Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.08 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
12
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10.37 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
Overall assessment factor (AF):
3

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.69 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance document and substance specific information as allowed in the Guidance
Overall assessment factor (AF):
3
Dose descriptor:
NOAEC
AF for differences in duration of exposure:
1
Justification:
Effects observed at 28 days were the same at 90 days of exposure. There was no progression of lesions, therefore duration of exposure is likely not important for this substance, but rather the peak concentration acheived
AF for interspecies differences (allometric scaling):
1
Justification:
Inhalation study - allometric scaling is not required
AF for other interspecies differences:
1
Justification:
Rats exhibit greater nasal remodelling than humans, so the effects observed are more severe in a rodent model than are to be expected in humans, therefore no additional interspecies assessment is required
AF for intraspecies differences:
3
Justification:
A value of 3 as proposed by the ECETOC in report TR-86 and TR-110 has been adopted. This value is believed protective based on the likely underlying mechanism of irritation as the inititiating event which likely has little intraspecies variability since the effect acts at via simple destruction of the membrane barrier. Therefore the substance specific information supports deviation from the value suggested in the guidance document.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
21.34 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Overall assessment factor (AF):
3
Dose descriptor starting point:
NOAEC

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
12.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
48
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no data available: testing technically not feasible
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no data available: testing technically not feasible
Acute/short term exposure
Hazard assessment conclusion:
no data available: testing technically not feasible

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

Introductory comment:

The assessment factors used to develop DNELs for Workers were based on those of ECETOC (Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86, pp 86, ECETOC, Brussels, February 2003).

Acute / short-term exposure: systemic effects

A DNEL for acute toxicity should be derived if an acute hazard leading to acute toxicity (e.g. C&L) has been identified and there is a potential for high peak exposures. These “peaks” are normally associated with inhalation exposure but are less common for skin contact (REACH TGD Appendix R.8-8). An acute DNEL was therefore derived only for the inhalation route, based on the acute LC50 for TBHP, modified according to Haber’s Law and converted to an NOAEC by application of 100-fold modification factor.

Acute / short-term exposure: local effects

Results of irritation testing indicate that TBHP is corrosive to skin and eye however no dose/response information is available and no DNEL can be derived. In contrast, results from a rat sub-acute inhalation study demonstrated changes in nasal epithelial histopathology and cell proliferation and, after adaptation through the application of Haber’s Law, were used to derive an acute local DNEL. While the possibly of cumulative effects (potentially leading to an over-estimate of potency) cannot be excluded, use of this information from this sub-acute study is considered acceptable for the purposes of deriving a DNEL for acute respiratory irritation.

Long-term exposure: systemic effects

Information from an OECD 422 Combined Repeated Dose and Reproductive/Developmental Toxicity Screening Test on TBHP performed using oral gavage treatment was used to develop a systemic DNEL for dermal and inhalation exposure using route-to-route extrapolation. It is noted that this is likely to lead to a highly conservative outcome given the very rapid conversion of TBHP to TBA in the body, effectively limiting systemic exposure to the parent substance.

Long-term exposure: local effects

Results from a rat 28-day inhalation study, showing microscopic changes to rat nasal epithelium following inhalation exposure to TBHP vapour, were used to develop a local DNEL for repeated inhalation exposure; modification of the dose descriptor using Haber's law is not appropriate in this instance (REACH TGD, Chaper 8, page 25, Ad 3). Results of skin irritation testing indicate that TBHP is corrosive however no dose/response information is available and hence no DNEL for repeated local toxicity can be derived for dermal contact.

Derived No Effect Level for Mutagenicity

It is not possible to develop a develop a DNEL for Mutagenicity as it is not possible to identify a threshold from which to begin the DNEL Assessment. From Part E Risk Characterisation E.3.4.2 it states that for in vivo mutagens with no relevant dose-response information and no cancer data , neither a DMEL nor a DNEL can be derived. Indeed for TBHP, no relevant dose-response information is available, therfore no DNEL has been calculated.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.91 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
20
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.22 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
Overall assessment factor (AF):
5

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.75 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
30
Dose descriptor:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
12.81 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Overall assessment factor (AF):
5
Dose descriptor starting point:
NOAEC

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
80
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no data available: testing technically not feasible
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no data available: testing technically not feasible
Acute/short term exposure
Hazard assessment conclusion:
no data available: testing technically not feasible

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.26 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
80
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - General Population

Introductory comment:

The assessment factors used to develop DNELs for the General Population were based on those of ECETOC (Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86, pp 86, ECETOC, Brussels, February 2003).

It should also be noted that according to the EU RAR, no unreacted TBHP remains in consumer products. Thus, absent such exposures, these values have been developed solely “for the record”.

Acute / short-term exposure: systemic effects

A DNEL for acute toxicity should be derived if an acute hazard leading to acute toxicity (e.g. C&L) has been identified and there is a potential for high peak exposures. These “peaks” are normally associated with inhalation exposure but are less common for skin contact and ingestion (REACH TGD Appendix R.8-8). An acute DNEL was therefore derived only for the inhalation route, based on the acute LC50 for TBHP, modified according to Haber’s Law and converted to an NOAEC by application of 100-fold modification factor.

Acute / short-term exposure: local effects

Results of irritation testing indicate that TBHP is corrosive to skin and eye however no dose/response information is available and no DNEL can be derived. In contrast, results from a rat sub-acute inhalation study demonstrated changes in nasal epithelial histopathology and cell proliferation and, after adaptation through the application of Haber’s Law, were used to derive an acute local DNEL. While the possibly of cumulative effects (potentially leading to an over-estimate of potency) cannot be excluded, use of this information from this sub-acute study is considered acceptable for the purposes of deriving a DNEL for acute respiratory irritation.

Long-term exposure: systemic effects

Information from an OECD 422 Combined Repeated Dose and Reproductive/Developmental Toxicity Screening Test on TBHP performed using oral gavage treatment was used to develop a systemic DNEL for oral exposure, and for dermal and inhalation exposure following route-to-route extrapolation. It is noted that this is likely to lead to a conservative outcome given the very rapid conversion of TBHP to TBA in the body, effectively limiting systemic exposure to the parent substance.

Long-term exposure: local effects

Results from a rat 90-day inhalation study, showing microscopic changes to rat nasal epithelium following inhalation exposure to TBHP vapour, were used to develop a local DNEL for repeated inhalation exposure; modification of the dose descriptor using Haber's law is not appropriate in this instance (REACH TDG, Chapter 8, page 25, Ad 3). Results of skin irritation testing indicate that TBHP is corrosive however no dose/response information is available and hence no DNEL for repeated local toxicity can be derived for dermal contact. No information is available for repeated local toxicity following oral exposure.

Derived No Effect Level for Mutagenicity

It is not possible to develop a develop a DNEL for Mutagenicity as it is not possible to identify a threshold from which to begin the DNEL Assessment. From Part E Risk Characterisation E.3.4.2 it states that for in vivo mutagens with no relevant dose-response information and no cancer data , neither a DMEL nor a DNEL can be derived. Indeed for TBHP, no relevant dose-response information is available, therfore no DNEL has been calculated.