Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
13.3 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
Modified dose descriptor starting point:
NOAEC
DNEL value:
165.8 mg/m³
Explanation for the modification of the dose descriptor starting point:

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals. As no data on effects of repeated inhalation exposure to alpha methylcinnamaldehyde or cinnamaldehyde in humans or

laboratory animals are available, route-to-route extrapolation to calculate a DNEL for such effects from repeated dose oral toxicity studies was considered a suitable alternative. The starting point of cinnamaldehyde must be corrected for the change in MW for alpha methylcinnamaldehyde So, 100 mg/kg/bw/d*(146/132) = 110.6 mg/kg/bw/day At least 85% of radiolabelled cinnamaldehyde was considered absorbed after 72h in male rats following a single gavage administration (Nutley, 1990). Although there is no specific information for the inhalation route of exposure, it is likely that absorption of alpha methylcinnamaldehyde will be similar to cinnamaldehyde and will also be complete following inhalation exposure. Therefore a health precautionary approach is to assume 85% oral absorption and 100% inhalation absorption. Therefore, to adjust for inhalation exposure 110.6 (mg/kg bw/day) / (100/85) = 94 mg/kg bw/day). Workers are assumed to be exposed for 8 h/day. Converting oral data to a corresponding air concentration in the rat is required. The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat of 0.38 m3/kg bw for 8 h/day (exposure of workers). Thus, 94 mg/kg bw/day / 0.38 m3/kg bw/day = 247 mg/m3 (8-h exposure of workers). To account for the presumed light activity of workers, this value has been corrected for an increase in breathing volume, thus 247 mg/m3x (6.7 m3/ 10 m3) = 165.8 mg/m3 (8-h exposure of workers, light activity).

AF for dose response relationship:
1
Justification:
Default ECHA AF; human health relevant NOAEL from well-conducted 720day dietary study.
AF for differences in duration of exposure:
1
Justification:
Default ECHA AF for chronic (720-day) exposure
AF for interspecies differences (allometric scaling):
1
Justification:
(allometric scaling); already considered in correcting starting point above
AF for other interspecies differences:
2.5
Justification:
Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
AF for intraspecies differences:
5
Justification:
Default ECHA AF for (healthy) worker
AF for the quality of the whole database:
1
Justification:
Default ECHA AF; the health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
13.3 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Dose descriptor:
NOAEC
AF for dose response relationship:
1
Justification:
Default ECHA AF; human health relevant NOAEL from well-conducted 720day dietary study.
AF for differences in duration of exposure:
1
Justification:
Default ECHA AF for chronic (720-day) exposure
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling already considered in correcting starting point above
AF for other interspecies differences:
2.5
Justification:
Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
AF for intraspecies differences:
5
Justification:
Default ECHA AF for (healthy) worker
AF for the quality of the whole database:
1
Justification:
Default ECHA AF; the health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high.
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:
2.21 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
Modified dose descriptor starting point:
NOAEL
DNEL value:
110.6 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals. As no relevant study data on effects of repeated dermal exposure to alpha methylcinnamaldehyde in humans or laboratory

animals are available, route-to-route extrapolation to calculate a dermal DNEL from repeated dose oral toxicity studies was considered a suitable alternative. In the absence of route-specific information on absorption the end route (dermal), an assumption equal to the oral absorption will be made. Therefore, the starting point is 100mg/kg/bw/day. The starting point of cinnamaldehyde must be corrected for the change in MW for alpha methylcinnamaldehyde. So, 100 mg/kg/bw/d*(146/132) = 110.6 mg/kg/bw/day. Workers are assumed to be exposed for 8 h/day

AF for dose response relationship:
1
Justification:
Default ECHA AF; human health relevant NOAEL from well-conducted 720day dietary study.
AF for differences in duration of exposure:
1
Justification:
Default ECHA AF for chronic (720-day) exposure
AF for interspecies differences (allometric scaling):
4
Justification:
Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling)
AF for other interspecies differences:
2.5
Justification:
Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
AF for intraspecies differences:
5
Justification:
Default ECHA AF for (healthy) worker
AF for the quality of the whole database:
1
Justification:
Default ECHA AF; the human health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.5 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Dose descriptor:
other: NOAEL
AF for dose response relationship:
1
Justification:
Default ECHA AF; human health relevant NOAEL from well-conducted study.
AF for differences in duration of exposure:
1
Justification:
Default ECHA AF for local exposure
AF for interspecies differences (allometric scaling):
1
Justification:
Default ECHA AF for human study (allometric scaling)
AF for other interspecies differences:
1
Justification:
Default ECHA AF for human study
AF for intraspecies differences:
1
Justification:
Default ECHA AF for (healthy) worker
AF for the quality of the whole database:
1
Justification:
Default ECHA AF; the human health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.5 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Dose descriptor starting point:
other: NOAEL
AF for dose response relationship:
1
Justification:
Default ECHA AF; human health relevant NOAEL from well-conducted study.
AF for interspecies differences (allometric scaling):
1
Justification:
Default ECHA AF for human study (allometric scaling)
AF for other interspecies differences:
1
Justification:
Default ECHA AF for human study
AF for intraspecies differences:
1
Justification:
Default ECHA AF for (healthy) worker
AF for the quality of the whole database:
1
Justification:
Default ECHA AF; the human health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high.

