O-(2-ethylhexyl) O,O-tert-pentyl peroxycarbonate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.41 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):

50

Dose descriptor starting point:

NOAEL

Value:

250 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

220.39 mg/m³

Explanation for the modification of the dose descriptor starting point:

There are no relevant data for repeated dose by inhalation. The NOAEL of 250 mglkglday from an OECD 421 repeat dose oral study with rats was used. Assuming an oral/inhaiation rate of absorption of 0.5, a dose descriptor of 220.39 mg/m3 was derived as the starting point.

AF for dose response relationship:

1

Justification:

Based on REACH guidance

AF for differences in duration of exposure:

4

Justification:

Based on REACH guidance for subacute to chronic

Justification:

Not applicable when setting an inhalation DNEL based on REACH guidance (respiratory interspecies differences are fully covered)

AF for other interspecies differences:

2.5

Justification:

Based on REACH guidance

AF for intraspecies differences:

5

Justification:

Based on REACH guidance

AF for the quality of the whole database:

1

Justification:

Based on 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

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 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):

200

Dose descriptor starting point:

NOAEL

Value:

250 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The NOAEL of 250 mg/kg/day was selected from an OECD 421 repeat dose oral (reproductive screening) study in rats. Oral absorption rat – oral/dermal absorption human: Assumed 25% dermal absorption based on the physical-chemical properties (low water solubility, higher log Kow, non-irritant to skin) in accordance with Endpoint Specific Guidance Chapter 8 and 7c (R.7.12). Therefore, a dose descriptor of 1000 mg/kg/day was derived as the starting point. Please see discussion for route to route extrapolation calculations.

AF for dose response relationship:

1

Justification:

Based on ECHA REACH guidance

AF for differences in duration of exposure:

4

Justification:

Based on ECHA REACH guidance

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

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

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

Correction of dose descriptors for route-to-route extrapolation, application of assessment factors and derivation of the endpoint specific DNEL

Phys-Chem data considered for the calculation of DNEL for CAS 70833-40-8:

Endpoint	CAS 70833 -40 -8
MW	260.4 g/mol, Liquid
WS	212.5 ug/L (measured, OECD 105)
Log Pow	5.8 (measured, OECD 117)
VP	10 Pa at 50^oC (measured, OECD 104); 0.028 at 25  ^oC
Skin irritation	Non irritant

 

Initial Dose Descriptor

In a 28-day oral gavage study with rats, a no-observed-adverse-effect-level (NOAEL) of 1000 mg/kg/day was established for the systemic toxic effects of O-(2 -ethylhexyl) O,O-tert-pentyl peroxycarbonate. Treatment-related microscopic findings were noted in the liver, kidney and forestomach. The no-observed-effect-level (NOEL) and the local no-observed-adverse-effect-level (NOAEL) were considered to be below 100 mg/kg/day, based on the irritative findings in the forestomach.

Increased severity of hyaline droplets in the renal proximal tubules was recorded in males treated with 1000 mg/kg/day. This was considered to be due to proteins specific to male rats and generally derived from hyperfunction of the liver. Slightly elevated liver weights noted in the females treated with 300 or 1000 mg/kg/day were considered to be adaptive, non-adverse changes of metabolic origin. Although minimal centrilobular hepatocellular hypertrophy was recorded in two rats treated with 1000 mg/kg/day, it was considered to be metabolic adaptation, and not adverse. Alpha2 microglobulin, a normal protein in male rats which undergoes reabsorption in the proximal cortical tubules (Alden, CL and Frith CH. Urinary System, Ch. 15, pp 315-387. In: Handbook of Toxicologic Pathology Eds. Haschek WM and Rousseaux CG. Academic Press, San Diego. 1991) is a typical example of proteins generally derived from hepatic hyperfunction. Although this may be an adverse finding in rats, this protein has no counterpart in humans and is therefore is of no toxicological relevance. Increased incidence and severity of renal tubular basophilia were considered to be secondary injuries caused by enhanced hyaline droplet deposition. A range of chemicals are known to increase hyaline droplet formation beyond the physiological capacity of the tubular epithelium which may then result in tubular epithelial cell damage (hyaline droplet nephropathy) which was evident in this study.

 

Forestomach mucosal necrosis was recorded in males treated with 100 mg/kg/day and both sexes treated with 300 mg/kg/day or 1000 mg/kg/day. In the affected rats, hyperkeratosis / parakeratosis, reactive squamous hypertrophy/hyperplasia, dyskeratosis and/or mucosal/submucosal edema as well as inflammatory cell infiltration were observed. These were considered to be local injuries in the forestomach due to a possible irritation caused by repeated oral gavage of the substance resulting in subsequent adverse reactions in affected rats. It is possible these may be due to local physicochemical effect(s) of this test item or its potential degradation product(s) in the acidic pH of the stomach. However, significant differences in the functional anatomy of rodent and human digestive system suggest that the above rat study findings may be considered not relevant to human exposure conditions (“Mode-of-action framework for evaluating the relevance of rodent forestomach tumors in cancer risk assessment” by Proctor, DM., Gatto, NM., Hong, SJ., and Allamneni, KP., Toxicological Sci., 98(2): 313 -326, 2007). Furthermore, the substance is not an irritant to the skin or eyes.

In summary, based on the entire study findings, the systemic NOAEL for DNEL calculations was set a 1000 mg/kg/day.

