction:

In this chapter, all the endpoints from α-Hexyl Cinnamic Aldehyde (HCA) are re-examined and analyzed in order to establish a DNEL (s)/DMEL (s) for each one of them if possible. The followed method is that proposed in the guidance for the implementation of Reach (Chapter R.8: Characterisation of dose (concentration)-response for human health, May 2008)

 

2. Classification according to the Directive 67/548/EEC and to the CLP Regulation (Regulation (EC) No. 1272/2008)

A self-classification is proposed for HCA:

- May cause sensitization by skin contact: Xn; R43 / Category 1 (H317)

- Irritating to the skin (Xi; R38)

 

According to the CLP Regulation, the major criterion for the irritant category is that at least 2 of 3 tested animals have a mean erythema or edema score of ≥ 2,3 - ≤ 4,0. Under the test conditions, HCA is classified as “Xi; R38, Irritating to skin” according to the criteria of Annex VI to the Directive 67/548/EEC but it is not classified according to the CLP Regulation, as the mean individual score for erythema and edema was 2 in all animals.

 

3. DNELs derivation according to the toxicological profile of HCA

Neither indications of carcinogenic nor reprotoxic potential were observed or expected. Tests assessing the mutagenic potential of HCA in vitro and in vivo provided no evidence of genotoxic activity (mutagenicity and cytogenicity).

 

3.1. Oral route

 

3.1.1. General population-DNEL acute for oral route – systemic effects:

No acute toxicity hazard has been identified and no peak exposure has been predicted for HCA, therefore the long-term DNEL by oral route ensure a sufficient level of protection. No acute DNEL for oral route has been derived.

 

3.1.2. General population -DNEL long-term for oral route – systemic effects:

The concentration descriptor has been obtained from a reproduction/development toxicity screening test (Lewis, 2010) conducted with HCA according to the OECD guideline No. 421 and in compliance with GLP. The only effects observed were a reduction of maternal body weight gain and food consumption in the 100mg/kg bw/day group on days 1 and 5 of lactation in comparison to the vehicle control group. Under the conditions of this study a NOAEL of 100mg/kg bw/day is concluded. This value is considered as the dose-descriptor.

 

The following Table 3.1.2/1 indicates the calculation of th oral DNEL-long term for systemic effects for HCA.

 

Table 3.1.2/1: Calculation of the long-term DNEL by oral route for systemic effects for HCA

General population

Systemic long-term DNEL / oral

Step a : determination of the critical dose

Key study

Lewis, 2010 /K, Kr1

Relevant dose descriptor

NOAEL = 100 mg/kg b.w./d

Step b : Correction for uncertainty factors

Differences in absorption depending on route of exposure (route-route extrapolation, human/animal)

-

(same oral absorption human/rat)

Modification for exposure

(experiment and human)

-

(not relevant considering oral exposure)

Correct starting point = relevant dose descriptor / overall factor for uncertainties

100 mg/kg b.w./d

Step c : Correction for assessment factors

Interspecies differences:

 

-Differences in metabolic rate per b.w. (allometric scalling)

 

- Toxicodynamic and toxicokinetic remaining differencies

 

 

4(rat)

 

 

2.5

Intraspecies differences

10

(general population)

Duration extrapolation

(sub-acute/sub-chronic/chronic)

6

(subacute to chronic extrapolation)

Issues related to dose-response

1

(NOAEL)

Quality of whole database

3

(Incomplete database)

Overall assessment factor

1800

DNEL calculation

0.056 mg/kg b.w./d

 

The long-term DNEL by oral route for systemic effect is 0.056 mg/kg b.w./d for the general population.

 

3.2. Inhalation route

 

3.2.1. General population-DNEL acute for inhalation route – local effects:

An acute inhalation study (Breckenridge, 1980) was conducted with HCA according to a limit test using a droplet aerosol. Clinical signs of toxicity included enlarged bronchial lymph nodes at the terminal kill, multiple grey-green foci on the lungs and occasional pulmonary congestion at the measured concentration of 2120 mg/m3. These effects are likely to be the consequence of a local irritation induced by HCA. These local respiratory effects are consistent with the HCA classification as a skin irritant. The concentration of 2120 mg/m3 is therefore considered as the LOAEC for local effect.

According to the physico-chemical (log Kow = 5.3 at 24°C; water solubility = 1.62 mg/L at 20°C and pH 4-5; molecular mass= 216.3 g/mol) and the toxicological properties, HCA is not likely to be systemically absorbed by inhalation at a significant rate during acute exposure (15-minute exposure period at peak concentration).Extrapolation of the DNEL for acute systemic effects is not relevant and route to route extrapolation cannot be used in any case considering the local effects.

Taking into account the irritant potential ofHCA, time scaling is not appropriate as the adverse effects are mainly driven by the exposure concentration.

Hence, the dose descriptor is not modified for the 15 min-human exposure and the LOAEC of 2120 mg/m3 is considered as the dose descriptor for DNEL derivation.

