Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
9.8 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):
12.5
Dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
123.4 mg/m³
Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation.

For details on calculations please refer to discussion.

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:
According to ECETOC "Guidance on Assessment Factors to Derive a DNEL" Technical Report No. 110 (October 2010) the AF 1 is applied, as the EOGRT study covers the complete reproduction cycle and no further extrapolation regarding exposure duration is necessary.
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:
Recommended AF for other interspecies differences.
AF for intraspecies differences:
5
Justification:
The 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:
There are no remaining uncertainties. For more details please refer to the discussion.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
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:
5.6 mg/kg bw/day
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
Dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
280 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated dermal exposure. Taken into account the physico-chemical properties of the substance, dermal absoption is anticipated to be 50 % of oral absorption. For details refer to discussion.

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:
According to ECETOC "Guidance on Assessment Factors to Derive a DNEL" Technical Report No. 110 (October 2010) the AF 1 is applied, as the EOGRT study covers the complete reproduction cycle and no further extrapolation regarding exposure duration is necessary.
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:
Recommended AF for other interspecies differences.
AF for intraspecies differences:
5
Justification:
The 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:
There are no remaining uncertainties. The same considerations as for DNEL derivation for inhalation apply.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Worker

General

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health (2012).

Acute, systemic DNEL

Tert-butyl 2-ethylperoxyhexanoate (TBPEH) is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral, dermal and inhalation toxicity.

Acute/long term DNEL for local effects

Skin irritation/corrosion: TBPEH is not classified for skin irritation/corrosion according to Regulation (EC) No 1272/2008 (CLP) based on the available experimental data. Therefore, no qualitative assessment is conducted.

Eye irritation

TBPEH is not classified for eye irritation based on the results of the eye irritation studies available. Therefore, no qualitative assessment is conducted.

Respiratory irritation

No severe signs of local irritation were observed in animals exposed to TBPEH via inhalation for 4 hours. Therefore, TBEPH is not classified for respiratory irritation. This assumption is supported by the results of the skin and eye irritation tests where no irritating effects were observed. No qualitative assessment is conducted.

Skin sensitisation

TBPEH was shown to be a skin sensitiser in a Buehler test (Springborn Laboratories, 1996). The substance is therefore classified as skin sensitiser, cat. 1 according to Regulation (EC) No 1272/2008 (CLP) and associated to the high Hazard Band. A qualitative risk assessment is conducted for acute dermal toxicity in order to ensure an appropriate level of protection regarding sensitisation.

 

Long term, systemic DNEL

Occupational exposure to TBPEH occurs mainly by dermal route, and may also occur by inhalation exposure. Therefore, two long-term DNELs are calculated for workers.

In view of the data used for evaluation, the "quality of whole database factor", “remaining interspecies differences” and "dose-response factor" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

General considerations on available and relevant data for Point of Departure (long term DNEL inhal and dermal)

The OECD 443 study (2019) is selected for providing the point of departure value for DNEL derivation. It is the most relevant repeated dose toxicity study available performed in accordance to OECD Test Guideline and GLP.

TBPEH is classified as toxic to reproduction cat. 1B based on findings in this EOGRTS. Clear impairment of female fertility was observed in the high dose and with lower incidence in the mid dose group (= LOAEL = 300 mg/kg bw/d). A clear NOAEL could be determined at 100 mg/kg bw/d (low dose) where no adverse effects on reproduction or any other signs toxicity were observed. In this study, animals were daily exposed to the test item by oral administration (gavage) for up to 17 weeks (Females of cohort 1B) with dose levels up to the limit dose of 1000 mg/kg bw/d as the high dose. Comprehensive set of parameters according to OECD 443 guideline were assessed.

An OECD 408 (90 -day) subchronic toxicity study in the rat is also available with the test item. In this study a NOAEL of 450 mg/kg bw/d was determined. Applying this NOAEL, the only difference for DNEL derivation would be application of an AF 2 instead of 1 for exposure duration considerations. Thus, the DNELfertility derived with the NOAEL of 100 mg/kg bw/d from the EOGRT study is considered to reflect the worst case and is thus applied in the hazard assessment.

In conclusion, results of the OECD 443 study are considered best basis for providing point of departure for DNEL derivation.


The NOAEL obtained from an OECD 414 study conducted in the rabbit is 30 mg/kg bw/d. However, this NOEAL is considered to not adequately reflect the toxicological potential of the test item and is thus not applicable for DNEL derivation. The NOEALsystemicwas determined in pregnant females only. Furthermore, the NOAEL was derived based on effects that are strongly linked to marked stress of the animals (less food intake, body weight loss, less or no feces). Thus, it can hardly be stated that these effects are solely induced by the test item but are rather intensified by a great sensitivity to stress as it is known for rabbits. Therefore, NOAELs obtained from the OECD 414 study in the rabbit are considered to highly overestimate the toxicity potential of the test item and are thus not applied for DNEL derivation.

Exposure by inhalation

 

Step 1: Selection of the relevant dose descriptor (starting point):

Please refer to general considerations on PoD above.