In a recent screening test (OECD 421) for reproductive/developmental effects and assessment of endocrine disruptor relevant endpoints, the administration of the test item [O‑(2‑ethylhexyl) O,O-tert-pentyl peroxycarbonate], by oral gavage, to Sprague Dawley rats for at least four weeks resulted in the following effects. Three groups of ten male and ten female rats received test item at doses of 50, 250 or 1000 mg/kg/day by oral gavage administration. Males were treated daily for two weeks before pairing, up to necropsy after a minimum of four consecutive weeks. Females were treated daily for two weeks before pairing, throughout pairing, gestation and until Day 12 of lactation. Females were allowed to litter, rear their offspring and were killed on Day 13 of lactation. The F1 generation received no direct administration of the test item; any exposure was in utero or via the milk. A similarly constituted Control group received the vehicle, PEG300, at the same volume dose as treated groups.

Treatment of the test item to parental animals at 50, 250 or 100 mg/kg/day for two weeks before pairing, during pairing and then up to termination of the males after 4 weeks of treatment and females on Day 13 of lactation was generally well tolerated. There was no adverse effect on parental clinical condition, body weight performance, food consumption, estrous cycles, mating performance or fertility. The clinical condition, body weight and survival of the subsequent F1 offspring were also unaffected by parental treatment. Treatment related findings were restricted to:(1)   Low implantations and subsequent live litter size on Days 1 and 4 of age at 1000 mg/kg/day. This effect was slight and in isolation with no effects on any other reproductive parameters or micropathology of the reproductive organs; (2)  Macroscopic and microscopic changes in the stomach of parental animals at 250 and 1000 mg/kg/day. The microscopic findings of epithelial hyperplasia and submucosal infiltration of inflammatory cells in the non-glandular region of the stomach were considered to be indicative of a local irritant effect of the test item at 250 and 1000 mg/kg/day, with a dose-relationship in male animals; in males this correlated with gross findings of a thickened forestomach. It may be noted that similar findings were noted again in the same organs (stomach and kidneys) and their irrelevance to human health is aready explained above. It was therefore concluded that the no-observed-adverse-effect-level (NOAEL) for reproductive performance and offspring development based on the effect on implantation count is 250 mg/kg/day. The no-observed effect level (NOEL) for parental effects considering the local irritant effect is 50 mg/kg/day with an overall parental NOAEL of 1000 mg/kg/day.

Therefore, the latter was chosen as the most sensitive endpoint, resulting in a NOAEL of 250 mg/kg bw/d for DNEL calculation purposes.

In terms of risk assessment, due to low vapor pressure, inhalation is not expected to be a major route of exposure. For the DNEL covering local effects of inhalation or dermal routes of exposure, route-specific data need to be available (Guidance on information requirements and chemical safety assessment R 8.1.2.6). Exposure to a repeated oral high dose is not expected under normal occupational settings and there are no consumer uses of this substance. Human exposure, via the environment, is unlikely due to the instability of the peroxide.

 

The test substance is a skin sensitizer, which is considered a systemic effect. Therefore, a qualitative risk assessment, for dermal systemic effects is conducted based on its classification as a Category 1 sensitizer which is considered as a high hazard (ECHA Guidance on information requirements and chemical safety assessment Part E, Table E.3 -1). However, DNELs were derived to cover non-sensitizing systemic effects.

DNEL dermal-systemic-worker for CAS 70833 -40-8

The NOAEL of 250 mg/kg/day was selected from an OECD 421 repeat dose oral study in rats. Assumed 25% dermal absorption based on the physical-chemical properties (low water solubility, higher log Kow, non-irritant to skin) in accordance with Endpoint Specific Guidance Chapter 8 and 7c (R.7.12). Therefore, a dose descriptor of 1000 mg/kg/day was derived as the starting point. See discussion for route to route extrapolation calculations.

DNEL dermal-systemic-worker:

250 mg/kg/day / 0.25 = 1000 mg/kg/day = 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 =  1000 mg/kg/day/10 = 100 mg/kg/day

Correction for intraspecies difference: 5

100 mg/kg/day/5 = 20 mg/kg/day

Correction for duration between sub-acute (OECD 421) to chronic: 4

20 mg/kg/day/4 = 5.0 mg/kg/day

Correction for dose-response: 1 due to NOAEL

5 mg/kg/day/1 = 5 mg/kg/day

Correction for whole database: 1 due to quality of study

5 mg/kg/day/1 = 5 mg/kg/day

Total AF = 200

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

 

DNEL inhalation-systemic-worker:

The dose descriptor of 250 mg/kg/day was selected from an OECD 421 repeat dose oral study in rats and corrected of inhalation exposure.

Assume ABSoral-rat/ABSinh-human is 50/100 = 0.5 based on physical-chemical 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 = 250 mg/kg/day x (1/0.38 m³/kg/day) x (0.5) x 6.7m³/10m³   =220.3947 mg/m³ = inhalation dose descriptor

 

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

Correction for interspecies differences: 2.5

220.3947 mg/m³/2.5 = 88.15789 mg/m³

Correction for intraspecies difference: 5

88.15789 mg/m3/5 = 17.63158 mg/m³

Correction for duration between sub-acute to chronic: 4

17.63158 mg/m3/4 = 4.407895 mg/m³

Correction for dose-response: 1

4.407895 mg/m3/1 = 4.407895 mg/m³

Correction for whole database: 1 due to quality of study

4.407895 mg/m3/1 = 4.407895 mg/m³

Total AF = 50

4.41 mg/m³DNEL inhalation-systemic-worker   

General Population - Hazard via inhalation 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

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:

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

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected