Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
88.8 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
6
Modified dose descriptor starting point:
NOAEC
DNEL value:
532 mg/m³
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
AF for interspecies differences (allometric scaling):
1
Justification:
not required for inhalation
AF for other interspecies differences:
1
Justification:
See discussion
AF for intraspecies differences:
3
Justification:
See discussion
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
353.3 mg/m³
Most sensitive endpoint:
neurotoxicity
DNEL related information
Overall assessment factor (AF):
3
Modified dose descriptor starting point:
NOAEC
DNEL value:
1 060 mg/m³
AF for dose response relationship:
1
AF for interspecies differences (allometric scaling):
1
Justification:
not required for inhalation
AF for other interspecies differences:
1
Justification:
see discussion
AF for intraspecies differences:
3
Justification:
see discussion
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1

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:
1 601 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
24
Modified dose descriptor starting point:
NOAEL
DNEL value:
38 400 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
From inhalation assuming 6hr respiratory volume of 0.29m3 for rat, 50% absorption by inhalation route and 0.2% by dermal route.
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
sub-chronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
rat to human
AF for other interspecies differences:
1
Justification:
see discussion
AF for intraspecies differences:
3
Justification:
see discussion
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

General discussion

According to the REACH “Guidance on information requirements and chemical safety assessment”, a leading DN(M) EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible.

The DNELs are derived using the scientifically based assessment factors as reported by ECETOC (2010).

Kinetics

The inhalation and dermal absorption percentages used for DNEL derivation (in case of applying route-to-route extrapolation) are 50% and 0.4%, respectively.

Acute toxicity

TAME is labelled for acute neurobehavioral effects (R67 or Specific Target Organ toxicity – Single exposure, Cat. 3 (H336)) and therefore derivation of a DNELacute is necessary in case peak exposures occur. Based on the CNS effects in the 28 (rats) and 90 (rats and mice) days studies the NOAEC is 250 ppm (1060 mg/m3).

TAME is classified for acute oral toxicity (Xn, R22). However, oral exposure is expressed as amount (per kg bw) per day. Therefore acute oral exposure (peaks; in mg/kg bw/day) will not be higher than a calculated total exposure per day (chronic; in mg/kg bw/day). Practically relevant peak exposure therefore do not occur for TAME and as TAME does not have to be classified based on the acute inhalation and dermal toxicity data, no acute DNEL is needed.

TAME is not irritating to the skin, eyes and respiratory tract and not sensitising to the skin. Therefore, no DNELs are derived for these endpoints.

Long-term toxicity

Regarding repeated dose toxicity, a NOAEC of 250 ppm (1060 mg/m3) is selected for inhalation exposure based on the organ (adrenals, kidneys and liver) weight increases seen in the 90 day study with male and female F-344 rats.

Regarding the oral route, a NOAEL of 125 mg/kg bw/day is selected from the 28 day study with rats. The critical effects observed were an increased adrenal (absolute and relative) and kidney (relative) weight in males.

No local effects were reported in the repeated dose toxicity studies with TAME. In general, due to the effective lipid extraction properties of TAME, it can be presumed that repeated skin exposure may result in skin fatigue (and consequent risk of toxic eczema), an effect common to a variety of organic solvents. No quantitative data on this effect are available. Therefore a qualitative risk characterisation will be performed.

TAME is assessed as being non-mutagenic and not carcinogenic. Based on this, no separate risk characterisation for mutagenicity and carcinogenicity is needed.

TAME did not cause effects on fertility. In rats, developmental toxicity effects were reported at concentrations at which also maternal toxicity was observed. In mice, malformations (cleft palate) at 1500 ppm and 3500 ppm (NOAEC of 250 ppm (1060 mg/m3)) were observed. There was clear maternal toxicity in the high dose animals (mice: 3500 ppm), while the signs of toxicity were less obvious in the intermediate dose for mice (1500 ppm). The available data do not trigger classification for developmental toxicity. Overall, the lowest NOAEC for developmental toxicity is comparable with the NOAEC for repeated dose toxicity (250 ppm (1060 mg/m3)) which is taken as starting point for the DNEL derivation.

