Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.704 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
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:
BMCL05
Value:
8.8 mg/m³
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated exposure by inhalation.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
1
Justification:
End point on which the 10mg/kg is based is for reproduction and therefore not influenced the duration of the study
AF for interspecies differences (allometric scaling):
1
Justification:
Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.
AF for other interspecies differences:
2.5
Justification:
The ECHA REACH TG default value was used for remaining differences
AF for intraspecies differences:
5
Justification:
The ECHA REACH TG default value for the relatively homogenous group "worker" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
BMDL05
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on the systemic effects as a results of dermal exposure.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
1
Justification:
The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
2.5
Justification:
The ECHA REACH TG default value for species differences
AF for intraspecies differences:
5
Justification:
The ECHA REACH TG default value for the relatively homogenous group "workers" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

Acute/short-term exposure - systemic effects

According to ECHA Guidance on information requirements and CSR, chapter R8, a DNEL for acute systemic toxicity should be derived only if an acute systemic toxicity hazard leading to C&L has been identified. AEEA has a low acute toxicity as indicated by the LD50 values of 2150 mg/kg bw and > 2000 mg/kg bw determined in rats for oral and dermal exposure, respectively. The inhalation of a saturated atmosphere (corresponding to 51.3 mg/m³) did not cause lethality in rats. Therefore, AEEA is not subject to classification and labelling and consequently the establishment of DNELs for acute/short-term exposure - systemic effects is not required.

Acute/short-term and acute long term exposure - local effects

AEEA is corrosive to skin and severely eye irritating. Experimental data on respiratory irritation are not available, but considering the local tissue damaging effects on skin and eye it can be assumed that AEEA has a respiratory irritation potential above a certain threshold concentration. In the local lymph node assay (LLNA) and guinea pig maximisation test AEEA was skin sensitising.

Below, local effects following acute/short term or long term exposure were assessed qualitatively. A quantitative assessment was not performed because of the following:

- There are no experimental data available allowing a quantitative assessment of local effects in the respiratory tract.

- The available skin and eye irritation studies allow only a qualitative assessment of irritation/corrosion following acute exposure.

- There have been several proposals made during the last years how to perform a quantitative assessment for sensitisation based on the LLNA’s EC3 value. However, at present there is no common agreement on the assessment factors to be used for a quantitative assessment. Thus, the regulatory acceptance of a proposed DNEL would be highly questionable.

- The establishment of a DNEL for long term dermal exposure could only be done for skin irritation (on the basis of the NOAEL for skin effects established in the 28-day dermal study in the rat), but would not cover skin sensitisation after repeated dermal exposure.

AEEA is classified and labelled with R34 (causes burns) according to Directive 67/548/EEC and with Cat 1 B / H314 (causes severe skin burns and eye damage) according to Regulation 1272/2008/EC. AEEA is a skin sensitising agent (R43 according to Directive 67/548/EEC and Cat 1 / H317 according to Regulation 1272/2008/EC). The EC3 values calculated from the results of two LLNAs were 15.2 % and 5.3 % and indicate a moderate skin sensitisation potential. Based on these data, AEEA is allocated to the moderate hazard category. The operation conditions and risk management measures indicated in the respective IUCLID 5 chapters are appropriate and sufficient for controlling the risks.

Long term exposure - systemic effects

AEEA was not genotoxic in the Ames test and a mammalian cell gene mutation assay in CHO cells and in an in-vivo mouse bone marrow micronucleus test. 

There are toxicokinetic studies and skin penetration studies using radio labelled AEEA available. These studies showed that AEEA was rapidly absorbed >85% by the oral route with most of the AEEA being excreted via the urine within 48 hours of dosing. Eight hour dermal application of a dose 10 times higher than that given orally did not produce quantifiable plasma levels of AEEA. Based on urinary excretion bioavailability was approximately 10% compared to the oral route. Comparative skin penetration with rat and human skin samples in vitro, there was a significant difference between the rat which showed up to 30% of the AEEA in the receptor fluid or retained in the viable skin compared to a maximum of 3.5% in the human skin samples. So it was concluded that the absorbed dose in the rat skin was approximately 10 fold higher than for human skin.

In a repeated dose 28-day dermal toxicity study in rats the NOAEL for systemic effects was 1000 mg/kg bw/day, the highest concentration tested. There were no treatment-related effects observed in mortality, clinical appearance, behaviour, in-life body weight, food consumption, hematology or clinical chemistry, gross pathology and histopathology of male or female animals.