Step 2: Modification into a correct starting point:

Using a conservative approach, a worker DNEL (long-term inhalation exposure) is derived. This worker DNEL is considered to ensure an appropriate level of protection with regard to acute inhalation exposure (no high peaks of exposure expected).

Relevant dose descriptor (NOAEL): 100 mg/kg bw/day

Body weight of worker: 70 kg

Oral absorption of the rat / inhalation absorption of humans (ABSoral-rat / ABSinh-human): 0.5

Worker respiratory volume (wRV) for 8 hours with light physical activity: 10 m³

Correction factor for duration of exposure (worker): 7 d / 5 d = 1.4

 

Corrected inhalatory NOAEC for workers

= 100 mg/kg bw/d × 0.5 × (1 / 0.38 m³/kg bw/d) × (6.7 m³/10 m³) x 1.4

= 123.4 mg/m³ 

 

Step 3: Use of assessment factors: 12.5

- Interspecies: Respiratory interspecies differences are fully covered by the corrected inhalatory NOAEC

- Interspecies AF, remaining differences: 2.5

- Intraspecies AF (worker): 5

- Exposure duration AF: 1

- Remaining uncertainties: 1

There are no remaining uncertainties.

According to ECHA guidance R.8 (2012) information from OECD TG 415 and 416 “can be used with confidence to identify substances as being toxic to reproduction (…) and thus can be used for risk assessment and DNEL calculation. From the studies the relevant NOAELs should be identified for effects on fertility (…) and DNELfertility calculations should be performed according to the general rules concerning conversion of the dose descriptor and the use of assessment factors.”

The available OECD 443 compliant study is considered to provide at least equivalent information quality compared to the former OECD 415 / 416 studies.

The test item is classified as toxic to reproduction cat. 1B based on results of an EOGRTS conducted according to OECD 443 TG and GLP. The impairment of fertility was the most sensitive endpoint in the absence of other clear signs of toxicity, while applying the recommended top dose of 1000 mg/kg bw/d as high dose under subchronic conditions.

Further considerations are:
The effects on reproduction were sex specific (females only) and affected fertility only. There was no developmental toxicity observed in relation with the test item treatment in a rodent and a non-rodent species, respectively.

Therefore, application of a NOAEL that is based on female fertility impairment as PoD for general systemic DNEL calculation is considered to reflect a worst case assumption that covers other subpopulations more than sufficiently.

 

In conclusion, a long term systemic inhalation DNEL, workers of 9.8 mg/m3 is established.

Dermal exposure

 

Step 1: Selection of the relevant dose descriptor (starting point):

The NOAEL of 100 mg/kg bw/d from an OECD TG 443 study (2019) is selected as basis for DNEL derivation, as discussed above under general considerations for PoD.

 

Step 2: Modification of the starting point:

Using a conservative approach, a worker DNEL (long-term dermal exposure) is derived. Based on the physico-chemical properties of TBPEH (log Kow: 4.79 and water solubility: 46.3 mg/L) a dermal absorption of 50% of oral absorption is assumed as a worst case.
Correction factor for duration of exposure (worker): 7d / 5d = 1.4

In conclusion, dermal NOAEL = 2 x oral NOAEL x 1.4 = 280 mg/kg bw/day.

 

Step 3: Use of assessment factors: 50

- Interspecies AF, allometric scaling (rat to human): 4

- Interspecies AF, remaining differences: 2.5

- Intraspecies AF (worker): 5

- Exposure duration AF: 1

Remaining uncertainties: 1

There are no remaining uncertainties. The same considerations as for DNEL derivation for inhalation apply.

In conclusion, a long term systemic dermal DNEL for workers of 5.6 mg/kg bw/day is established.

 

References

(not included as endpoint study record)

- ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2.1.

- ECHA (2017) guidance on information requirements and chemical safety assessment R7c, 2017 

- ECHA (2012) Practical Guide 15: How to undertake a qualitative human health assessment and document it in a chemical safety report, November 2012.

- ECETOC Technical Report 110 (2010): Guidance on Assessment Factors to derive a DNEL

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.74 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):
25
Dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
43.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

Please refer to the discussion below.

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:
According to ECETOC "Guidance on Assessment Factors to Derive a DNEL" Technical Report No. 110 (October 2010) the AF 1 is applied, as the EOGRT study covers the complete reproduction cycle and no further extrapolation regarding exposure duration is necessary.
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:
Recommended AF for other interspecies differences.
AF for intraspecies differences:
10
Justification:
The default value for the relatively heterogenous 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:
There are no remaining uncertainties. For more details please refer to the discussion.
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:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

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:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Please refer to the discussion below.

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:
According to ECETOC "Guidance on Assessment Factors to Derive a DNEL" Technical Report No. 110 (October 2010) the AF 1 is applied, as the EOGRT study covers the complete reproduction cycle and no further extrapolation regarding exposure duration is necessary.
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:
Recommended AF for other interspecies differences.
AF for intraspecies differences:
10
Justification:
The default value for the relatively heterogenous 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:
There are no remaining uncertainties. The same considerations as for DNEL derivation for inhalation apply.
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

General population: man via environment

DNEL derivation for the registered substance is performed under consideration of the recommendations of ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health (2012).

