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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:
10.23 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):
25
Modified dose descriptor starting point:
NOAEC
DNEL value:
255.66 mg/m³
Explanation for the modification of the dose descriptor starting point:
Due to the low vapour pressure of the test substance acute exposure hazard via inhalation is unlikely for humans. Therefore a route-to -route extrapolation from an oral repeated dose study with the related substance methyl trans-styryl ketone, as a worst case is justified.
AF for dose response relationship:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for differences in duration of exposure:
2
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for other interspecies differences:
2.5
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for intraspecies differences:
5
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for the quality of the whole database:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for remaining uncertainties:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

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

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.875 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
DNEL value:
87.5 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Long-term systemic DNEL for dermal route has been derived from the NOAEL of 87.5 mg/kg bw established in the dermal 3-month study in rats with the related substance methyl trans-styryl ketone (NTP, 2012a). The substance is systemically available by the oral and dermal route and caused decreased body weights and body weight gains and dermal irritation in the treated animals in the two highest dose groups (175 and 350 mg/kg bw). Treatment-related lesions of the skin were limited to the site of application. There were increased incidences of epidermal hyperplasia, hyperkeratosis, chronic active inflammation, epidermal necrosis, and sebaceous gland hypertrophy in dosed groups of males and females. The substance produced no changes in haematology or clinical chemistry. As seen in the acute dermal study in rats, the substance was not systemically toxic by the dermal route and it has also been shown to be of lower systemic toxicity after prolonged exposure with the skin. The starting point for the DNEL derivation is the dermal NOAEL.
AF for dose response relationship:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for differences in duration of exposure:
2
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for interspecies differences (allometric scaling):
4
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for other interspecies differences:
2.5
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for intraspecies differences:
5
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for the quality of the whole database:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for remaining uncertainties:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.617 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1 500
Dose descriptor starting point:
other: LOAEL
AF for dose response relationship:
3
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for interspecies differences (allometric scaling):
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for other interspecies differences:
10
Justification:
in accordance with the principles given in ECHA R8 (2010) - this value is the assessment factor for interspecies variation in case of local effects
AF for intraspecies differences:
5
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for the quality of the whole database:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for remaining uncertainties:
10
Justification:
in accordance with the principles given in ECHA R8 (2010) - this value is the assessment factor for vehicle of matrix effect (AF 5), which applies because it can not be ruled out that the substance of interest is used in a matrix with penetration enhancers as fatty acids and a factor of 2 for different exposure conditions

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

The calculation of the DNELs is performed in accordance with the principles given in ECHA (2010) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health” .

Available dose descriptors:

For benzalacetone, the following dose descriptors are available:

Acute/short-term exposure – systemic effects (dermal DNEL):

There are two acute values available: oral and dermal. The published oral LD50 of 2030 mg/kg bw (Opdyke, 1973) does not lead to classification of the substance. However, oral route of exposure is not relevant for workers and risk arising from an accidental intake of the substance orally should be controlled qualitatively (inclusion of appropriate RMMs and OCs as well as personal training). Benzalacetone was not acutely toxic after dermal administration to rats (Opdyke, 1973). A LD50 of 3000 mg/kg bw is considered to show no risk. Therefore, a DNEL for acute systemic effects by the dermal route is unnecessary since the long-term DNEL covers sufficiently the risk of short-term exposure.

Acute/short-term exposure – systemic effects (inhalation DNEL):

No acute DNEL for systemic effects by inhalation can be established since there is no dose descriptor available. The substance has a low vapour pressure (1.34 Paat 25°C) and is not expected to bear a significant airborne hazard.

Acute/short-term exposure – local effects (dermal DNEL):

The substance is irritating to the skin (Opdyke, 1973) and does possess sensitisation potential (Opdyke, 1973). Therefore the DNEL for acute dermal local-effects is derived. This acute short-term dermal DNEL represents a specific DNEL for sensitisation. The EC3 value given in the publication of Gerberick and colleagues (2005) was used to derive the DNEL for acute local effects (dermal). The EC3 value of 3.7 % was converted, taking into account the dose volume of 25 µL and the estimated application aera of 1 cm² (mouse ear). This results in a factor of 250 (EC3 = 0.925 mg/cm² = 925 µg/cm²). The EC3 value was considered as the LOAEL for induction. The assessment factors are: 3 for dose response relationship as the EC3 value is considered to be the LOAEL, 1 for allometric scaling as this does not apply for local effects, 10 for other interspecies differences (intespecies variation), 5 for intraspecies differences for workers and 1 for the quality of the whole database. In addition, an assessment factor for vehicle of matrix effect (AF 5), which applies because it can not be ruled out that the substance of interest is used in a matrix with penetration enhancers as fatty acids and a factor of 2 for different exposure conditions is used.