In a repeated dose 28-day oral toxicity study in rats the NOEL was 60 mg/kg bw/day. At higher dose levels of 250 or 1000 mg/kg bw/day substance related effects concerning hematology, blood chemistry, urinalyses and histopathology were noted. The kidney was identified as the target organ.

In a developmental toxicity study (OECD 414), AEEA was administered to female Wistar rats by oral gavage at dose levels of 0, 0.5, 2, 10 or 50 mg/kg bw/day from days 6 through 19 of gestation.The NOAEL for maternal and prenatal developmental toxicity was 50 mg/kg bw/day.There was no indication of teratogenicity, in particular there were no effects on the fetal great vessels.

The most significant findings were in the OECD421 reproduction/developmental toxicity screening study which included dose levels of 0, 50, 250, and 1000 mg/kg bw/day. There was clear systemic toxicity and reduced fertility in the 1000mg/kg group with no live pups, there were also more still born pups in the 250 mg/kg group. Post mortem examination of the pups revealed a high incidence of abnormalities, especially affecting the pericardial vessels in terms of aneurysms, dilatations and abnormal course in 48% of pups in the 50 mg/kg and 89% of pups in the 250 mg/kg groups. Pups with these abnormalities were found in all litters in these groups.

A second OECD 421 study carried out with dose levels of 0, 0.2, 1, 5 or 50 mg/kg bw/day. The NOAEL for the parental animals for systemic toxicity and reproductive performance and fertility was 50 mg/kg. A NOAEL for developmental toxicity in the F1 progeny was not established, because aneurysms of the pericardial vessels occurred at all tested levels. The LOAEL was therefore 0.2 mg/kg bw/day. Haemorrhages of the pericardial blood vessels of the pups were seen in all dose groups including the controls (one male affected). Haemorrhages are regarded as precursor lesion of aneurysms, which were seen to also develop in untreated controls. This observation prevented the determination of a clear NOAEL or LOAEL. There is a lack of historical data concerning such findings as the pericardial blood vessels are not routinely examined in OECD 421/422 studies.

Determination of DNEL’s 

A Benchmark dose (BMD) was calculated for the adverse developmental effects seen in the second OECD 421 study. Benchmark dose is seen as much more reliable point of departure for calculating DNELs particularly in studies such as this one where there is no clear NOAEL. This approach takes into account all the effects seen in each dose level. The value that is generally used for reproduction data is the 95% bounds of the BMD, referred to as the BMDL5, this was calculated and an average across the three models used was 10 mg/kg bw/day. Based on this, DNELs have been calculated using all the ECHA suggested assessment factors.

Inhalation (workers and general population):

For inhalation the BMDL5 was first transformed to a NOAEC which was then adjusted for the difference in respiration rate relative to bodyweight from rats to humans. Firstly the BMDL5 is divided by 2 (ECHA factor to extrapolate from oral to inhalation) to give a point of departure of 5mg/kg. For workers this gives a NOAEC of 5 x 1.76 =8.8 mg/m3 this is then divided by the additional factor for interspecies differences of 2.5 multiplied by the assessment factor intra-species variability for worker of 5, the factor for duration is 1 as the end point on which the 10 mg/kg is based is for reproduction and therefore not influenced the duration of the study. The factor for the quality of the data was 1. So this gives 8.8/2.5x 5x 1 x 1= 0.704mg/m3.

For the general population the NOAEC is 5 x 0.869565217 = 4.347826085. This is then divided by the additional factor for interspecies differences of 2.5 multiplied by the assessment factor intra-species variability for worker of 10 again with 1 for duration. The factor for the quality of the data was 1. This gives 4.347826085/ 2.5x 10 x 1x 1 = 0.174mg/m3.

Dermal (workers and general population):

The dermal DNELs are more potentially contentious, these were based on the 1000mg/kg NOAEL in the 28 day dermal study and are significantly higher than those calculated based on either the BMDL5 from the second OECD 421 study or those from the NOAEL in the 28 day oral study. This would be expected due to the low dermal absorption demonstrated for AEEA.

