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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:
88.8 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
6
Modified dose descriptor starting point:
NOAEC
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

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

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
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

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

Based on the considerations described in the document “Read-across substantiation C5-6 branched alkylmethyl-ethers” (incl. the supporting references Tuppurainen et al., 2007 and Niska et al., 2008) (see attachment), it can be concluded that the available information of TAME can be used to predict the human toxicological properties of the substance ‘C5-6 branched alkylmethyl-ethers’ with sufficient certainty.

The DNELs are derived using the scientifically based assessment factors as reported by ECETOC (ECETOC, 2003. Derivation of assessment factors for human health risk assessment. Technical report No. 86, ECETOC, February 2003).

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

The substance does have to be 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 do occur. Based on the CNS effects in the 28 (rats) and 90 (rats and mice) days studies with the read-across substance TAME, the NOAEC is set at 250 ppm (1060 mg/m3).

The substance has to be 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 does not occur and as the substance does not have to be classified based on the acute inhalation and dermal toxicity data, no acute DNEL is needed.

The substance is not expected to be irritating to the skin, eyes and respiratory tract and not sensitising to the skin. Therefore, no DNELs have been 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 of the read-across substance TAME with male and female F-344 rats.

Regarding the oral route, a NOAEL of 125 mg/kg bw/day is selected from the 28 days study of the read-across substance TAME 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 the substance, 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.

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

The substance is not expected to cause effects on fertility. In rats, developmental toxicity effects were reported at concentrations at which also maternal toxicity was observed for the read-across substance TAME. 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. 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 of the read-across substance TAME 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.

 

Intraspecies

3

A default assessment factor for workers, as proposed by ECETOC.

 

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 with the read-across substance TAME

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.

Intraspecies

3

A default assessment factor for workers, as proposed by ECETOC.

Exposure duration

2

Extrapolation to chronic exposure based on a 90 days study.

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

1060 x 6/8 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 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 with the read-across substance TAME.

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 with the read-across substance TAME

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

For rats the allometric scaling factor is 4

Intraspecies

3

A default assessment factor for workers, as proposed by ECETOC

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 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
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

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

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
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
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

Based on the considerations described in the document “Read-across substantiation C5-6 branched alkylmethyl-ethers” (incl. the supporting references Tuppurainen et al., 2007 and Niska et al., 2008) (see attachment), it can be concluded that the available information of TAME can be used to predict the human toxicological properties of the substance ‘C5-6 branched alkylmethyl-ethers’ with sufficient certainty.

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 with the read-across substance TAME

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.

Intraspecies

5

As general population includes elderly and juvenile citizens, which are considered to be more sensitive, a default assessment factor of 5 is proposed by ECETOC.

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 with the read-across substance TAME

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.

Intraspecies

5

As general population includes elderly and juvenile citizens, which are considered to be more sensitive, a default assessment factor of 5 is proposed by ECETOC.

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 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 of the read-across substance TAME.

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 with the read-across substance TAME

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

For rats the allometric scaling factor is 4

Intraspecies

5

As general population includes elderly and juvenile citizens, which are considered to be more sensitive, a default assessment factor of 5 is proposed by ECETOC.

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 with the read-across substance TAME

Step 2) Modification of starting point

-

-

Step 3) Assessment factors

 

 

Interspecies

4

For rats the allometric scaling factor is 4

Intraspecies

5

As general population includes elderly and juvenile citizens, which are considered to be more sensitive, a default assessment factor of 5 is proposed by ECETOC.

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


[1] Exposure duration for humans indirect exposed via the environment is assumed 24 hours per day, for consumers the exposure duration is assumed 1-24 hours per day (depending on the exposure scenario).