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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.65 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):
50
Dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
132.24 mg/m³
Explanation for the modification of the dose descriptor starting point:

Correction factor for differences in bioavailability (ABS), oral vs. inhalation absorption: 0.5

Correction factor for differences in respiratory volume (SRV): 2.63 (1/0.38 m3/kg)

Correction factor for light activity at work (WORKER): 0.67 (6.7 m3/10 m3)

AF for dose response relationship:
1
Justification:
Default factor
AF for differences in duration of exposure:
4
Justification:
POD: OECD 422 study (4 weeks < exposure duration < 13 weeks)
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling factor is applied because an oral-to-inhalation route extrapolation
AF for other interspecies differences:
2.5
Justification:
default factor
AF for intraspecies differences:
5
Justification:
default factor
AF for the quality of the whole database:
1
Justification:
default factor
AF for remaining uncertainties:
1
Justification:
default factor
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:
3.75 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
Dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
750 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Correction factor for differences in bioavailability (ABS), dermal vs. oral absorption: 0.2

Based on Guidance on information requirements and chemical safety assessment, Chapter R 7.12: dermal absorption is supposed low to moderate for several reasons.The substance is liquid and little soluble in water (10.7 mg/l), the log Kow is 4.4; therefore very little of the substance is expected to permeate from the stratum corneum to the epidermidis. The molecular weight is 208.3 g/mol which is rather in favour of dermal absortpion. As the substance is a skin irritant, increased of skin absorption could occur. However, calculations based on modeling suggested a default absorption value of 10%. Therefore, dermal absorption can be reasonably estimated to be lower than 20 % of oral absorption factor.

AF for dose response relationship:
1
Justification:
Default factor
AF for differences in duration of exposure:
4
Justification:
POD: OECD 422 study (4 weeks < exposure duration < 13 weeks)
AF for interspecies differences (allometric scaling):
4
Justification:
Default factor for rats.
AF for other interspecies differences:
2.5
Justification:
Default factor
AF for intraspecies differences:
5
Justification:
Default factor
AF for the quality of the whole database:
1
Justification:
Default factor
AF for remaining uncertainties:
1
Justification:
Default factor
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:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

DNEL Calculations:

Endpoint

              

CAS no. 3457-61-2

Mol. wt

Grams/Mole

208.297

WS

mg/L, in water (measured)

10.66 at 20oC

Log Pow

 (OECD 117)

      4.4 at 25oC

VP

Pa (measured)

14 at 40oC

Skin/eye irritation

(measured) 

Cat. 2

NOAEL, oral, rat (OECD 422)

mg/kg bw/day

150 

Data from relevant routes of exposure were considered for acute systemic exposures but were not appropriate to calculate short term Worker DNELs. Exposure to TBCP by repeated oral high dose is not expected under normal occupational settings and there are no consumer uses of this substance. Occupational exposure, if any, may only be by dermal or inhalation exposures. Therefore, two long-term DNELs are calculated for workers. For local effects, qualitative assessment is made due to its skin irritating nature (Cat. 2) upon potential acute dermal exposure. Human exposure, via the environment, is unlikely due to the general instability of the peroxide. The general population is not exposed to the substance by inhalation, dermal or oral exposure exposures. The discharge of the substance in the environment (water, air) is extremely low. Therefore, no inhalation and no dermal DNEL is derived for general population.

The OECD TG 422 (combined repeated-dose and reproduction / developmental screening) study (Liberati, 2013) is selected for DNEL derivation as it is a repeated dose study of good quality (GLP, OECD guideline) and males and females were exposed for 4 -5 weeks and provided a NOAEL of 150 mg/kg bw/d. While a 90 -day study (GLP study) with a NOAEL of 400 mg/kgbw/d and an OECD 414 study (GLP), with a NOAEL of 150 mg/kg bw/d are also available, they yielded DNEL values 4 to 5 times higher (due to different assessment factors). Thus, the smallest, most sensitive and conservative DNEL value from the OECD 422 study was chosen. In the OECD 422 study, the parental oral NOAEL is 150 mg/kg/day and the oral LOAEL is 600 mg/kg/day based on clinical signs, reduced body weight both in male and in females, and on kidney effects in males (species and gender-specific). For reproduction/developmental toxicity, this NOAEL is based on the decrease of fertility index, decrease of corpora lutea, decrease of litter weight and litter size at 600 mg/kg/day. Based both on parental and fetal toxicity, the oral NOAEL was 150 mg/kg bw/day.  Toxicity to reproduction was only observed at doses leading to maternal toxicity, it is therefore not relevant to derive a DNEL based on reproductive effects. Only DNEL based on systemic effects is calculated. The toxicologically significant findings are provided below.