Regarding general population, there is no need to derive a DNEL as the registered substance is not intended to be used by consumers but in industrial settings only. Thus, for consumers, no risk and thus no hazard assessment is required.

However, since the annual tonnage volume of the registered substance is > 1000 tpa and it is classified as toxic to reproduction cat. 1B, its risk in terms of “man via environment” considerations has to be assessed. Therefore, a chronic systemic DNEL for the inhalation as well as for the oral route is derived for the general population in order to conduct a risk assessment for man via environment.

Long term, systemic DNEL

In general, DNEL derivation for general population takes into account the same considerations as applied for worker DNELs (see above).
In view of the data used for evaluation, the "quality of whole database factor", “remaining interspecies differences” and "dose-response factor" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

General considerations on available and relevant data for Point of Departure

The OECD 443 study (2019) is selected for providing the point of departure value for DNEL derivation. It is the most relevant repeated dose toxicity study available performed in accordance to OECD Test Guideline and GLP.

TBPEH is classified as toxic to reproduction cat. 1B based on findings in this EOGRTS. Clear impairment of female fertility was observed in the high dose and with lower incidence in the mid dose group (= LOAEL = 300 mg/kg bw/d). A clear NOAEL could be determined at 100 mg/kg bw/d (low dose) where no adverse effects on reproduction or any other signs toxicity were observed. In this study, animals were daily exposed to the test item by oral administration (gavage) for up to 17 weeks (Females of cohort 1B) with dose levels up to the limit dose of 1000 mg/kg bw/d as the high dose. Comprehensive set of parameters according to OECD 443 guideline were assessed.

An OECD 408 (90 -day) subchronic toxicity study in the rat is also available with the test item. In this study a NOAEL of 450 mg/kg bw/d was determined. Applying this NOAEL, the only difference for DNEL derivation would be application of an AF 2 instead of 1 for exposure duration considerations. Thus, the DNELfertility derived with the NOAEL of 100 mg/kg bw/d from the EOGRT study is considered to reflect the worst case and is thus applied in the hazard assessment.

In conclusion, results of the OECD 443 study are considered best basis for providing point of departure for DNEL derivation.


The NOAEL obtained from an OECD 414 study conducted in the rabbit is 30 mg/kg bw/d. However, this NOEAL is considered to not adequately reflect the toxicological potential of the test item and is thus not applicable for DNEL derivation. The NOEALsystemicwas determined in pregnant females only. Furthermore, the NOAEL was derived based on effects that are strongly linked to marked stress of the animals (less food intake, body weight loss, less or no feces). Thus, it can hardly be stated that these effects are solely induced by the test item but are rather intensified by a great sensitivity to stress as it is known for rabbits. Therefore, NOAELs obtained from the OECD 414 study in the rabbit are considered to highly overestimate the toxicity potential of the test item and are thus not applied for DNEL derivation.

 

Exposure by inhalation

Step 1: Selection of the relevant dose descriptor (starting point):

Please refer to general considerations on PoD above.

Step 2: Modification into a correct starting point:

Using a conservative approach, a consumer DNEL (long-term inhalation exposure) is derived. This consumer DNEL is considered to ensure an appropriate level of protection with regard to acute inhalation exposure (no high peaks of exposure expected, if any).

Relevant dose descriptor (NOAEL): 100 mg/kg bw/day

Oral absorption of the rat / inhalation absorption of humans (ABSoral-rat / ABSinh-human): 0.5

Standard respiratory volume of the rat (sRVrat) for 24 hours: 1.15 m3/kg bw 

Corrected inhalatory NOAEC for general population 

= 100 mg/kg bw/d × 0.5 × (1 / 1.15 m³/kg bw/d) 

= 43.5 mg/m³ 

Step 3: Use of assessment factors: 25

Interspecies: Respiratory interspecies differences are fully covered by the modification of the NOAEC

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Exposure duration AF: 1

Remaining uncertainties: 1

There are no remaining uncertainties.

 

In conclusion, long term systemic inhalation DNEL, workers = 1.74 mg/m3

Oral exposure

 

Step 1: Selection of the relevant dose descriptor (starting point):

Please refer to general considerations on PoD above.

 

Step 2: Modification of the starting point:

Not applicable as the PoD is an oral NOAEL, being the same route of exposure as the DNEL to be derived.

PoD: NOAEL = 100 mg/kg bw/d

Step 3: Use of assessment factors: 100

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Exposure duration AF: 1

Remaining uncertainties: 1

There are no remaining uncertainties.

In conclusion, a long term systemic oral DNEL for general population of 1 mg/kg bw/day is established

 

References

(not included as endpoint study record)

- ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2.1.

- ECHA (2017) guidance on information requirements and chemical safety assessment R7c, 2017 

- ECHA (2012) Practical Guide 15: How to undertake a qualitative human health assessment and document it in a chemical safety report, November 2012.

- ECETOC Technical Report 110 (2010): Guidance on Assessment Factors to derive a DNEL