 

The following Table 3..2/1 indicates the calculation of the acute DNELby inhalation for local effects.

 

Table 3..2/1: Calculation of the acute DNEL by inhalation for local effects for HCA

General population

Acute DNEL / inhalation / Local effects

Step a : determination of the critical dose

Key study

Breckenridge, 1980/ similar to OECD 403, K2

Relevant dose descriptor

LOAEC = 2120 mg/m3(foci on the lungs and lung congestion)

Step b : Correction for uncertainty factors

Modification for exposure

(experiment in animal and human)

-

(adverse effects mainly driven by exposure concentration)

Modification for the respiratory volume

-

Correct starting point = relevant dose descriptor / overall factor for uncertainties

2120 mg/m3

Step c : Correction for assessment factors

Interspecies differences:

 

-Differences in metabolic rate per b.w. (allometric scalling)

 

- Remaining differencies (toxicodynamics and toxicokinetics)

 

 

-

(local effects)

 

2.5

 

Intraspecies differences

10

(general population)

Duration extrapolation

(sub-acute/sub-chronic/chronic)

-

(acute DNEL from acute toxicity study)

Issues related to dose-response

6

(Extrapolation of the LOAEC from a limit test to the No Adverse Effect Concentration (NAEC))

Quality of the whole database

3

(Incomplete database)

Overall assessment factor

450

DNEL calculation

4.71 mg/m3

4.71 * 0.208 / 60 = 0.016 mg/kg bw/d

 

The acute DNEL by inhalation for local effects is 4.71 mg/m3 for general population.

 

3.2.2. General population-DNEL long-term for inhalation route – systemic effects:

For potential systemic effects during inhalation exposure, route-to-route extrapolation from the oral NOAEL value was performed.

A reproduction/development toxicity screening test (Lewis, 2010) was conducted with HCA according to the OECD guideline No. 421 and in compliance with GLP. The only effects observed were a slight transient reduction of maternal body weight gain and food consumption in the 100 mg/kg bw/day group on days 1 and 5 of lactation in comparison to the vehicle control group. Under the conditions of this study a NOAEL of 100 mg/kg bw/day is determined. This value is considered as the dose-descriptor for route-to-route extrapolation.

 

Using available data (Yuan, 1993), it was assumed that 10% absorption occurs by the oral route (see § 7.1). To secure a conservative external NOAEL a maximum absorption should be assumed for the inhalation route (i.e.; 100%) (see Guidance Document, Chapter R.8, pp 25). To convert the oral NOAEL into inhalatory NOAEC, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 1.15 m3/kg bw/24 h).

Thus, the corrected dose descriptor for inhalation is 8.7 mg/m3 for general population.

 

The following Table 3..2/2 indicates the calculation of the long-term DNEL by inhalation for systemic effects.

 

Table 3.2/2 Calculation of the long-term DNEL by inhalation for systemic effects for HCA

General population

Systemic long-term DNEL / inhalation

Step a: Determination of the critical dose

Key study

Lewis, 2010/ OECD 421, K1

Relevant dose descriptor

NOAEL = 100 mg/kg bw/d

Step b: Correction for uncertainty factors

Differences in absorption depending on route of exposure (route-route extrapolation, human/animal)

10/100

Modification for exposure

(experiment and human)

(1/1.15)

Correct starting point

8.7 mg/m3

Step c: Correction for assessment factors

Interspecies differences:

 

-Differences in metabolic rate per b.w. (allometric scalling)

 

- Remaining differencies (toxicodynamics and toxicokinetics)

 

 

-

 

 

2.5

 

Intraspecies differences

10

(general population)

Duration extrapolation

(sub-acute/sub-chronic/chronic)

6

(sub-acute to chronic extrapolation)

Issues related to dose-response

1

(NOAEL)

Quality of whole database

3

Overall assessment factor

450

DNEL calculation

0.019 mg/m3

0.0063 mg/kg bw/day*

*20 m3respiratory volume during 24h/ 60 kg bw

 

The long-term DNEL by inhalation for systemic effects is 0.019 mg/m3 for general population.

 

Conclusion on inhalation:

The acute DNEL by inhalation for local effects is 4.71 mg/m3 for general population.

The long-term DNEL by inhalation for systemic effects is 0.019 mg/m3 for general population.

 

3.3. Dermal route:

 

3.3.1. General population – DNEL long term for dermal route –systemic effects:

Based on the observed effects in the sub-chronic dermal toxicity study (Lough, 1980), a relevant NOAEL for systemic effects cannot be determined for dermal-only exposure since the animals were exposed both by dermal and oral route. However, as no systemic effect was observed at 125 mg/kg bw/d (as routes were confused), it is assumed that the NOAEL for systemic effect by dermal route is likely much higher than this dose for dermal-only exposure.