There are no indications from the available data that dams are more sensitive regarding systemic effects compared to animals exposed in the repeated dose toxicity studies.

Explanation of ECETOC Assessment Factors

The ECHA default interspecies assessment factors are useful for an isolated study for only one toxicological endpoint. In all other cases the ECETOC factors should be preferred for the following reasons: In case of existing high production volume chemicals there is at least one study for each toxicological endpoint and many times more studies for the same toxicological endpoint. So the confidence in the real No Observed Adverse Effect Level (NOAEL) is much higher than in case of an isolated study for only one toxicological endpoint. Also developmental and reproductive toxicity studies and studies focused on neurotoxicity contribute to the evidence of the true NOAEL.

ECETOC interspecies extrapolation to human is based on allometric scaling. Comparison of tolerable repeated dose levels in rodents and humans for many substances has revealed that allometric scaling provided the appropriate adjustment of rodent tolerable repeated dose levels to human repeated dose levels.

Intraspecies sensitivity extrapolation from rat to man is done by extrapolation from the already interspecies extrapolated rodent EC05 (= EC05 interspecies adjusted rat to human) to an assumed human EC05 (= NOAEL human). It is assumed, that the rodent EC05 is a NOAEL and is conservatively 3.16 times smaller than the rodent EC50 and 10 times smaller than the rodent EC95. So the ratio between the rat EC95 and EC05 is assumed to be a factor of 10. This is in agreement with the applied dose range in a rodent study being at least a factor of 10 (see the long term NTP rodent studies).

* The ECETOC intraspecies factor of 3, applied to the interspecies extrapolated rodent EC05 (= EC05 interspecies adjusted rat to human) means, that the ratio between worker EC95 and EC05 is assumed to be 90.

* The ECETOC intraspecies factor of 5, applied to the interspecies extrapolated rodent EC05 (= EC05 interspecies adjusted rat to human) means, that the ratio between consumer EC95 and EC05 is assumed to be 250.

* The ECHA intraspecies factor of 5, applied to the interspecies extrapolated rodent EC05 (= EC05 interspecies adjusted rat to human) means, that the ratio between worker EC95 and EC05 is assumed to be 250.

* The ECHA intraspecies factor of 10, applied to the interspecies extrapolated rodent EC05 (= EC05 interspecies adjusted rat to human) means, that the ratio between consumer EC95 and EC05 is assumed to be 1000.

In the general population the ratio between the EC95 and EC05 is about a factor of 25. That is larger than that in the rat. The intraspecies assessment factors of ECETOC account for this factor of 25 and in addition, for statistical uncertainty in the comparison between human and animal studies on repeated tolerable dose levels. Therefore, the ECETOC intraspecies assessment factors are conservative for deriving a DNEL for workers and for consumers (=general population).

Acute – inhalation, systemic effects  

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEC: 250 ppm (1060 mg/m3)

Based on acute CNS effects in a 90-day neurotoxicity study with rats:

- depression of central nervous system and neuromuscular junction impairment (FOB observations);

- clinical observations: animals were prostrate and lethargic.

Step 2) Modification of starting point

-

From the available data, it is clear that acute CNS effects occurred during the daily exposures, but it is not clear at which time point during exposure these effects occurred. In the REACH guidance (R.8, Appendix R. 8-8), it is mentioned: ‘If a DNEL for acute toxicity needs to be established, this should be derived only for a specified fraction of the daily exposure duration (usually 15 minutes) ’. As it is not clear at which time point during exposure the effects occurred, a calculation to a DNEL for 15 minutes (which results in a higher starting point) cannot be performed.

The REACH guidance prescribes a factor for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3). The application of this factor results in a lower starting point.

