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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:
3.53 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:
88.156 mg/m³
Explanation for the modification of the dose descriptor starting point:

No inhalation study data are available. The NOAEL of 100 mg/kg/day from the 90 -day repeat dose oral study with rats was used as the starting point to calculate the DNEL. Assuming an oral/inhalation rate of absorption of 0.5, a dose descriptor of 88.156 mg/m3 was derived as the starting point. See discussion under "Additional information - Workers" for route to route extrapolation calculations.

AF for dose response relationship:
1
Justification:
Based on REACH guidance
AF for differences in duration of exposure:
2
Justification:
Based on REACH guidance for subchronic 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:
10 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
Modified dose descriptor starting point:
NOAEL
DNEL value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The NOAEL of 100 mg/kg/day from a 90-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 1000 mg/kg/day was derived as the starting point. See discussion under "Additional information - Workers" for route to extrapolation calculation.
AF for dose response relationship:
1
Justification:
Based on ECHA REACH guidance
AF for differences in duration of exposure:
2
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

Phys-chem properties considered for the calculation of DNEL for CAS 133-14-2.

Endpoint

Peroxide

MW

380 g/mol, solid (test substance is a paste)

WS

<2 ug/L, which is the detection limit (measured, OECD 105)

Log Pow

6 at 27oC (measured, OECD 117)

VP

< 0.009 Pa at 25oC

(Read across)

Skin irritation

Non irritant (in vivo, OECD 104)

 

Initial Dose Descriptor

 

In a 28-day oral gavage study with rats, a No Observed Adverse Effect Level (NOAEL) of 300 mg/kg bw/day was established for the systemic effects of Bis(2,4-dichlorobenzoyl) peroxide (CAS 133-14-2), paste, 50% in silicone oil based on the microscopic changes in the testes and epididymis.  Treatment at 1000 mg/kg bw/day was associated with the following changes: Statistically significant differences from control were noted for blood chemistry parameters (e.g., increased albumin/globulin ratio, alanine aminotransferase and alkaline phosphatase levels; lower total cholesterol level), but were considered to be of no toxicological significance. For example, the liver enzyme changes were likely to be associated with the adaptive histopathological liver changes and were considered not to represent an adverse effect of treatment. Increased absolute and body weight relative liver weights attained statistical significance when compared with control. Histopathological examination revealed cytoplasmic eosinophilic change of hepatocytes in the centrilobular region at a minimal severity in three males and three females. The hepatocytic cytoplasmic change was considered to be of metabolic nature and of adaptive character, and therefore was considered not to represent an adverse effect of treatment. Lower prostate/seminal vesicle and spleen weights and higher kidney weight ( males) and lower pituitary weight (females) attained statistical significance when compared with control but these differences, in the absence of any evidence of histopathological change, were considered to be of no toxicological significance. Thyroid follicular cell hypertrophy was recorded at minimal severity in one male and three females. This change is deemed to be associated with the increased hepatic metabolization of thyroid hormones (T3/T4) due to the above mentioned hepatocellular cytoplasmic change. Such thyroidal change is deemed to represent a secondary effect, and hence, deemed not to be adverse. Three animals showed Increased Sertoli-cell vacuolation with focal, segmental tubular degeneration in the testes, with two of these also showing spermatid retention in stage X tubule at a minimal severity. All three of these animals showed interstitial edema with inflammatory cell or mononuclear cell infiltration as well as oligospermia and/or increased intraductal cellular debris were observed in the epididymis. In summary, based on these findings, the NOAEL for DNEL calculations could be set at 300 mg/kg/day.

An oral (gavage) study of Bis(2,4-dichlorobenzoyl) peroxide (CAS# 133-14-2), paste, 50% in silicone oil, for 90 days, to Wistar Han™:RccHan™:WIST strain rats (10/sex/group) at dose levels of 100, 300 or 1000 mg/kg bw/day was conducted (OECD 408 test guideline, GLP). A vehicle alone (Arachis oil BP) group was included. Standard parameters were evaluated. To assess recovery, two recovery groups, each of ten males and ten females, were treated with the high dose (1000 mg/kg bw/ day) or the vehicle alone for ninety consecutive days and then maintained without treatment for a further twenty-eight days and were evaluated. Conclusion: Treatment-related effects in body weight development, hematology parameters (anemia), sperm analysis (reduced sperm concentration, motility and an increase in sperm morphological abnormalities), reduced testes, epididymides and cauda epididymis weight and microscopic changes in the bone marrow (fatty vacuolation and subsequent decreased cellularity), testes/epididymides (tubular atrophy with an accompanying aspermia in the epididymis) and thymus (atrophy) at 1000 mg/kg bw/day and similar microscopic changes in the testes and epididymides in males treated with 300 mg/kg bw/day. These changes were considered to represent an adverse effect of treatment. After recovery period, microscopic changes in thymus had completely resolved, while the reversibility of bone marrow changes were not complete. In testes and epididymis, the microscopic changes and aspermia persisted. No toxicologically significant effects were evident in females treated with 300 mg/kg bw/day or in animals of either sex treated with 100 mg/kg bw/day. The 'No Observed Adverse Effect Level (NOAEL) was therefore considered to be 300 mg/kg bw/day for females and 100 mg/kg bw/day for males.

Based on the subchronic study data and the worst case scenarion approach, 100 mg/kg bw/d was chosen as the NOAEL for DNEL dose descriptor calculations on systemic effects.

For the DNEL covering local effects of inhalation and dermal routes of exposure, route-specific data need to be available (Guidance on information requirements and chemical safety assessment R 8.1.2.6). no such information is available. There are no consumer uses of this substance. Human exposure, via the environment, is unlikely due to the instability of the peroxide. The substance is a skin sensitizer, which is considered a systemic effect. Therefore, a qualitative risk assessment was done for dermal systemic effects. However, DNELs were calculated for non-sensitizing systemic effects.

 

DNEL dermal-systemic-worker for CAS 133-14-2.

The dose descriptor of 100 mg/kg/day was selected from a 90-day repeat dose oral study in rats. 

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) in accordance with Endpoint Specific Guidance Chapter 8 and 7c (R.7.12) and the substance not being classified for skin irritation.

DNEL dermal-systemic-worker

100 mg/kg/day / 0.1 =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-chronic to chronic: 2

20 mg/kg/day/2 = 10 mg/kg/day

Correction for dose-response: 1 due to NOAEL

10 mg/kg/day/1 = 10 mg/kg/day

Correction for whole database: 1 due to quality of study

10 mg/kg/day/1 = 10 mg/kg/day

Total AF = 100

10 mg/kg/day = DNEL dermal-worker-systemic

 

DNEL inhalation-systemic-worker

The dose descriptor of 100 mg/kg/day was selected from a 90-day repeat dose oral study in rats.

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 = 100mg/kg/day x (1/0.38m3/kg/day) x (0.5) x 6.7m3/10m3= 88.156 mg/m3(inhalation dose descriptor)

 

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

Correction for interspecies differences: 2.5

88.156 mg/m3/2.5 = 35.2624 mg/m3

Correction for intraspecies difference: 5

35.2624 mg/m3/5 = 7.0525 mg/m3

Correction for duration between sub-chronic to chronic: 2

7.0525 mg/m3/2 = 3.5262 mg/m3

Correction for dose-response: 1

3.5262 mg/m3/1 = 3.5262 mg/m3

Correction for whole database: 1 due to quality of study

3.5262 mg/m3/1 = 3.5262 mg/m3

Total AF = 25

3.53 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 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

Additional information - General Population