Based on a 1000mg/kg NOAEL the dermal DNELs are calculated to be 3.333 mg/kg for workers and 1.667mg/kg for the general population. As exposure was for 6 hours a day in the dermal study, the DNELs were adjusted by multiplying them by 6/8. This gives a dermal DNEL for workers of 2.5 mg/kg and for the general population of 1.25 mg/kg. This is compared to 0.2mg/kg for workers and 0.1mg/kg for the general population calculated from the oral studies (28-day or BMDL5 for the OECD 421). While the DNELs calculated from the 28 -day dermal study are acceptable to protect from systemic toxic effect from dermal exposure to AEEA, it is not certain that they would protect from the adverse developmental effects following oral exposure.

There are two main apparent reasons for the difference in DNELs between the routes of exposure, for the oral route local irritant effects in the stomach can influence the NOAEL, also the available toxicokinetic information indicates a >85% oral absorption, compared to information indicating on 10% bioavailability following 8 hours dermal application. In vitro measurements using radio labelled AEEA indicated absorption through rat skin including the residual in the skin was 11-30% compared to 3-3.5% for human skin. It was concluded that human skin was 10 times more permeable to AEEA than rats. When multiplying the calculated Dermal long-term DNELs by a factor of 10, this results in a dermal DNEL for workers of 25 mg/kg and for the general population of 12.5 mg/kg. If the same factor of 10 is now applied to the oral 28-day or OECD421 derived DNELs, then the dermal DNEL for workers will be 2.0 mg/kg and for the general population 1.0mg/kg.

It could be considered to in addition adjust the DNELs based on the oral dosed rat for the difference in oral absorption and the maximum of 30% dermal absorption in rats this would give a dermal DNEL for workers of 2.0 x 85/30 = 5.6 mg/kg and for the general population 1.0 x 85/30 = 2.8mg/kg. However due to the sensitive nature of the developmental end point the factor of 10 for skin absorption species difference was used and correction for oral to dermal route extrapolation was not applied. Based on this the long term dermal DNELs of 2.0 mg/kg for workers and 1.0mg/kg for the general population were derived.

Oral (general population):

A Benchmark dose (BMD) was calculated for the adverse developmental effects seen in the second OECD421 study described previously. The BMDL5 that was calculated was 10 mg/kg bw/day and the starting point to determine the oral DNEL for the general population. The starting point was not adjusted since there was no route to route extrapolation. The following assessment factors were applied: 4 for allometric scalling (rats to humans), 2.5 for other interspecies differences (ECHA REACH TG default value) and 10 for the intraspecies differences (ECHA REACH TG default value for the relatively homogenous group "general population"). All remaining assessment factors had a value of 1. This resulted in an oral DNEL of 10/(4*2.5*10) = 0.1 mg/kg bw/day.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.174 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
BMCL05
Value:
4.348 mg/m³
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated exposure by inhalation.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used
AF for differences in duration of exposure:
1
Justification:
End point on which the 10mg/kg is based is for reproduction and therefore not influenced the duration of the study
AF for interspecies differences (allometric scaling):
1
Justification:
Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.
AF for other interspecies differences:
2.5
Justification:
The ECHA REACH TG default value was used for remaining differences
AF for intraspecies differences:
10
Justification:
The ECHA REACH TG default value for the relatively homogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
BMDL05
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on the systemic effects as a results of dermal exposure.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used
AF for differences in duration of exposure:
1
Justification:
End point on which the 10mg/kg is based is for reproduction and therefore not influenced the duration of the study
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
2.5
Justification:
The ECHA REACH TG default value was used for remaining differences
AF for intraspecies differences:
10
Justification:
The ECHA REACH TG default value for the relatively homogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.1 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
BMDL05
Value:
10 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
no route to route extrapolation
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used
AF for differences in duration of exposure:
1
Justification:
End point on which the 10mg/kg is based is for reproduction and therefore not influenced the duration of the study
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
2.5
Justification:
The ECHA REACH TG default value was used for remaining differences
AF for intraspecies differences:
10
Justification:
The ECHA REACH TG default value for the relatively homogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

AEEA is neither marketed to the general public nor intentionally added to consumer products. Also, consumer products do not contain substances from which AEEA is intended to be released. Thus, the derivation of DNELs for the general population is not required. Nonetheless, DNELs for systemic toxicity after long-term exposure have been derived and an explanation regarding the DNELs derived for the general population is provided in the discussion field above.