Based on a qualitative assessment of the above two subjects, it is considered acceptable that no modification of the starting point will be applied.

Step 3) Assessment factors

 

 

Interspecies

1

No allometric scaling is needed in case of inhalation exposure because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animal and humans breathe at a rate depending on their caloric requirements (ECETOC, 2010). No additional assessment factor is required for “remaining differences” since inter- and intraspecies variability are not independent variables, with any remaining uncertainty accounted for already in the intraspecies assessment factor (ECETOC, 2010). The systemic toxic effects have been thoroughly studied for TAME and there are no indications that humans in comparison to animal test species would significantly differ in their responses, hence the additional adjustment factor of 2.5 is not warranted. 

Intraspecies

3

 An informed assessment factor of 3 is proposed (ECETOC, 2010) based on an analysis of the available scientific literature rather than the adoption of standard defaults. Intraspecies sensitivity extrapolation from rat to man is done by extrapolation from the already interspecies extrapolated rodent EC05 (=NOAEL) to an assumed human EC05 (=NOAEL). Assuming the ratio between the EC95 and EC5 in a rat is 10, observed in many studies, and applying the ECHA intraspecies factor of 5 on the interspecies extrapolated rat EC05 in order to achieve the worker EC05 means that the ratio between the EC95 and EC05 in workers is assumed to be 250. A factor of 250 for the ratio between the worker EC95 and EC05 is far outside general clinical evidence. Therefore the ECETOC intraspecies assessment factors should be preferred.

Exposure duration

not applicable

 

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

1060 / (1 x 3 x 1 x 1) =353.3 mg/m3

Long-term - inhalation, systemic effects

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEC: 250 ppm (1060 mg/m3)

Based on liver, kidney and adrenal weight increases in male and female rats in a 90-day toxicity study

Step 2) Modification of starting point

6/8

 

 

 

6.7 m3/10 m3

Correction of exposure duration in study (6 hrs/day, 5 days/week) to default worker exposure (8 hrs/day, 5 days/week);

 

Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3).

Step 3) Assessment factors

 

 

Interspecies

1

No allometric scaling is needed in case of inhalation exposure because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animal and humans breathe at a rate depending on their caloric requirements (ECETOC, 2010). No additional assessment factor is required for “remaining differences” since inter- and intraspecies variability are not independent variables, with any remaining uncertainty accounted for already in the intraspecies assessment factor (ECETOC, 2010). The systemic toxic effects have been thoroughly studied for TAME and there are no indications that humans in comparison to animal test species would significantly differ in their responses, hence the additional adjustment factor of 2.5 is not warranted. 

Intraspecies

3

 An informed assessment factor of 3 is proposed (ECETOC, 2010) based on an analysis of the available scientific literature rather than the adoption of standard defaults. Intraspecies sensitivity extrapolation from rat to man is done by extrapolation from the already interspecies extrapolated rodent EC05 (=NOAEL) to an assumed human EC05 (=NOAEL). Assuming the ratio between the EC95 and EC5 in a rat is 10, observed in many studies, and applying the ECHA intraspecies factor of 5 on the interspecies extrapolated rat EC05 in order to achieve the worker EC05 means that the ratio between the EC95 and EC05 in workers is assumed to be 250. A factor of 250 for the ratio between the worker EC95 and EC05 is far outside general clinical evidence. Therefore the ECETOC intraspecies assessment factors should be preferred.

Exposure duration

2

Extrapolation to chronic exposure based on a 90 day study.

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

 

1060 x 6/8 x 6.7/10 / (1 x 3 x 2 x 1 x 1) =88.8 mg/m3

Long-term – dermal, systemic effects (based on the repeated dose inhalation NOAEC)

As no toxicity data on repeated dermal exposure of TAME is available, route to route extrapolation will be applied to derive a DNEL for the dermal route based on the NOAEC of 250 ppm (1060 mg/m3) from the inhalation repeated dose toxicity study.

