Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
20 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
DNEL value:
503 mg/m³
Explanation for the modification of the dose descriptor starting point:
Long-term systemic DNELs were derived using the NOAEC from a 90-day inhalation rat study and applying the appropriate assessment factors as described in the Guidance on Information Requirements and Chemical Safety Assessments, Chapter 8.
AF for dose response relationship:
1
Justification:
In accordance with REACH guidance
AF for differences in duration of exposure:
2
Justification:
In accordance with REACH guidance
AF for interspecies differences (allometric scaling):
1
Justification:
In accordance with REACH guidance
AF for other interspecies differences:
2.5
Justification:
In accordance with REACH guidance
AF for intraspecies differences:
5
Justification:
In accordance with REACH guidance
AF for the quality of the whole database:
1
Justification:
In accordance with REACH guidance
AF for remaining uncertainties:
1
Justification:
In accordance with REACH guidance
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3 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
DNEL value:
600 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Long-term systemic DNELs were derived using the NOAEL from a 28-day oral rat gavage study (OECD 422) and applying the appropriate assessment factors as described in the Guidance on Information Requirements and Chemical Safety Assessments, Chapter 8.
AF for dose response relationship:
1
Justification:
In accordance with REACH guidance
AF for differences in duration of exposure:
4
Justification:
In accordance with REACH guidance (exposure period in OECD 422 to chronic)
AF for interspecies differences (allometric scaling):
4
Justification:
In accordance with REACH guidance
AF for other interspecies differences:
2.5
Justification:
In accordance with REACH guidance
AF for intraspecies differences:
5
Justification:
In accordance with REACH guidance
AF for the quality of the whole database:
1
Justification:
In accordance with REACH guidance
AF for remaining uncertainties:
1
Justification:
In accordance with REACH guidance
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

June 17, 2014

Discussion

Systemic Dermal DNEL Workers

In an OECD 422 study, treatment at 1000 mg/kg/day and 300 mg/kg/day was associated with increased liver and kidney weights.  Histopathological effects were noted in liver (minimal cetrilobular and diffuse hepatocellular hypertrophy with association of a consequent increase in diffuse follicular sell hypertrophy in thyroid glands in males and females at 1000 mg/kg/day), kidneys (moderate diffuse tubular degeneration/regeneration with slight multifocal single cell necrosis and hyaline casts as well as hyaline droplets in males at 1000 mg/kg/day), and forestomach (minimally increased incidence and severity of diffuse hyperkeratosis in males at 1000 mg/kg/day and females at 1000 mg/kg/day and 300 mg/kg/day).

The microscopic findings occurring in the high dose group animals or being increased in the high dose animals, were considered to be likely related to an effect of the test item. All other microscopic findings noted in various organs and in all groups examined were considered to be incidental in nature since their morphology, severity, and incidence were indistinguishable from controls. Therefore, 300 mg/kg/day will be used as the NOAEL for DNEL calculation.

 

A systemic NOAEL of 300 mg/kg/day is based on the 28-day oral rat gavage study (OECD 422).

Oral absorption rat — oral/dermal absorption human: Assume 50% dermal absorption based on molecular weight of 146.23, log Pow of 3.2, water solubility of 170 mg/l and vapor pressure 35 mbar (3.5 kPa) at 20 °C. Dermal absorption is favored by the low molecular weight and moderate water solubility and partition coefficient. However, absorption is expected to be limited due to loss to air by rapid evaporation due to the high vapor pressure.

 

= 300 mg/kg bw/day/0.5

= 600 mg/kg bw/day dermal dose descriptor

Correction for interspecies differences (apply factor for allometric scaling 4 for rat x 2.5 for additional factors):10

= 600 mg/kg bw/day/10

= 60 mg/kg bw/day

Correction for intraspecies differences: 5

= 60 mg/kg bw/day/5

= 12 mg/kg bw/day

Correction for duration between OECD 422 repeat dosing to chronic: 4

= 12 mg/kg bw/day/4

= 3.0 mg/kg bw/day

Correction for dose-response: 1 due to NOEL

= 3.0 mg/kg bw/day/1

= 3.0 mg/kg bw/day

Correction of whole database: 1 due to quality of study

= 3.0 mg/kg bw/day/1

= 3.0 mg/kg bw/day (DNEL dermal-worker-systemic)

based on an overall AF of 200

 

Systemic Inhalation DNEL Workers

A 90-day inhalation study was conducted in the rat at test concentration of 0.1, 0.3 and 1 g/m3. Considering the modest magnitude of the organ weight changes and the absence of corroborative histopathological alterations or clinical chemical indicators of organ damage, the higher liver and kidney weights in male rats of the high-concentration group were considered not to represent adverse effects of the test material. Under the conditions of this study exposure to di-tert-butyl peroxide CAS# 110-05-4 resulted in a few modest changes at the highest concentration tested (increases in liver and kidney weight and altered plasma levels of cholesterol and creatinine). No treatment-related changes were observed at the lower concentrations. Since the changes at the high-concentration were considered not to constitute adverse effects, this exposure level (0.993 g/m3actual concentration) was a No-Observed-Adverse-Effect Concentration (NOAEC).

 

Corrected inhalation NOAEC from 90-day NOAEL

 

= NOAEC x exp. cond rat/exp. cond human x sRVhuman/wRV

= 1000 mg/m3 x (6 hr/day/8 hr/day) x (6.7m3/10m3)

= 503 mg/m3inhalation dose descriptor

 

Correction for interspecies differences: 2.5

= 503 mg/m3/ 2.5

= 201 mg/m3

Correction for intraspecies differences: 5

= 201 mg/m3/ 5

= 40.24 mg/m3

Correction for duration between sub-chronic to chronic: 2

= 20.12 rng/m3/6

= 20.12 mg/m3

Correction for dose-response: 1 due to NOAEC

= 20.12 mg/m3/1

= 20.12 mg/m3

Correction of whole database: 1 due to quality of study

= 20.12 mg/m3/1

= 20 mg/m3(DNELinhalation-worker-systemic)

based on an overall AF of 25.

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