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.27 mg/m³
Most sensitive endpoint:
effect on fertility
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:
163.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

Modification of starting point. In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals. Route-to-route extrapolation to calculate an inhalation DNEL (fertility) from oral studies was

considered suitable. The starting point of cinnamaldehyde must be corrected for the change in MW for alpha methylcinnamaldehyde So, 200 mg/kg/bw/d*(146/132) = 221.2 mg/kg/bw/day As explained previously, a health precautionary approach is to assume 100% absorption following inhalation exposure. Therefore, the starting point has been corrected to reflect 85% oral absorption (seen in the cinnamaldehyde study) and 100% inhalation absorption. Thus, 221.2 mg/kg bw/day / (100/85) = 188 mg/kg bw/day General population exposure is assumed to be continuous (24 h/day, 7 d/wk). Only limited consumer exposure is expected. The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat of 1.15 m3/kg bw for 24 h/day. Thus, 188 mg/kg bw/day / 1.15 m3/kg bw/day = 163.5mg/m3 (24-h exposure of the general population).

AF for dose response relationship:
2
Justification:
ECHA AF; human health relevant NOAEL from well-conducted 720day dietary study. A higher AF has been selected because the study is not a specfic reproductive one
AF for differences in duration of exposure:
1
Justification:
Default ECHA AF for chronic (720-day) exposure
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling already considered in correcting starting point above
AF for other interspecies differences:
2.5
Justification:
Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
AF for intraspecies differences:
10
Justification:
Default ECHA AF for general population
AF for the quality of the whole database:
1
Justification:
Default ECHA AF; the health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.27 mg/m³
Most sensitive endpoint:
effect on fertility
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Dose descriptor:
NOAEC
AF for dose response relationship:
2
Justification:
ECHA AF; no adverse effects on fertility outcomes at highest tested dose in well-conducted chronic studies. A higher AF has been selected because the study is not a specific reproductive one
AF for differences in duration of exposure:
1
Justification:
Default ECHA AF for chronic (720-day) exposure
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling already considered in correcting starting point above
AF for other interspecies differences:
2.5
Justification:
Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
AF for intraspecies differences:
10
Justification:
Default ECHA AF for general population
AF for the quality of the whole database:
1
Justification:
Default ECHA AF; the health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high.
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:
1.11 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):
100
Modified dose descriptor starting point:
NOAEL
DNEL value:
110.6 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals. As no relevant study data on effects of repeated dermal exposure to alpha methylcinnamaldehyde in humans or laboratory

animals are available, route-to-route extrapolation to calculate a dermal DNEL from repeated dose oral toxicity studies was considered a suitable alternative. In the absence of route-specific information on absorption the end route (dermal), an assumption equal to the oral absorption will be made. Therefore, the starting point is 100mg/kg/bw/day. The starting point of cinnamaldehyde must be corrected for the change in MW for alpha methylcinnamaldehyde So, 100 mg/kg/bw/d*(146/132) = 110.6 mg/kg/bw/day General population exposure via the environment is assumed to be continuous (24 h/day, 7 d/wk)

AF for dose response relationship:
1
Justification:
Default ECHA AF; human health relevant NOAEL from well-conducted 720-day dietary study. Effects at the LOAEL slight reduction in body weight gain were not considered severe enough
AF for differences in duration of exposure:
1
Justification:
Default ECHA AF for chronic (720day) exposure
AF for interspecies differences (allometric scaling):
4
Justification:
Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling)
AF for other interspecies differences:
2.5
Justification:
Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
AF for intraspecies differences:
10
Justification:
Default ECHA AF for general population
AF for the quality of the whole database:
1
Justification:
Default ECHA AF; the health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.5 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Dose descriptor:
other: NOAEL
AF for dose response relationship:
1
Justification:
Default ECHA AF; human health relevant NOAEL from well-conducted study.
AF for differences in duration of exposure:
1
Justification:
Default ECHA AF for local exposure
AF for interspecies differences (allometric scaling):
1
Justification:
Default ECHA AF for human study (allometric scaling)
AF for other interspecies differences:
1
Justification:
Default ECHA AF for human study
AF for intraspecies differences:
1
Justification:
Default ECHA AF for (healthy) worker
AF for the quality of the whole database:
1
Justification:
Default ECHA AF; the human health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.5 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Dose descriptor starting point:
other: NOAEL
AF for dose response relationship:
1
Justification:
Default ECHA AF; human health relevant NOAEL from well-conducted study.
AF for interspecies differences (allometric scaling):
1
Justification:
Default ECHA AF for human study (allometric scaling)
AF for other interspecies differences:
1
Justification:
Default ECHA AF for human study
AF for intraspecies differences:
1
Justification:
Default ECHA AF for (healthy) worker
AF for the quality of the whole database:
1
Justification:
Default ECHA AF; the human health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high.

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.1 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
DNEL value:
110.6 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals The starting point of cinnamaldehyde must be corrected for the change in MW for alpha methylcinnamaldehyde So,

100 mg/kg/bw/d*(146/132) = 110.6 mg/kg/bw/day

AF for dose response relationship:
1
Justification:
Default ECHA AF; human health relevant NOAEL from well-conducted 720day dietary study.
AF for differences in duration of exposure:
1
Justification:
Default ECHA AF for chronic (720-day) exposure
AF for interspecies differences (allometric scaling):
4
Justification:
Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling)
AF for other interspecies differences:
2.5
Justification:
Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
AF for intraspecies differences:
10
Justification:
Default ECHA AF for general population
AF for the quality of the whole database:
1
Justification:
Default ECHA AF; health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high.
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

For Justification of endpoint selections please see attachment.