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEC: 250 ppm (1060 mg/m3)

Based on liver, kidney and adrenal weight increases in male and female rats in a 90-day toxicity study

Step 2) Modification of starting point

0.29

 

 

 

50 / 0.4

Conversion into dermal NAEL (in mg/kg bw/day) by using a 6 h respiratory volume of 0.29 m3/kg bw for the rat.

 

Correction for absorption: 50% inhalation absorption and 0.4% dermal absorption.

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling from rats to humans as proposed by ECETOC (2010). No additional assessment factor is required for “remaining differences” since inter- and intraspecies variability are not independent variables, with any remaining uncertainty accounted for already through the use of allometric scaling (where appropriate) and in the intraspecies assessment factor (ECETOC, 2010). The systemic toxic effects have been thoroughly studied for TAME and there are no indications that humans in comparison to animal test species would significantly differ in their responses, hence the additional adjustment factor of 2.5 is not warranted.

Intraspecies

3

An informed assessment factor of 3 is proposed (ECETOC, 2010) based on an analysis of the available scientific literature rather than the adoption of standard defaults. Intraspecies sensitivity extrapolation from rat to man is done by extrapolation from the already interspecies extrapolated rodent EC05 (=NOAEL) to an assumed human EC05 (=NOAEL). Assuming the ratio between the EC95 and EC5 in a rat is 10, observed in many studies, and applying the ECHA intraspecies factor of 5 on the interspecies extrapolated rat EC05 in order to achieve the worker EC05 means that the ratio between the EC95 and EC05 in workers is assumed to be 250. A factor of 250 for the ratio between the worker EC95 and EC05 is far outside general clinical evidence. Therefore the ECETOC intraspecies assessment factors should be preferred

Exposure duration

2

Extrapolation to chronic exposure based on a 90 day study

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

 

1060 x 0.29 x 50/0.4 / (4 x 3 x 2 x 1 x 1) =1601 mg/kg bw/day

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
26.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC
DNEL value:
265 mg/m³
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Not required for inhalation
AF for other interspecies differences:
1
Justification:
see discussion
AF for intraspecies differences:
5
Justification:
see discussion
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
212 mg/m³
Most sensitive endpoint:
neurotoxicity
DNEL related information
Overall assessment factor (AF):
5
Modified dose descriptor starting point:
NOAEC
DNEL value:
1 060 mg/m³
AF for dose response relationship:
1
AF for interspecies differences (allometric scaling):
1
Justification:
not required for inhalation
AF for other interspecies differences:
1
Justification:
see discussion
AF for intraspecies differences:
5
Justification:
see discussion
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1

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:
961 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
DNEL value:
38 440 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
From inhalation assuming 6hr respiratory volume of 0.29m3 for rat, 50% absorption by inhalation route and 0.2% by dermal route.
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
rat to human
AF for other interspecies differences:
1
Justification:
see discussion
AF for intraspecies differences:
5
Justification:
see discussion
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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:
DNEL (Derived No Effect Level)
Value:
1 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
DNEL value:
125 mg/kg bw/day
AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
sub-acute to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
rat to human
AF for other interspecies differences:
1
Justification:
see discussion
AF for intraspecies differences:
5
Justification:
see discussion
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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

See discussion and attachments to this record.

See above for general information on the selection of critical values used for DNEL derivation and use of ECETOC assessment factors.

Acute – inhalation, systemic effects 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEC: 250 ppm (1060 mg/m3)

Based on CNS effects for single exposure in a 90-day neurotoxicity study with rats

Step 2) Modification of starting point

-

From the available data, it is clear that acute CNS effects occurred during the daily exposures, but it is not clear at which time point during exposure these effects occurred. In the REACH guidance (R.8, Appendix R. 8-8), it is mentioned: ‘If a DNEL for acute toxicity needs to be established, this should be derived only for a specified fraction of the daily exposure duration (usually 15 minutes) ’. As it is not clear at which time point during exposure the effects occurred, a calculation to a DNEL for 15 minutes (which results in a higher starting point) cannot be performed.

