Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
35 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):
50
Modified dose descriptor starting point:
NOAEC
Value:
1 763 mg/m³
Explanation for the modification of the dose descriptor starting point:

The dose descriptor of 1000 mg/kg/day was selected from an OECD 422 oral study with rats.  See the discussion for route to route extrapolation calculation.

AF for dose response relationship:
1
Justification:
Based on ECHA REACH Guidance
AF for differences in duration of exposure:
4
Justification:
Based on extrapolation from exposure in a OECD 422 to Chronic exposure
AF for interspecies differences (allometric scaling):
1
Justification:
NA Based on ECHA REACH Guidance
AF for other interspecies differences:
2.5
Justification:
Based on ECHA REACH Guidance
AF for intraspecies differences:
5
Justification:
Based on ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
Based on ECHA REACH Guidance
AF for remaining uncertainties:
1
Justification:
Based on ECHA REACH 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:
50 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):
200
Modified dose descriptor starting point:
NOAEL
Value:
10 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The dose descriptor of 1000 mg/kg/day was selected from an OECD 422 oral study with rats.  See the discussion for route to route extrapolation calculation.

AF for dose response relationship:
1
Justification:
Based on ECHA REACH Guidance
AF for differences in duration of exposure:
4
Justification:
Based on extrapolation from exposure in a OECD 422 to Chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
Based on ECHA REACH Guidance
AF for other interspecies differences:
2.5
Justification:
Based on ECHA REACH Guidance
AF for intraspecies differences:
5
Justification:
Based on ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
Based on ECHA REACH Guidance
AF for remaining uncertainties:
1
Justification:
Based on ECHA REACH 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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

1,1,4,4-tetramethylbutane-1,4,diyl bis(2-ethylperoxyhexanoate) CAS# 13052-09-0

 DNEL Discussion

Initial Dose Descriptor

The oral administration of 1,1,4,4-tetramethylbutane-1,4-diylbis(2-

ethylperoxyhexanoate) (CAS 13052-09-0) to rats by gavage, at dose levels of 30, 300

and 1000 mg/kg bw/day, resulted in treatment related findings in animals of either sex

treated with 30, 300 and 1000 mg/kg bw/day. The effects detected in females were

mainly confined to adaptive microscopic thyroid changes and there were no findings

observed that were considered to represent an adverse effect of treatment. The ‘No

Observed Adverse Effect Level' (NOAEL) for females was considered to be 1000 mg/kg

bw/day.

 

The effects detected in males were mainly confined to adaptive microscopic liver and

thyroid changes and hyaline droplet nephropathy at 300 and 1000 mg/kg bw/day. The

hyaline droplet nephropathy of the kidney consisted of increased incidence and severity

of hyaline droplets, tubular degeneration, granulated tubular casts and interstitial

inflammatory infiltrate. This nephropathy was deemed to be related to treatment and to

represent an adverse effect of treatment to the rat. Hyaline droplets were also present

for males at 30 mg/kg bw/day but these occurred in the absence of any degenerative

changes and the No Observed Adverse Effect Level' (NOAEL) for males was therefore

considered to be 30 mg/kg bw/day. However, the hyaline droplets nephropathy at higher

dosages were consistent with well documented changes that are peculiar to the male rat

in response to treatment with some hydrocarbons. This effect is, therefore, not indicative

of a hazard to human health. In the context of this study, the remaining kidney findings,

consisting of tubular and/or degeneration, tubular dilation/vacuolation, granulated tubular

casts and interstitial inflammatory infiltrate detected in males are more likely to be

correlated to the same condition as hyaline droplet accumulation and are, therefore,

considered to represent limited relevance to humans.

 

Enhanced evaluation of reproduction for this study did not indicate any effect of

treatment on reproduction including litter size and offspring survival, growth and

development at dosages up to 1000 mg/kg bw/day. The ‘No Observed Effect Level’

(NOEL) for reproductive toxicity was considered to be 1000 mg/kg bw/day.

  

Therefore, the NOAEL, for DNEL calculation, was set a 1000 mg/kg/day.

DNEL dermal-systemic-worker

The dose descriptor of 1000 mg/kg/day, was selected from an OECD 422 oral study with rats.

Oral absorption rat – oral/dermal absorption human: Assume 10% absorption based on the physical-chemical properties, in accordance with Endpoint Specific Guidance Chapter 8 and 7c (R.7.12).

1000 mg/kg/day/0.10 mg/kg/day = 10000 = 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

10000 mg/kg/day/10 = 1000 mg/kg/day

Correction for intraspecies difference: 5

1000 mg/kg/day/5 = 200 mg/kg/day

Correction for duration: 4

200 mg/kg/day/4 = 50 mg/kg/day

Correction for dose-response: 1 due to NOAEL

50 mg/kg/day/1 = 50

Correction for whole database: 1 due to quality of study

50 mg/kg/day/1 = 50 mg/kg/day

Total AF = 200

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

 

DNEL inhalation-systemic-worker

The dose descriptor of 1000 mg/kg/day, was selected from an OECD 422 oral study with rats.

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 = 1000 mg/kg/day x (1/0.38 m3/kg/day) x (1.0) x 6.7 m3/10m3

                               = 1763 mg/m3

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

Correction for interspecies differences: 2.5

1763 mg/m3/2.5 = 705 mg/m3

Correction for intraspecies differences: 5

705 mg/m3/5 = 141 mg/m3

Correction for duration: 4

141 mg/m3/4 = 35 mg/m3

Correction for dose-response: 1

35 mg/m3/1 = 35 mg/m3

Correction for whole database: 1 due to quality of study

35 mg/m3/1 = 35 mg/m3

Total AF = 50

35 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

1,1,4,4-tetramethylbutane-1,4-diyl bis(2-ethylperoxyhexanoate) CAS# 13052-09-0

Oral* Absorption

Dermal* Absorption

Inhalation* Absorption

MW

430.618

y

moderate

liquid

WS

27.9 ug/L

n

n

n*****

Log Pow

>6.5 (7.1 extrapolated)

y****

n***

y****

VP

The VP of the test substance at 25 deg C is well below 0.01 Pa

NA

y**

n

Skin irritation

not irritating

 

n

 

Sensitization

No

 

 

 

Toxicity Data

 

y

 

 

Overall Absorption

 

y (based on log P and tox data)

n (perhaps 10% max)

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 compoud 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