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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:
11.75 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):
75
Modified dose descriptor starting point:
NOAEC
DNEL value:
881 mg/m³
Explanation for the modification of the dose descriptor starting point:
The NOAEL of 1000 mglkglday from a 28-day repeat dose oral study with rats was used. Assuming an oral/inhalation rate of absorption of 0.5, a dose descriptor of 881 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:
6
Justification:
based on REACH guidance for subacute to chronic
Justification:
not applicable when setting an inhalation DNEL based on REACH guidance
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:
13.33 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):
300
Modified dose descriptor starting point:
NOAEL
DNEL value:
4 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
A NOAEL of 1000 mg/kg/day was selected from a 28-day repeat dose oral study with rats.  Oral absorption rat – oral/dermal absorption human: Assume 25% absorption based on the physical-chemical properties (water solubility, liquid nature, low molecular weight) in accordance with Endpoint Specific Guidance Chapter 8 and 7c (R.7.12). Therefore, a dose descriptor of 4000 mg/kg/day was derived as the starting point. See discussion for route to route extrapolation caluculations.
AF for dose response relationship:
1
Justification:
Based on REACH guidance.
AF for differences in duration of exposure:
6
Justification:
Based on REACH guidance.
AF for interspecies differences (allometric scaling):
4
Justification:
Based on REACH guidance.
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:
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:
low hazard (no threshold derived)

Additional information - workers

Endpoint

Peroxide

MW

134.1 g/mol, liquid

WS

Freely soluble (>500 g/L) (measured, OECD 105)

Log Pow

1.1 (measured, OECD 117)

VP

6.28 Pa at 20oC (measured, OECD 104)

Skin irritation

Non irritant

Initial Dose Descriptor

In a 28-day oral gavage study with rats, based on treatment-related microscopic findings of squamous hyperplasia and hyperkeratosis of forestomach, as well as mucosal necrosis of glandular stomach in males and females treated with 1000 mg/kg/day, a No-Observed-Adverse-Effect-Level (NOAEL) of 300 mg/kg body weight/day of 2,4 -Pentanedione, peroxide was suggested for the rat. Other test item-related non-adverse and typically adaptive microscopic findings included hypertrophy of mucosal epithelium of duodenum, centrilobular hepatocellular hypertrophy and increased incidence and severity of extramedullary erythrocytic hemopoiesis (i.e. erythropoiesis) in both sexes treated with 1000 mg/kg/day, increased erythropoiesis in femur bone marrow in females treated with 1000 mg/kg/day, and enhanced hyaline droplets in renal proximal tubules as well as increased incidence and severity of tubular basophilia in the kidney in males treated with 300 and 1000 mg/kg/day.

 

Although the study report shows 300 mg/kg/d as the NOAEL, the following findings were re-considered and regarded as irrelevant to humans or non-adverse or typically adaptive in nature.The lesions observed in the forestomach, glandular stomach and duodenum were considered to be a local reaction of the epithelial lining to the repeated gavage administration of the test item. This reasoning, along with the known 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). The hematology parameter changes are generally recognized as reversible after exposure is discontinued. The clinical biochemistry parameters of males and females at 1000 mg/kg/day showed mild aberrations in lipid metabolism that was attributed to metabolic adaptation. The centrilobular hepatocellular hypertrophy was considered to be of metabolic nature and of adaptive character. Increased renal tubular basophilia were deemed to be caused by the enhanced hyaline droplet deposition, which in turn was considered to be due to the overload of synthetic protein that is specific to male rats resulting from liver hyperfunction. Alpha2μglobulin, 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. 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. Based on these considerations, the dose descriptor NOAEL for DNEL calculations was set a 1000 mg/kg/day.

Due to low vapor pressure, inhalation is not expected to be a major route of exposure. For the DNEL covering local effects of inhalation, 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 will be 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 for non-sensitizing systemic effects.

DNEL dermal-systemic-worker for CAS 37187 -22 -7

A NOAEL of 1000 mg/kg/day was selected from a 28-day repeat dose oral study with rats. 

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

DNEL dermal-systemic-worker

1000 mg/kg/day / 0.25 = 4000 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

=  4000 mg/kg/day/10 = 400 mg/kg/day

Correction for intraspecies difference: 5

400 mg/kg/day/5 = 80 mg/kg/day

Correction for duration between sub-acute to chronic: 6

80 mg/kg/day/6 = 13.33 mg/kg/day

Correction for dose-response: 1 due to NOAEL

13.33 mg/kg/day/1 = 13.33 mg/kg/day

Correction for whole database: 1 due to quality of study

13.33 mg/kg/day/1 = 13.33 mg/kg/day

Total AF = 300

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

DNEL inhalation-systemic-worker

The dose descriptor of 1000 mg/kg/day was selected from a 28-day repeat dose oral study in rats.

Assume ABSoral-rat/ABSinh-human is 50/100 = 0.5 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 (0.5) x 6.7m3/10m3

= 881 mg/m3 = inhalation dose descriptor

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

Correction for interspecies differences: 2.5

881 mg/m3/2.5 = 352.4 mg/m3

Correction for intraspecies difference: 5

352.4 mg/m3/5 = 70.48 mg/m3

Correction for duration between sub-acute to chronic: 6

70.48 mg/m3/6 = 11.75 mg/m3

Correction for dose-response: 1

11.75 mg/m3/1 = 11.75 mg/m3

Correction for whole database: 1 due to quality of study

11.75 mg/m3/1 = 11.75 mg/m3

Total AF = 75

11.75 mg/m3 DNEL 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 (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
hazard unknown (no further information necessary)

Additional information - General Population