Step 3) Assessment factors

 

 

Interspecies

1

No allometric scaling is needed in case of inhalation exposure because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animal and humans breathe at a rate depending on their caloric requirements (ECETOC, 2010). No additional assessment factor is required for “remaining differences” since inter- and intraspecies variability are not independent variables, with any remaining uncertainty accounted for already in the intraspecies assessment factor (ECETOC, 2010). The systemic toxic effects have been thoroughly studied for TAME and there are no indications that humans in comparison to animal test species would significantly differ in their responses, hence the additional adjustment factor of 2.5 is not warranted.

Intraspecies

5

 An informed assessment factor of 5 is proposed (ECETOC, 2010) based on an analysis of the available scientific literature rather than the adoption of standard defaults. This is considered adequate to protect the general population as well as the elderly and young. Intraspecies sensitivity extrapolation from rat to man is done by extrapolation from the already interspecies extrapolated rodent EC05 (=NOAEL) to an assumed human EC05 (=NOAEL). Assuming the ratio between the EC95 and EC5 in a rat is 10, observed in many studies, and applying the ECHA intraspecies factor of 10 on the interspecies extrapolated rat EC05 in order to achieve the consumer EC05 means, that the ratio between the EC95 and EC05 in consumers is assumed to be 1000. A factor of 1000 for the ratio between the consumer EC95 and EC05 is far outside general clinical evidence. Therefore the ECETOC intraspecies assessment factors should be preferred.

Exposure duration

Not applicable

 

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

 

1060 / (1 x 5 x 1 x 1) =212 mg/m3

Long-term – inhalation, systemic effects

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEC: 250 ppm (1060 mg/m3)

Based on liver, kidney and adrenal weight increases in male and female rats in a 90-day toxicity study

Step 2) Modification of starting point

6/24

Correction of exposure duration in study (6 hrs/day) to default general population exposure (24 hrs/day) [1].

Step 3) Assessment factors

 

 

Interspecies

1

No allometric scaling is needed in case of inhalation exposure because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animal and humans breathe at a rate depending on their caloric requirements ECETOC, 2010). No additional assessment factor is required for “remaining differences” since inter- and intraspecies variability are not independent variables, with any remaining uncertainty accounted for in the intraspecies assessment factor (ECETOC, 2010). The systemic toxic effects have been thoroughly studied for TAME and there are no indications that humans in comparison to animal test species would significantly differ in their responses, hence the additional adjustment factor of 2.5 is not warranted.

Intraspecies

5

 An informed assessment factor of 5 is proposed (ECETOC, 2010) based on an analysis of the available scientific literature rather than the adoption of standard defaults. This is considered adequate to protect the general population as well as the elderly and young. Intraspecies sensitivity extrapolation from rat to man is done by extrapolation from the already interspecies extrapolated rodent EC05 (=NOAEL) to an assumed human EC05 (=NOAEL). Assuming the ratio between the EC95 and EC5 in a rat is 10, observed in many studies, and applying the ECHA intraspecies factor of 10 on the interspecies extrapolated rat EC05 in order to achieve the consumer EC05 means, that the ratio between the EC95 and EC05 in consumers is assumed to be 1000. A factor of 1000 for the ratio between the consumer EC95 and EC05 is far outside general clinical evidence. Therefore the ECETOC intraspecies assessment factors should be preferred.

Exposure duration

2

Extrapolation to chronic exposure based on a 90 days study.

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

 

1060 x 6/24 / (1 x 5 x 1 x 2 x 1 x 1) =26.5 mg/m3

Long-term – dermal, systemic effects (based on the repeated dose inhalation NOAEC)

As no toxicity data on repeated dermal exposure of TAME is available, route to route extrapolation will be applied to derive a DNEL for the dermal route based on the NOAEC of 250 ppm (1060 mg/m3) from the inhalation repeated dose toxicity study.