 

Acute/short-term exposure – local effects (inhalation DNEL):

The substance does not bear a significant airborne hazard (and is not suspected to be irritating or sensitising to the respiratory system). The long-term inhalation DNEL for systemic effects covers sufficiently for local effects.

 

Long-term exposure – systemic effects (dermal DNEL)

Long-term systemic DNEL for the dermal route has been derived from the NOAEC of 87.5 mg/kg bw of the subchronic rat-study with the related substance methyl trans-styryl ketone (NTP, 2012a). The substance is systemically available by the oral and dermal route and caused decreased body weights and body weight gains and dermal irritation in the treated animals in the two highest dose groups (175 and 350 mg/kg bw). As seen in the acute dermal study in rats, the substance was not systemically toxic by the dermal route and it has also shown to be of lower systemic toxicity after prolonged exposure with the skin. The starting point for the DNEL derivation is the dermal NOAEL.

 

Long-term exposure – systemic effects (inhalation DNEL)

There are no long-term inhalation studies with the target substance available. The inhalation DNEL can be derived from the dermal NOAEL of 87.5 mg/kg bw established in the 3 month dermal study in rats (NTP, 2012a) by route-to-route extrapolation.

 

Long-term exposure – local effects (dermal DNEL)

No long-term dermal DNEL for local effects can be derived because there is no data is available on effect levels for the target substance. This will be adressed qualitatively and please take the specific DNEL for sensitisation into account.

 

Long-term exposure – local effects (inhalation DNEL)

No long-term inhalation DNEL for local effects can be derived because there is no data is available on effect levels for the target substance. Local effects are covered sufficiently by the long-term DNEL for systemic effects.

For the other non-threshold endpoints (mutagenicity, eye and skin irritation/corrosion) no DNELs can be derived because no No Observed Effect Level could be established from the relevant studies. The controlling of risk of any hazard relevant for these endpoints should be covered by the long-term DNELs and by the DNELs derived for local effects.

 

Modification of the starting point:

From all available data for the different human health endpoints it is clear that benzalacetone exerts its effects by a threshold mode of action. Thus, DNELs can be calculated for the different threshold endpoints based on the most relevant dose descriptors per endpoint. DNELs are derived based on the available toxicity data for the target substance, reflecting the routes, the duration and the frequency of exposure.

 

Bioavailability (absorption)

There is no substance-specific information on absorption by the oral, dermal and inhalation route available. The absorption rates are assessed based on the physico-chemical properties and on the effects observed in the studies. However, there are data available for the absorption of methyl trans-styryl ketone (Sauer, 1997). They indicate that the substance s readily absorbed after oral and topical administration. Due to the effects seen in the 3 month oral study in rats, 100% absorption by oral route is considered for the target substance (for the detailed information on absorption please refer to section "Toxicokinetics, metabolism and distribution" of this CSR or section 7.1 of IUCLID file). Dermal absorption is also expected for the substance (log Pow of 2.04 and water solubility of 1890 mg/L point to an absorption through the skin). In addition, dermal absorption is also likely, since the molecular weight of 146.1858 is under 500 and according to the TGD, Part I, Appendix VI, 100% of dermal absorption should be considered in this case. Dermal absorption in rats and in humans is assumed to be the same since no information for dermal absorption of the target chemical in humans is available. 100% absorption is assumed for oral and inhalation routes in rats and in humans (worst case; according to the ECETOC Report No 110, 100% absorption for inhalation can be used in case of absence of substance specific data for absorption).

 

Route-to-route extrapolation:

Oral-to-inhalation extrapolation is performed to obtain long-term inhalation NOAEC for systemic effects. The following formula was used: corrected inhalatory NOAEC = oral NOAEL x (1/sRVrat) x (ABSoral-rat/ABSinh-human) x (6.7 m³/10 m³) where sRV is standard respiratory volume of rats during 8 hours (= 0.38 m³/kg/day); ABS-absorption ( 100 % oral absorption and 100 % for the inhalation) and 6.7 m³ and 10 m³ are standard respiratory volumes for workers under normal conditions and by light activity.

 

Exposure conditions:

No modification of the starting points for exposure conditions was necessary since the systemic dose after oral administration of the test material was already assessed in respiratory volume taken for rats during 8 h (0.38m³).

 

Applying of assessment factors and calculation of DNELs:

The assessment factors have been applied to the corrected starting point to obtain the endpoint specific DNELs. Assessment factors (AFs) correct uncertainties and variability within and between species in the effect data.

 

Interspecies differences:

The species-specific default assessment factor of 4 for allometric scaling for rats was applied in the case of employment of the dermal LD50(=NOAEL) to derive dermal short-term DNEL, in case of the dermal NOAEL from 3-month study, which was used to derive the dermal long-term DNEL and when the dermal long-term NOAEC was used for the derivation of dermal long-term DNEL;

No allometric scaling factor was applied when the oral NOAEL from the 3 month study was used for the derivation of inhalation long-term DNEL;

An assessment factor of 2.5 was applied for remaining interspecies differences in toxicodynamics between rat and human in all cases.

 

Intraspecies differences:

An assessment factor of 5 was applied for workers in all cases.

 

Extrapolation of duration:

An assessment factor of 1 was applied for duration of exposure when acute study was used for the derivation of the acute dermal DNEL.

An assessment factor of 2 was applied for duration of exposure (subchronic-to-chronic).

 

Quality of whole data base:

The assessment factors for uncertainties to the quality of the data base were used: 1 in all cases (GLP studies and a reviewed NTP-report were used).

 

Issues related to dose response:

A default assessment factor of 1 was applied when NOAEL was used.

 

Calculation of DNELs:

 

Acute exposure - local effects (dermal DNEL)

The EC3 value (925 µg/cm², equivalent to the LOAEL) was used for derivation of the dermal DNEL:

DNEL = 925 µg/cm² / (3 x 1 x 10 x 5 x 1 x 10) = 0.617 µg/cm²/day. Assessement factors are: 1 - interspecies, 10 - other interspecies differences, 5 - intraspecies, 1 study duration, 3 - dose response, 1- quality of data base (default), 10 - (5 for vehicle of matrix effect / 2 for different exposure conditions.

Long-term exposure – systemic effects (dermal DNEL)

The dermal NOAEC of 145 mg/kg bw was used for derivation of the dermal NOAEL:

DNEL = 87.5 mg/kg bw/(4 x 2.5 x 5 x 2 x 1 x 1) = 0.875 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 5 – intraspecies, 2 – study duration (sub-chronic study), 1 – dose response (clear dose response), 1 – quality of data base (default).

 

Long-term exposure – systemic effects (inhalation DNEL):

The oral NOAEL of 145 mg/kg bw was converted into the inhalation NOAEC:

Inhalation NOAEC = dermal NOAEL x (1/sRVrat) x (ABS oral-rat/ABS inhal-human) x (6.7 m³/10 m³) = 145 mg/kg bw x (1/0.38 m³/kg/day) x (100%/100%) x (6.7/10) = 255.66 mg/m³

DNEL = 255.66 mg/m³/(2.5 x 5 x 2 x 1 x 1) = 10.23 mg/m³. Assessment factors are: 2.5 – remaining interspecies differences, 5 – intraspecies, 2 – study duration (sub-chronic study), 1 – dose response (clear dose response), 1 – quality of data base (default).

 

Selection of the leading health effects and the corresponding DNELs

The critical DNELs should be the lowest DNELs obtained for each exposure pattern. Systemic effects should be assessed using the corresponding long-term DNELs. Local effects should be covered by DNELs for systemic effects. As seen from all available studies for the target chemical, toxicity to the skin occurs after prolonged dermal exposure to the chemical.

The risk of dermal short-term exposure should be controlled qualitatively. Dermal short-term DNEL of 0.617 µg/cm²/day for acute local effects is appropriate for remaining risks (after RMMs and OCs are implemented) and for accidental cases. Long-term dermal DNEL protects sufficiently against short-term exposures.
The long-term DNELs for systemic effects are the lowest DNELs and they cover any hazard arising for systemic effects. They ensure that organ toxicity will not occur in humans.

