Cyclohexylidenebis[tert-butyl] peroxide

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.29 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

Modified dose descriptor starting point:

NOAEC

Value:

132.24 mg/m³

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation. A conservative approach is used assuming a two times higher absorption via the inhalation route (end route) as compared to the oral route (starting route).

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

As the NOAEL of a repeated dose toxicity study (OECD408) with an exposure time of 90 days (males and females) was used as point of depature an AF of 2 is considered as adequate for the exposure duration extrapolation.

AF for interspecies differences (allometric scaling):

1

Justification:

Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

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:

15 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

Value:

1 500 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated dermal exposure. Due to the physico-chemical properties (logPow >7; water solubility < 1 mg/L) dermal absorption (end route) is assumed to be 10 % of oral absorption (starting route).

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

As the NOAEL of a repeated dose toxicity study (OECD408) with an exposure time of 90 days (males and females) was used as point of depature an AF of 2 is considered as adequate for the exposure duration extrapolation.

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

DNEL derivation for the test item cyclohexylidenebis[tert-butyl] peroxid is performed under consideration of the recommendations of ECHA (2010).

 

Acute/short-term systemic DNEL

Short-term DNELs are not required as the acute toxicity of cyclohexylidenebis[tert-butyl] peroxid is low. Cyclohexylidenebis[tert-butyl] peroxide is not classified and labelled for acute systemic toxicity, according to Regulation EC 1272/2008 (CLP), based on the test data for acute oral and dermal toxicity. No skin sensitisation potential was observed in the available Buehler test with cyclohexylidenebis[tert-butyl] peroxide.

Acute/long-term, local effects

Respiratory irritation: No study for local respiratory effects of the test material is available. However, since the test material showed no eye irritation potential and the volatility is low exposure via inhalation route is not likely to occur. Therefore, no adverse effects on respiratory system are expected and no local DNEL (long-term-inhalation) was derived.

 

Skin irritation/corrosion: Cyclohexylidenebis[tert-butyl] peroxide is not classified for skin irritation based on the skin irritation study available. Therefore, no qualitative risk assessment is required.

 

Eye irritation: Cyclohexylidenebis[tert-butyl] peroxide is not classified for eye irritation based on the results of the eye irritation studies available. Therefore, no qualitative risk assessment is required.

 

Long-term, systemic DNEL

Occupational exposure to cyclohexylidenebis[tert-butyl] peroxide occurs mainly by dermal route, and may also occur by inhalation exposure. Therefore two long-term DNELs are calculated for workers. In view of the data used for evaluation, the "quality of whole database factor" and "dose-response factor" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

 

Exposure by inhalation

Step 1: Selection of the relevant dose descriptor (starting point):

The NOAEL of 150 mg/kg bw/d, assessed in the key repeated dose oral toxicity study (OECD 408, 2016) is identified as the relevant dose descriptor and starting point.

 

Step 2: Modification into a correct starting point:

Using a conservative approach, a worker DNEL (long-term inhalation exposure) is derived. This worker DNEL is considered to ensure an appropriate level of protection with regard to acute inhalation exposure (no high peaks of exposure expected).

 

Relevant dose descriptor (NOAEL): 150 mg/kg bw/d

Standard respiratory volume of the rat (sRVrat) for 8 hours: 0.38 m³/kg bw/d

Oral absorption of the rat / inhalation absorption of humans (ABSoral-rat / ABSinh-human): 0.5

Standard respiratory volume of humans (sRVhuman) for 8 hours: 6.7 m³

Worker respiratory volume (wRV) for 8 hours with light physical activity: 10 m³

 

Corrected inhalatory NOAEC for workers

= 150 mg/kg bw/d × 0.5 × (1 / 0.38 m³/kg bw/d) × (6.7 m³/10 m³)

= 132.24 mg/m³

 

Step 3: Use of assessment factors: 25

Interspecies: no allometric scaling factor is applied because an oral-to-inhalation route extrapolation is performed.

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

Exposure duration AF (OECD408, exposure period 90 days): 2

 

In conclusion, long-term systemic inhalation DNEL, workers = 5.29 mg/m3

Dermal exposure

 

Step 1: Selection of the relevant dose descriptor (starting point):

The OECD TG 408 study (2016) is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral NOAEL, based on effects on reduced body weight and organ pathology in rats is 150 mg/kg bw/day.

 

Step 2: Modification of the starting point:

Using a conservative approach, a worker DNEL (long-term dermal exposure) is derived. The water solubility of cyclohexylidenebis[tert-butyl] peroxide is estimated to be < 1 mg/L. If the water solubility is below 1 mg/L, dermal uptake is likely to be low as partition from the stratum corneum into the epidermis is low. In addition, the log Pow value of cyclohexylidenebis[tert-butyl] peroxide is 7.2. Generally, a log Pow above 6 limit absorption across the skin and the rate of transfer between the stratum corneum and the epidermis will be slow. Uptake into the stratum corneum itself may be slow. Based on the physico-chemical properties a dermal absorption of 10 % is assumed as a worst case scenario. In conclusion, dermal NOAEL = oral NOAEL × 10 = 1500 mg/kg bw/d.

 

Step 3: Use of assessment factors: 100

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

Exposure duration AF (OECD408, exposure period 90 days): 2

 

In conclusion, long-term systemic dermal DNEL, workers = 15 mg/kg bw/day

 

References

(not included as endpoint study record)

 

- ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2. ECHA-2010 -G-19 –EN.  

- ECHA (2014). Guidance on information requirements and chemical safety assessment. Chapter R.7.C: Endpoint specific guidance: Guidance on Toxicokinetics. Nov 2014.  

- ECHA (2012) Practical Guide 15: How to undertake a qualitative human health assessment and document it in a chemical safety report, November 2012.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

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

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

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

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

General

 

General population is not intended to be exposed to cyclohexylidenebis[tert-butyl] peroxid via inhalation or dermal route. Therefore, no DNEL (long-term, inhalation and dermal exposure) is derived for general population.

Cyclohexylidenebis[tert-butyl] peroxide has a low bioaccumulation potential and a low biodegradability. However there is no identified potential to cause toxic effects if accumulated in the higher food chain. Therefore, no DNEL (long-term, oral exposure) is derived for the general population.

 

References

(not included as endpoint study record)

 

- ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2. ECHA-2010 -G-19 –EN.  

- ECHA (2017). Guidance on information requirements and chemical safety assessment. Chapter R.7.C: Endpoint specific guidance: Guidance on Toxicokinetics. Nov 2017.  

- ECHA (2012) Practical Guide 15: How to undertake a qualitative human health assessment and document it in a chemical safety report, November 2012.