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEC: 250 ppm (1060 mg/m3)

Based on liver, kidney and adrenal weight increases in male and female rats in a 90-day toxicity study

Step 2) Modification of starting point

0.29

 

 

 

50 / 0.4

Conversion into dermal NAEL (in mg/kg bw/day) by using a 6 h respiratory volume of 0.29 m3/kg bw for the rat.

 

Correction for absorption: 50% inhalation absorption and 0.4% dermal absorption

Step 3) Assessment factors

 

 

Interspecies

4

 Assessment factor for allometric scaling from rats to humans as proposed by ECETOC (2010). No additional assessment factor is required for “remaining differences” since inter- and intraspecies variability are not independent variables, with any remaining uncertainty accounted for already through the use of allometric scaling (where appropriate) and in the intraspecies assessment factor (ECETOC, 2010).The systemic toxic effects have been thoroughly studied for TAME and there are no indications that humans in comparison to animal test species would significantly differ in their responses, hence the additional adjustment factor of 2.5 is not warranted.

Intraspecies

5

 An informed assessment factor of 5 is proposed (ECETOC, 2010) based on an analysis of the available scientific literature rather than the adoption of standard defaults. This is considered adequate to protect the general population as well as the elderly and young.Intraspecies sensitivity extrapolation from rat to man is done by extrapolation from the already interspecies extrapolated rodent EC05 (=NOAEL) to an assumed human EC05 (=NOAEL). Assuming the ratio between the EC95 and EC5 in a rat is 10, observed in many studies, and applying the ECHA intraspecies factor of 10 on the interspecies extrapolated rat EC05 in order to achieve the consumer EC05 means, that the ratio between the EC95 and EC05 in consumers is assumed to be 1000. A factor of 1000 for the ratio between the consumer EC95 and EC05 is far outside general clinical evidence. Therefore the ECETOC intraspecies assessment factors should be preferred.

Exposure duration

2

Extrapolation to chronic exposure based on a 90 days study

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

 

1060 x 0.29 x 50/0.4 / (4 x 5 x 2 x 1 x 1) =961 mg/kg bw/day

Long-term – oral, systemic effects

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 125 mg/kg bw/day

Based on an increase in adrenal and kidney weight in male rats in the 28-day toxicity study

Step 2) Modification of starting point

-

Not applicable

Step 3) Assessment factors

 

 

Interspecies

4

 Assessment factor for allometric scaling from rats to humans as proposed by ECETOC (2010). No additional assessment factor is required for “remaining differences” since inter- and intraspecies variability are not independent variables, with any remaining uncertainty accounted for already through the use of allometric scaling (where appropriate) and in the intraspecies assessment factor (ECETOC, 2010). The systemic toxic effects have been thoroughly studied for TAME and there are no indications that humans in comparison to animal test species would significantly differ in their responses, hence the additional adjustment factor of 2.5 is not warranted.

Intraspecies

5

 An informed assessment factor of 5 is proposed (ECETOC, 2010) based on an analysis of the available scientific literature rather than the adoption of standard defaults. This is considered adequate to protect the general population as well as the elderly and young. Intraspecies sensitivity extrapolation from rat to man is done by extrapolation from the already interspecies extrapolated rodent EC05 (=NOAEL) to an assumed human EC05 (=NOAEL). Assuming the ratio between the EC95 and EC5 in a rat is 10, observed in many studies, and applying the ECHA intraspecies factor of 10 on the interspecies extrapolated rat EC05 in order to achieve the consumer EC05 means, that the ratio between the EC95 and EC05 in consumers is assumed to be 1000. A factor of 1000 for the ratio between the consumer EC95 and EC05 is far outside general clinical evidence. Therefore the ECETOC intraspecies assessment factors should be preferred.

Exposure duration

6

Extrapolation to chronic exposure based on a 28 days study.

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

 

125 / (4 x 5 x 6 x 1 x 1) =1.0 mg/kg bw/day