 

As the above study is not considered as adequate for dermal-only exposure and on a worst-case assumption, route-to-route extrapolation from the oral NOAEL value was preferred to evaluate the potential effect during long-term dermal exposure.

Under the conditions of the screening reproductive oral study (see §3.2) a NOAEL of 100 mg/kg bw/day is concluded based on a slight and transient reduction of maternal body weight gain and food consumption at this dose level. This value is considered as the dose-descriptor for route-to-route extrapolation.

Using available data (Yuan, 1993), it was assumed that 10%absorption occurs by the oral route and only 0.183% by dermal route (see §7.1).

Thus, the corrected dose descriptor for dermal route is 5465mg/kg bw/d for general population.

The following Table 3.3/1 indicates the calculation of the long term DNEL by dermal route for systemic effects of HCA

Table3.3/1: Calculation of the long-term DNEL by dermal route for systemic effects for HCA

General population

Systemic long-term DNEL / inhalation

Step a: Determination of the critical dose

Key study

Lewis, 2010/ OECD 421, K1

Relevant dose descriptor

NOAEL = 100 mg/kg bw/d

Step b: Correction for uncertainty factors

Differences in absorption depending on route of exposure (route-route extrapolation, human/animal)

10/0.183

Modification for exposure

(experiment and human)

-

Correct starting point

5465mg/kg bw/d

Step c: Correction for assessment factors

Interspecies differences

 

-      Differences in metabolic rate per b.w. (allometric scaling)

 

-      Remaining differences (toxicokinetics and toxicodynamics)

 

 

4(rats)

 

 

2.5

 

Intraspecies differences

10

(general population)

Duration extrapolation

(sub-acute/sub-chronic/chronic)

2*

Issues related to dose-response

1

(NOAEL)

Quality of whole database

3

Overall assessment factor

600

DNEL calculation

9.11 mg/kg bw/d

*An assessment factor of 2 for duration extrapolation was used instead of 6 as no systemic effects were observed in the study of Lough (1980), following dermal/oral exposure to 125 mg HCA/kg bw/d for 90 days (see IUCLID §7.5.2).

The long-term DNEL by dermal routefor systemic effects is 9.11 mg/kg bw/d for the general population.

3.3.2. General population - Induction specific DNEL:

According to the CLP criteria, HCA is classified as skin sensitizer but not as skin irritating. The general approach for sensitizers is a two-step procedure involving:

- a qualitative approach using potency categorization to define the risk management measure (RMMs) and operational conditions (OCs),

- and setting a DNEL to judge the remaining / residual likehood of risks after these RMMs and OCs are implemented.

 

Data obtained from both local lymph node assays (see §7.4.1) and historical predictive human test data (see §7.10.4) were used to provide information on the potency for induction, as well as on dose-response relationships of HCA.

 

HCA is recommended as positive control in skin sensitisation studies under OECD Guideline 406 and OECD Guideline 429. As such, HCA is recognised as a skin sensitiser and extensive data on its response in the LLNA are available. EC3 derived were in the range 6.6-11.5% (1650-2875 µg/cm2).

 

A NESIL or NOAEL of 23600 µg/cm2 (highest concentration tested showing no sensitisation in human), was obtained in the Human Repeated Insult Patch Test conducted by the RIFM (see section 7.10.4).

 

Although there is not a good agreement between LLNA EC3 and NOAEL derived from HRIPT studies, the HRIPT NOAEL was considered sufficiently robust and relevant as the study is conducted in human to override the EC3 value. Indeed the HRIPT was conducted according to Good Clinical Practice and following the RIFM standard test method.

 

Thus the dose descriptor for sensitisation is 23600 µg/cm2.

 

The following table 3.3/2 indicates the calculation of the induction specific DNEL.

 

Table 3.3/2: Calculation of the induction specific DNEL for HCA

General population

Induction specific DNEL

Step a: Determination of the critical dose

Key study

WoE

Relevant dose descriptor

NOAEL = 23600 µg/cm2

Step b: Correction for assessment factors

Interspecies differences

-      Differences in metabolic rate per b.w. (allometric scaling)

 

-      Remaining differences (toxicokinetics and toxicodynamics)

-

Intraspecies differences

10

(general population)

Issues related to dose-response

1

(NOAEL)

Quality of whole database

1

Vehicle or matrix effect

3

(Matrix for the product not the same as the experimental conditions and may be designed to enhance penetration)

Exposure considerations

10

(taking into potential whole body exposure, dermal integrity, effect of occlusion and environmental conditions)

Overall assessment factor

300

DNEL calculation

78.7 µg/cm2/d

 

The induction specific DNEL is 78.7 µg/cm2/d for the general population.

 

Conclusion on dermal route:

 

Considering the difference, by dermal route, between the long-term DNEL for systemic effects and the induction specific DNEL, the risk caracterisation for the general population has to be assess using both DNELs in order to determine the worst-case risk according to the different uses of HCA.