Repeated dose systemic effects on the parents: The toxic effects on rats of both sexes after repeated dosing with the test item (97% tert-butyl cumyl peroxide) by oral route was evaluated in an OECD 422 study (Liberati, 2013). The test item, suspended in corn oil, was administered by oral gavage to 3 groups of 10 males and 10 females each at 75, 150 and 600 mg/kg bw/d. A similar constituted control group (Group 1) received the vehicle alone during the treatment period. Males were treated for a total of 33 days including 2 weeks prior to pairing and continuously thereafter, up to the day before necropsy. Females were treated for 2 weeks before pairing, thereafter during pairing, post coitum and lactation periods until Day 3 postpartum. Tremors, piloerection and salivation were the most relevant clinical signs detected in high dose males and females during the whole treatment period. Body weight (BW) and body weight gain of both sexes were significantly lower at statistical analysis in the high dose group of both sexes compared to controls throughout the study. Food consumption was reduced only in high dose females starting from post coitum Day 14. Terminal BW was significantly lower in the high dose group of both sexes compared to controls. Statistically significant higher liver and kidneys weight was observed in high dose males and females compared to controls. A significant increase was also detected in the kidney weight of both sexes in the mid-dose group. At final sacrifice, treatment related changes were seen in the liver and kidneys. Significant treatment-related findings were noted in the liver of the high dosed group(mild) of both sexes and in mid-dose (minimal) male group, consisting of centrilobular hepatocytic hypertrophy associated with cytoplasmic eosinophilia. As the hepatocytic hypertrophy was not associated with other changes in the hepatocytes (i.e., degeneration and/or necrosis), this change was not considered as adverse, but rather as potentially adaptive. In the kidneys of the males treated with the intermediate and high dose, a dose-related increased incidence of minimal cortical basophilic tubules was noted. As organ weight data indicated a statistically significant increase of the relative kidney weight in these groups, as well as macroscopically cases of enlarged kidneys were seen only in the males treated with the high dose, it is suggested that the dose-related increased incidence of minimal cortical basophilic tubules is potentially related to treatment. However, the increase in incidence and severity of cortical hyaline droplets in the kidneys of males is considered to represent 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.). 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.In conclusion, the NOAEL for general toxicity is 150 mg/kg/day for males and females, based on clinical signs, reduced body weight and body weight gain at 600 mg/kg bw/day (compared to controls.

 

Toxicologically significant findings on fertility were as follows: A total of 5 females were found not pregnant at necropsy: 2 in the mid-dose group and 3 in the high dose group. One mid-dose female had total litter loss on Day 0 postpartum and was sacrificed on Day 3 postpartum. The number of females with live pups on Day 4 postpartum was: 9 in the control group, 10 in the low dose group, 7 each in the mid-dose and high dose groups. Two females in the mid-dose group and 3 females in the high dose group were found not pregnant at necropsy. The fertility index (in males and females) at mid dose was decreased compared to the control group. Statistically significant decreased corpora lutea, implantations and total litter size and an increase in pre-birth loss percentage were detected in the high dose females respect to the controls. On Day 4 postpartum, live litter size, number of females and litter weight were still significantly reduced compared to controls. The NOAEL for reproduction/developmental toxicity is 150 mg/kg bw/d and is based on the decrease of fertility index, decrease of corpora lutea and implantation sites, litter weight and litter size at 600 mg/kg/day.

 

DNEL inhalation-systemic-workerfortert-butyl cumyl peroxide:                                                                      

Corrected inhalatoary NOAEC: Oral NOAEL x (1/sRVrat) x (ABSoral-rat/ABSinh-human) x (sRVhuman/wRV)

Correction for inhalation and oral absorption rates: 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).                                                                          

Conversion into an inhalatory rat NOAEC: dividing by 0.38 m3/kg (8-hour respiratory volume in the rat)                       

Correction for activity driven differences in respiratory volume in workers compared to individuals at rest: (6.7 m3/10 m3) [ABS: absorption; sRV: standard Respiratory Volume; wRV: worker Respiratory Volume]                         

Corrected NOAEC = 150 mg/kg/day x (1/0.38 m3/kg/day) x (0.5) x 6.7 m3/10m3 = 132.24 mg/m3 (Inhalatory dose descriptor)                       

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

Correction for interspecies differences: 2.5                                                                                                                                  

132.24 mg/m3 / 2.5 = 52.89 mg/m3                                                                                                                                            

Correction for intraspecies differences: 5                                                                                                                                     

52.89 mg/m3 / 5 = 10.58 mg/m3 

Correction for duration between subacute to chronic: 4                                                                                                            

10.58 mg/m3 / 4 = 2.65mg/m3

Correction for dose-response:1

2.65mg/m3 / 1=2.65 mg/m3                                                                                                                                                      

Correction for whole database: 1 due to quality of study                                                                                                           

2.65 mg/m3 / 1 =2.65mg/m3                                                                                                                                                       

Total AF = 50                                                                                                                                                    

2.65 mg/m3, DNEL inhalation-systemic-worker

                                                                                                                                                   

DNEL dermal-systemic-workerfor tert-butyl cumyl peroxide:            

Correction for dermal and oral absorption rates of tert-butyl cumyl peroxide (based on Guidance on information requirements and chemical safety assessment, Chapter R 7.12): Dermal absorption is assumed to be low to moderate for several reasons. 1. While no actual absorption data exist, calculations based on modelling suggested a low absorption default value of 10%. However, since the substance is a liquid with water solubility (10.66mg/L) and log Kow (4.4) values and Cat. 2 skin irritant (but not a sensitizer to the skin), skin absorption is assumed to be 20% (correction factor= 0.2). No data is available on absorption by oral route. It is therefore assumed that oral absorption factor is 100 %.                                             

Oral NOAEL (150 mg/kg/day) / 0.2 = 750 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  

750 mg/kg/day/10 = 75 mg/kg/day                                                                                                                                                

Correction for intraspecies difference: 5                                                                                                                                       

75 mg/kg/day/5 = 15 mg/kg/day                                                                                                                                                   

Correction for duration between sub-acute to chronic: 4                                                                                                           

15 mg/kg/day / 4 = 3.75 mg/kg/day

Correction for dose-response: 1 due to NOAEL                                                                                                                           

3.75 mg/kg/day / 1 = 3.75

Correction for whole database: 1 due to quality of study                                                                                                           

3.75 mg/kg/day / 1 = 3.75 mg/kg/day                                                                                                                                           

Total AF = 200                                                                                                                                                 

3.75 mg/kg/day, DNEL dermal-worker-systemic

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
Explanation for the modification of the dose descriptor starting point:

There are no consumer uses for this substance. Human exposure, via the environment, is unlikely. Only DNELs for the relevant populations will have to be derived (Guidance on information requirements and chemical safety assessment R.8.1.2.3).

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