Bis(4-methylbenzoyl)peroxide

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

23.49 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

Value:

1 762 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/inhaiation rate of absorption of 1.0, a dose descriptor of 1762 mg/m3 was derived as the starting point. See discussion for route to route extrapolation calculation.

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

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:

33.33 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

Value:

10 000 mg/kg bw/day

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. Oral absorption rat – oral/dermal absorption human: Assume 10% absorption based on the physical-chemical properties (poor water solubility, test substance is a paste, higher log Pow, and non-irritating to the skin) in accordance with Endpoint Specific Guidance Chapter 8 and 7c (R.7.12). Therefore, a dose descriptor of 10000 mg/kg/day was derived as the starting point. See 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:

6

Justification:

Based on ECHA REACH guidance for subacute to chronic

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:

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Phys-chem data considered for the calculation of DNEL for CAS 895-85-2;

Endpoint	Peroxide
MW	270.28 g/mol, powder
WS	poorly soluble (0.043 mg/L) (measured, OECD 105)
Log Pow	4.7 (measured, OECD 117)
VP	0.0012 Pa at 25^oC (calculated)
Skin irritation	Non-irritant

Initial Dose Descriptor

 

The peroxide is a low molecular weight substance with poor water solubility (23 ug/L) and a relatively high log Pow value of 4.7. Any lipophilic compound may be taken up by micellar solubilization but this mechanism may be of particular importance for highly lipophilic compounds (log P > 4), particularly those that are poorly soluble in water (< 1 mg/L) that would otherwise be poorly absorbed.

 

In a 28-day oral gavage study with rats based on treatment-related findings that were either statistically or toxicologically insignificant in males and females treated up to 1000 mg/kg/day, a No-Observed-Adverse-Effect-Level (NOAEL) of 1000 mg/kg body weight/day of Di-(4 -Methylbenzoyl)-peroxid (INTEROX-PMBP) was established (Hoff, 1992). Minor histopathologic findings in cecum, liver and adrenal glands of some animals were concluded toxicologically insignificant. The presence of polyethylene glycol 400 (vehicle) in the oral gavage formulation could have slightly increased the test substance’s absorption from the digestive tract due greater chances of emulsification and digestion. Still, the results suggest the test substance was either poorly absorbed and/or efficiently metabolized/eliminated by the rats. Based on these considerations, the NOAEL for DNEL calculations was set at 1000 mg/kg/day.

 

Exposure to a repeated oral high dose is not expected under normal occupational settings and there are no consumer uses for this substance.

Inhalation: The estimated vapor pressure (0.0012 Pa at 25^oC) of the test substance is low. Therefore, inhalation is not expected to be a major route of exposure. Because the low vapor pressure, particle size (>100 um), and poor water solubility, a factor of 1.0 is used for oral to inhalation conversion. Particles with aerodynamic diameters <100 um have the potential to be inspired (inhaled). Granulometry of the test item showed that practically no particles <100 um were present in the test item. Therefore, no systemic toxicity effects are expected (European commission, “Guidance Document on the Determination of Particle Size Distribution, Fiber Length, Diameter Distribution of Chemical Substances”, 2002). 

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). Human exposure, via the environment, is unlikely.

DNEL dermal-systemic-worker for CAS 895-85-2

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

The LD50 for acute dermal toxicity in rats was > 2000 mg/kg b.w. The test item is neither an irritant to the rat skin nor a sensitizer to the guinea pig skin suggesting poor uptake or systemic effects. Based on the physical properties (low molecular weight; poor water solubility; log P = 4.7; low vapor pressure, 0.0012 Pa at 25 degrees C), the test substance is expected to have a relatively low dermal absorption rate.

 

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).

DNEL dermal-systemic-worker

1000 mg/kg/day / 0.10 = 10000 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 =  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 between sub-acute to chronic: 6

200 mg/kg/day/6 = 33.33 mg/kg/day

Correction for dose-response: 1 due to NOAEL

33.33 mg/kg/day/1 = 33.33 mg/kg/day

Correction for whole database: 1 due to quality of study

33.33 mg/kg/day/1 = 33.33 mg/kg/day

Total AF = 300

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

 

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 100/100 = 1.0 based on phys-chem properties (not inhalable, based on particle size) 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 6.7m³/10m³=1762 mg/m³= inhalation dose descriptor

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

Correction for interspecies differences: 2.5

1762 mg/m³/2.5 = 704.8 mg/m³

Correction for intraspecies difference: 5

704.8 mg/m³/5 = 140.96 mg/m³

Correction for duration between sub-acute to chronic: 6

140.96 mg/m³/6 = 23.49 mg/m³

Correction for dose-response: 1

23.49 mg/m³/1 = 23.49 mg/m³

Correction for whole database: 1 due to quality of study

23.49 mg/m³/1 = 23.49 mg/m³

Total AF = 75

23.49 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