Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.82 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Dose descriptor starting point:
NOAEL
Value:
40 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
35.3 mg/m³
Explanation for the modification of the dose descriptor starting point:

The exposure conditions for experimental rats in the repeated dose 28-day oral toxicitystudy (with CAE after a 14-day exposure period) are different from that of target population (worker exposed to CAE). Indeed workers are expected to be mainly exposed to CAE via dermal and inhalation routes.

Therefore the following formulae are used to calculate corrected inhalatory dose levels using the dose descriptor defined as an oral NOAEL:

 

- Conversion of oral NOAEL rat (in mg/kg b.w./day) into inhalatory NOAEC rat (in mg/m3)

 

Corrected inhalatoryNOAEC =oralNOAEL * [(ABSoral rat* sRVhuman) / (sRVrat* ABSinh human* wRV)]

 

where:

ABSoral rat:           rat oral absorption (50% default value in absence of toxicokinetic data)

sRVhuman:            human Standard Respiratory Volume (6.7 m3/person for 8 h exposure)

sRVrat:                rat standard Respiratory Volume (0.38 m3/kg b.w. for 8 h exposure)

ABSinh human:         human inhalation absorption (100% default value in absence of toxicokinetic data)

wRV:                 worker Respiratory Volume (10 m3/person for 8 h exposure)

AF for dose response relationship:
1
Justification:
The starting point for the DNEL is a NOAEL.
AF for differences in duration of exposure:
1
Justification:
A review was performed on the existing toxicological data from PIAS and PIAD (which are close to CAE in terms of composition). In order to avoid unnecessary additional experimentation on animals, these data were extrapolated to CAE to complete its toxicological profile.
A 6-month oral toxicity study was performed in rats treated with a wide dose range of PIAS (0, 50, 200 and 750 mg/kg b.w./day). Clinical observations were made at the dose levels of 200 and 750 mg/kg b.w./day; the NOAEL was established at 50 mg/kg b.w./day which is higher than the worst-case NOAEL of 10 mg/kg b.w./day established with PIAD. Taking into account also reprotoxicological data, this suggests that chronic toxicity profile is not expected to be more severe than subacute and subchronic for CAE, PIAS and PIAD.
Based on experimental data, chronic toxicity for CAE with a NOAEL of 50 mg/kg b.w./day established with PIAS in rat is not expected to be more severe than subacute and subchronic toxicity with a worst-case NOAEL of 10 mg/kg b.w./day in rat established with PIAD. Therefore, no assessment factor for the difference in exposure duration is applied.
AF for interspecies differences (allometric scaling):
1
Justification:
The allometric scalling is already taken into account in NOAEC calculation.
AF for other interspecies differences:
2.5
Justification:
see Guidance R8, Point 8.4.3.3, Table R.8-6
AF for intraspecies differences:
5
Justification:
see Guidance R8, Point 8.4.3.3, Table R.8-6
AF for the quality of the whole database:
1
Justification:
Default value
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.6 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Dose descriptor starting point:
NOAEL
Value:
40 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
80 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The exposure conditions for experimental rats in the repeated dose 28-day oral toxicitystudy (with CAE after a 14-day exposure period) are different from that of target population (worker exposed to CAE). Indeed workers are expected to be mainly exposed to CAEviadermal and inhalation routes.

Therefore the following formulae are used to calculate corrected dermal dose levels using the dose descriptor defined as an oral NOAEL:

 

- Conversion of oral NOAEL rat (in mg/kg b.w./day) into dermal NOAEL rat (in mg/kg b.w./day)

 

Corrected dermalNOAEL =oralNOAEL * (ABSoral rat/ ABSderm human)

 

where:

ABSoral rat:           rat oral absorption (50% default value in absence of toxicokinetic data)

ABSderm human:       human dermal absorption (25% default value)

 

 

Corrected dermalNOAEL = 40 * (50% / 25%) = 80 mg/kg b.w./day

NB: default dermal absorption values

In Chapter R.7c from ECHA “Guidance on information requirements and chemical safety assessment” (November 2012)[1], default dermal absorption values were proposed:

- 10% in case of substance with specific physico-chemical properties (MW > 500 g.mol-1and
log Pow< -1 or > 4),

- 100%.

However these default values previously used by EFSA were refined in a more recent scientific opinion (Guidance on Dermal absorption, December 2012)[2] which recommends:

- 25% for product containing > 5% (50 g/kg for solids or 50 g/L for liquids) active substance,

- 75% for product containing ≤ 5% active substance,

- 10% is still available in case of substance with specific physico-chemical properties (MW > 500 g.mol-1and log Pow< -1 or > 4).

 

In the present assessment, since CAE is composed of glycerides (46.3%), free fatty acids (21.4%) and unsaponifiables such as alkyl furans (18.1%) and alkyl triols (7.0%), a 25% default dermal absorption is set.


[1]ECHA Guidance on information requirements and chemical safety assessment, Chapter R.7c : Endpoint specific guidance, Version: 1.1, November 2012

[2]Scientific Opinion Guidance on Dermal Absorption (EFSA Journal 2012;10(4):2665)

AF for dose response relationship:
1
Justification:
The starting point for the DNEL is a NOAEL.
AF for differences in duration of exposure:
1
Justification:
A review was performed on the existing toxicological data from PIAS and PIAD (which are close to CAE in terms of composition). In order to avoid unnecessary additional experimentation on animals, these data were extrapolated to CAE to complete its toxicological profile.
A 6-month oral toxicity study was performed in rats treated with a wide dose range of PIAS (0, 50, 200 and 750 mg/kg b.w./day). Clinical observations were made at the dose levels of 200 and 750 mg/kg b.w./day; the NOAEL was established at 50 mg/kg b.w./day which is higher than the worst-case NOAEL of 10 mg/kg b.w./day established with PIAD. Taking into account also reprotoxicological data, this suggests that chronic toxicity profile is not expected to be more severe than subacute and subchronic for CAE, PIAS and PIAD.
Based on experimental data, chronic toxicity for CAE with a NOAEL of 50 mg/kg b.w./day established with PIAS in rat is not expected to be more severe than subacute and subchronic toxicity with a worst-case NOAEL of 10 mg/kg b.w./day in rat established with PIAD. Therefore, no assessment factor for the difference in exposure duration is applied.
AF for interspecies differences (allometric scaling):
4
Justification:
AF metabolic differences with rat: 4 (see Point 8.4.3.1, Table R.8-3)

AF for other interspecies differences:
2.5
Justification:
AF remaining differences: 2.5 (see Point 8.4.3.3, Table R.8-6)
AF for intraspecies differences:
5
Justification:
see Point 8.4.3.3, Table R.8-6.
AF for the quality of the whole database:
1
Justification:
Default value
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population