Di-tert-butyl 1,1,4,4-tetramethylbut-2-yn-1,4-ylene diperoxide

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

10.58 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:

264.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation. Corrected inhalation NOAEC from oral NOAEL of 150 mg/kg/day. Assume ABSoral-rat/ABSinh-human is equal (1) = 150 mg/kg bw/day x (1/0.38 m³/kg bw/day) x (1.0) x (6.7 m³/10 m³) = 264.5 mg/m³ inhalation dose.

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:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

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

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 exposure by dermal route. Corrected dermal NOAEC from oral NOAEL of 150 mg/kg/day, assuming 10 % dermal absorption as compared with oral absorption.

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:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

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

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

General 

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA (2010). 
 
Workers – Hazard via inhalation route
Long term, systemic inhalation DNEL
Occupational exposure to the test substance 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. 

 

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

For risk characterisation an inhalation NOAEC was derived by route to route extrapolation. The oral NOAEL of 150 mg/kg bw/day, obtained from subacute toxicity testing in rats (Akzo Nobel 2014), was considered as key value for the chemical safety assessment and therefore, most relevant starting point. 

 

Step 2: Modification into a correct starting point:
In a first step the oral NOAEL was transferred to humans with a factor of 4 for allometric scaling from rats. For worker a NOEC long-term, inhalation was calculated assuming 70 kg per person, 8h light activity (10 m³ breathing volume), 100 % absorption via oral routes and 100 % absorption via inhalatory routes.
 
NOEC (Worker)inhalation = 150 mg/kg bw/day * 1/0.38 kg * 6.7 m³/10 m³ * 100% Abs (oral) / 100% abs (inhal)
                                                = 264.5 mg/m³
 
Step 3: Use of assessment factors: 25
Interspecies: Respiratory interspecies differences are fully covered by the modification of the NOAEC
Interspecies AF, remaining differences: 2.5
Intraspecies AF (worker): 5
Exposure duration AF: 2
 
DNEL (Worker)inhalation = 264.5 mg/m³ / 25
                  = 10.58 mg/m³
 
In conclusion, long term systemic inhalation DNEL, workers = 10.58 mg/m³ 
 
Acute, systemic inhalation DNEL
The test substance is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral, dermal and inhalation toxicity.
 
Local effects
No data on respiratory irritation is available. As the substance is not classified as skin and eye irritating also no adverse effects on respiratory system is expected (in accordance with "Guidance on information requirements and chemical safety assessments, chapter R8"). Thus, DNEL, and no qualitative assessment is required.


Workers - Hazard via dermal route
Long term, systemic dermal DNEL
Step 1: Selection of the relevant dose descriptor (starting point)
For risk characterisation an inhalation NOAEC was derived by route to route extrapolation. The oral NOAEL of 150 mg/kg bw/day, obtained from subacute toxicity testing in rats (Akzo Nobel 2014), was considered as key value for the chemical safety assessment and therefore, most relevant starting point.
 
Step 2: Modification into a correct starting point:
Correction for dermal absorption rates (based on Guidance on information requirements and chemical safety assessment, Chapter R 7.12): 10 % dermal absorption is assumed based on molecular weight of 290.4, a log Pow of 7.34, water solubility of 131 µg/L and calculated vapor pressure of 0.00951 mm Hg (1.268 Pa) at 25 °C. Dermal absorption is unlikely due to the low water solubility and high partition coefficient.
 
NOAEC (Worker)dermal = 150 mg/kg bw/day / 0.1
                                             = 1500 mg/kg bw/day
 
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: 2  
 
DNEL (Worker)dermal = 1500 mg/kg bw /day/100
                                          = 15 mg/kg bw/day
                        
In conclusion, long term systemic dermal DNEL, workers = 15 mg/kg bw/day

Acute/short-term dermal DNEL
The test substance is not classified and labelled for acute dermal toxicity, according to Regulation (EC) No 1272/2008 (CLP). Thus, in accordance with "Guidance on information requirements and chemical safety assessment chapter R8: Characterisation of dose (concentration)-response for human health", no DNEL is required.
 
Worker - Hazard for the eyes
According to the EU (GHS) criteria for classification and labelling requirements for dangerous substances and preparations the test item does not have to be classified and has no obligatory requirements for eye irritation.
 
References  (not included as endpoint study record):  
- ECHA (2010). 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 (2010). Guidance on information requirements and chemical safety assessment. Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. May 2008  
- 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 di-tert-butyl 1,1,4,4-tetramethylbut-2-yn-1,4-ylene diperoxide (DYBP) via inhalation or dermal route. Therefore, no DNEL (long-term, inhalation and dermal exposure) is derived for general population. As DYBP has no bioaccumulation potential no risk assessment for secondary poisoning is required for the general population.

 

 References

(not included as endpoint study record)

 

- ECHA (2010) 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 (2011) Guidance on information requirements and chemical safety assessment. Part B: Hazard assessment. Version 2