Selected DNELs

Acute - local - dermal DNEL = 0.617 µg/cm²/day

Long-term – dermal DNEL (systemic and local effects) = 0.875 mg/kg bw

Long-term – inhalation DNEL (systemic and local effects) = 10.23 mg/m³

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.52 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):
50
Modified dose descriptor starting point:
NOAEC
DNEL value:
126.09 mg/m³
Explanation for the modification of the dose descriptor starting point:
Due to the low vapour pressure of the test substance acute exposure hazard via inhalation is unlikely for humans. Therefore a route-to -route extrapolation from an oral repeated dose study with the related substance methyl trans-styryl ketone, as a worst case is justified.
AF for dose response relationship:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for differences in duration of exposure:
2
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for other interspecies differences:
2.5
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for intraspecies differences:
10
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for the quality of the whole database:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

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

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.438 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
DNEL value:
87.5 mg/kg bw/day
AF for dose response relationship:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for differences in duration of exposure:
2
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for interspecies differences (allometric scaling):
4
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for other interspecies differences:
2.5
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for intraspecies differences:
10
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for the quality of the whole database:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.308 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
3 000
Dose descriptor starting point:
other: LOAEL
AF for dose response relationship:
3
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for interspecies differences (allometric scaling):
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for other interspecies differences:
10
Justification:
in accordance with the principles given in ECHA R8 (2010) - this value is the assessment factor for interspecies variation in case of local effects
AF for intraspecies differences:
10
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for the quality of the whole database:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for remaining uncertainties:
10
Justification:
in accordance with the principles given in ECHA R8 (2010) - this value is the assessment factor for vehicle of matrix effect (AF 5), which applies because it can not be ruled out that the substance of interest is used in a matrix with penetration enhancers as fatty acids and a factor of 2 for different exposure conditions

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.725 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):
200
Modified dose descriptor starting point:
NOAEL
DNEL value:
145 mg/kg bw/day
AF for dose response relationship:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for differences in duration of exposure:
2
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for interspecies differences (allometric scaling):
4
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for other interspecies differences:
2.5
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for intraspecies differences:
10
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for the quality of the whole database:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
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

The principles of the DNEL calculation for the general population are the same as already described for workers. However, there are additional considerations or deviations which are described as follows:

Modification of the starting point:

Bioavailability (absorption by oral route)

The oral absorption in rats and in humans is assumed to be the same since no information for oral absorption for target chemical in rats and in humans is available.

 

Respiratory volumes:

No differences in the respiratory volumes under normal conditions and by light activity in humans were taken into account.

 

Applying of assessment factors:

A higher assessment factor of 10 (in place of 5 for workers) for intraspecies variation/differences of human population was used.

 

Calculation of endpoint-specific DNEL for general population

 

Acute exposure - local effects (dermal DNEL)

The EC3 value (925 µg/cm², equivalent to the LOAEL) was used for derivation of the dermal DNEL:

DNEL = 925 µg/cm² / (3 x 1 x 10 x 10 x 1 x 10) = 0.3083 µg/cm²/day. Assessment factors are: 1 - interspecies, 10 - other interspecies differences, 10 - intraspecies, 1 study duration, 3 - dose response, 1- quality of data base (default), 10 - (5 for vehicle of matrix effect / 2 for different exposure conditions.

Long-term exposure – systemic effects (dermal DNEL)

The dermal NOAEL of 87.5 mg/kg bw was used:

DNEL = 87.5 mg/kg bw/(4 x 2.5 x 10 x 2 x 1 x 1) = 0.4375 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 2 – study duration (sub-chronic study), 1 – dose response (clear dose response), 1 – quality of data base (default).

 

Long-term exposure – systemic effects (inhalation DNEL)

The oral NOAEL of 145 mg/kg bw from the related substance methyl trans-styryl ketone was converted into the inhalation NOAEC:

Corrected inhalation NOAEC = oral rat NOAEL x (1/1.15 m³/kg bw/day) x (ABS oral-rat/ABS inhal-human),where 1.15 is standard respiratory volume (m³/kg bw) of rats during 24 h exposure, ABS is absorption (values are the same as described for workers).

Corrected Inhalation NOAEC = 145 mg/kg bw x (1/1.15 m³/kg/day) x (100%/100%) = 126.09 mg/m³

DNEL = 126.09 mg/m³/ (2.5 x 10 x 2 x 1 x 1) = 2.52 mg/m³. Assessment factors are: 2.5 – remaining interspecies differences, 10 – intraspecies, 2 – study duration (sub-chronic study), 1 – dose response (clear dose response), 1 – quality of data base (default).

 

Long-term exposure – systemic effects (oral DNEL)

The oral NOAEL of 145 mg/kg bw was not modified for differences in absorption by oral route since no substance- and route specific information is available:

DNEL = 145 mg/kg bw/(4 x 2.5 x 10 x 2 x 1 x 1) = 0.725 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 2 – study duration (sub-chronic study), 1 – dose response (clear dose response), 1 – quality of data base (default).