Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.52 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
88.15 mg/m³
Explanation for the modification of the dose descriptor starting point:

The dose descriptor of 88.15 mg/m3, (based on the NOAEL of 100 mg/kg/day from a 90-day oral study) was calculated. See discussion for route to route extrapolaton calculation. Taking into account the worst case assumption to include a default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) in case of oral to dermal extrapolation.

AF for dose response relationship:
1
Justification:
Based on ECHA Guidance
AF for differences in duration of exposure:
2
Justification:
sub-chronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
NA Based on ECHA Guidance
AF for other interspecies differences:
2.5
Justification:
Based on ECHA Guidance
AF for intraspecies differences:
5
Justification:
Based on ECHA Guidance
AF for the quality of the whole database:
1
Justification:
Based on ECHA Guidance
AF for remaining uncertainties:
1
Justification:
Based on ECHA Guidance
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
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:
4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
400 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The dose descriptor of 400 mg/kg/day, (based on the NOAEL of 100 mg/kg/day from a 90-day oral study) was calculated. See discussion for route to route extrapolaton calculation.

AF for dose response relationship:
1
Justification:
Based on ECHA Guidance
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Based on ECHA Guidance
AF for other interspecies differences:
2.5
Justification:
Based on ECHA Guidance
AF for intraspecies differences:
5
Justification:
Based on ECHA Guidance
AF for the quality of the whole database:
1
Justification:
Based on ECHA Guidance
AF for remaining uncertainties:
1
Justification:
Based on ECHA Guidance
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
DNEL related information

Local effects

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

DNEL Discussion for 1,1,3,3-tetramethylbutyl peroxy-2-ethylhexanoate (Trigonox 421) CAS# 22288-43-3

 

The key study for derivation of the DNELs is a 90-day study in rats dosed via oral gavage. The NOAEL from the 90-day study is 100 mg/kg/day, the mid-dose tested.  Therefore, the starting dose for the calculation of a DNEL for CAS# 22288-43-3 will be 100 mg/kg/day. 

While DNELS have been calculated, a qualitative risk assessment is also performed as the CAS#22288-43-3 is a skin sensitizer, 1b (low to moderate potency).

 

DNEL dermal-systemic-worker

Oral absorption rat – oral/dermal absorption human: Assume 25% absorption based on the physical-chemical properties, in accordance with Endpoint Specific Guidance Chapter 8 and 7c (R.7.12).

 

100 mg/kg/day/0.25 mg/kg/day = 400 = dermal dose descriptor

 

Applying assessment factors in accordance with Endpoint Specific Guidance Chapter 8:

Correction for interspecies differences (apply factor for allometric scaling 4 for rat x 2.5 for additional factors): 10

400 mg/kg/day/10 = 40 mg/kg/day

Correction for intraspecies difference: 5

40 mg/kg/day/5 = 8 mg/kg/day

Correction for duration between sub-chronic to chronic: 2

8 mg/kg/day/2= 4 mg/kg/day

Correction for dose-response: 1 due to NOAEL

4 mg/kg/day/1 = 4

Correction for whole database: 1 due to quality of study

4 mg/kg/day/1 = 4 mg/kg/day

Correction for remaining uncertainties: 1

4 mg/kg/day/1 = 4 mg/kg/day

Total AF = 100

 

4 mg/kg/day DNEL dermal-worker-systemic

 

DNEL inhalation-systemic-worker

 

Assume ABSoral-rat/ABSinh-human is 1 based on phys-chem properties and Endpoint Specific Guidance

chapters 8 and 7c (R.7.12).

 

Corrected inhalatory NOAEC from oral NOAEL

Oral NOAEL x (1/sRVrat) x (ABSoral-rat/ABSinh-human) x (sRVhuman/wRV)

[ABS: absorption; sRV: standard Respiratory Volume; wRV: worker Respiratory Volume]

Corrected NOAEC = 100 mg/kg/day x (1/0.38 m3/kg/day) x (1.0) x 6.7 m3/10m3= 176.3 mg/m3

 

Taking into account the worst case assumption to include a default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) in case of oral to dermal extrapolation. The dose descriptor of 88.15 mg/m3, (based on the NOAEL of 100 mg/kg/day from a 90-day oral study) was calculated.

 

Applying remaining assessment factors in accordance with Endpoint Specific Guidance Chapter 8:

 

Correction for interspecies differences: 2.5

88.12 mg/m3/2.5 = 35.26 mg/m3

Correction for intraspecies differences: 5

35.26 mg/m3/5 = 7.05 mg/m3

Correction for duration between sub-chronic to chronic: 2

7.05 mg/m3/2 = 3.52 mg/m3

Correction for dose-response: 1

3.52 mg/m3/1 = 3.52 mg/m3

Correction for whole database: 1 due to quality of study

3.52 mg/m3/1 = 3.52 mg/m3

Correction for remaining uncertainties: 1

3.52 mg/m3/2 = 3.52

Total AF = 25

 

3.52 mg/m3 DNEL inhalation-systemic-worker

 

 

NOTE:

There are no consumer uses of this substance. Human exposure, via the environment, is unlikely due to the instability of the peroxide.  Only DNELs for the relevant populations will have to be derived (Guidance on information requirements and chemical safety assessment R.8.1.2.3).

 

Properties Considered for DNEL Derivation

 

Endpoint

1,1,3,3-tetramethylbutyl peroxy-2-ethylhexanoate CAS# 22288-43-3

Oral* Absorption

 

Dermal* Absorption

 

Inhalation* Absorption

 

MW

 

272.43

 

y

 

moderate

Y

WS

 

306 ug/L at 20 deg C

 

n

n

n*****

Log Pow

 

6.2

 

y****

n***

y****

VP

 

< 1 Pa

 

 

na

y**

n

Skin irritation

 

not irritating

 

n

n

N

Sensitization

Cat 1B

 

na

 

y

 

no data

Toxicity Data

 

 

y

y

no data

Overall Absorption

 

 

y (based on log P and tox data)

 

n (perhaps 25% as skin sensitization was demonstrated)

n (based on WS and VP)

 

 

* per ECHA Guidance on information requirements and chemical safety assessment Ch 7C

** VPs below 100 Pa are likely to be well absorbed and the amount absorbed dermally may be more than 10% of the amount that would be absorbed by inhalation

***Above 6 the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skis. Uptake into the stratum corneum itself may be slow.

****Any lipophilic compound may be taken up by micellular solubilization but this mechanism may be of particular importance for highly lipophillic compounds (log P >4) particularly those that are poorly soluble in water (1 mg/L or less) that would otherwise be poorly absorbed.

*****Low water solubility, like small particle size enhances penetration to the lower respiratory tract.  For absorption of deposited material similar criteria as for GI absorption apply.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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:
no hazard identified
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:
no hazard identified
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