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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.2 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):
30
Modified dose descriptor starting point:
NOAEC
Value:
35.3 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.
AF for differences in duration of exposure:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (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:
1
Justification:
There is no evidence for species differences in the general mode of action or kinetics as outlined in the Discussion.
AF for intraspecies differences:
5
Justification:
The default value for the relatively homogenous group "Workers" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole database 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. Please refer to the Discussion.
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:
0.3 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):
120
Modified dose descriptor starting point:
NOAEL
Value:
40 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated dermal exposure. A conservative approach is used assuming identical dermal and oral absorption values even though a low dermal absorption value can be expected based on the physico-chemical properties of 4-OH-TEMPO.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable.
AF for differences in duration of exposure:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point)
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for differences between rats and humans is used.
AF for other interspecies differences:
1
Justification:
There is no evidence for species differences in the general mode of action or kinetics as outlined in the discussion.
AF for intraspecies differences:
5
Justification:
The default value for the relatively homogenous group "Workers" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole database is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factor is required. Please refer to the Discussion.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
60
Modified dose descriptor starting point:
LOAEL
Value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on acute or short term dermal exposure. A conservative approach is used assuming identical dermal and oral absorption values even though a low dermal absorption value can be expected based on the physico-chemical properties of 4-OH-TEMPO.
AF for dose response relationship:
3
Justification:
This assessment factor is used for LOAEL to NAEL ("true" no adverse effect level) extrapolation.
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for differences between rats and humans is used.
AF for other interspecies differences:
1
Justification:
There is no evidence for species differences in the general mode of action or kinetics.
AF for intraspecies differences:
5
Justification:
The default value for the relatively homogenous group "Workers" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole database is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factor is required.

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

General

 

DNEL derivation for the substance 4-Hydroxy TEMPO is performed under consideration of the recommendations of ECHA (2010). In view of the data used for evaluation, the "quality of whole database factors" and "dose-response factors" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

 

 

Acute/short-term exposure - systemic effects

 

Based on the acute oral LD50of 1053 mg/kg bw (both sexes combined; CIBA-GEIGY Ltd., 1983; TK11725/2) established in rats for 4-Hydroxy TEMPO , the substance is considered to be harmful if swallowed and to be subject to classification according to Regulation (EC) No 1272/2008. In view of this acute toxicity hazard, a worker DNEL (acute/short-term dermal exposure) is derived to account for potential peak exposures to 4-Hydroxy TEMPO ,i.e.exposures exceeding the respective long-term DNEL.

 

Dermal exposure: In the acute oral toxicity study, the LOAEL was 500 mg/kg bw based on clinical signs (dyspnoea, exophthalmus, ruffled fur, curved body position) noted at this dose level shortly after test item administration until days 5-8 post exposure. Assuming identical values for oral and dermal absorption (worst case), this LOAEL is considered to represent the appropriate dose descriptor and starting point for derivation of the worker DNEL (acute/short-term dermal exposure). The default factor of 2.5 for remaining interspecies differences (rat-to-human) after consideration of allometric scaling is not applied, because there is no evidence for species differences in the general mode of action or kinetics. For both rats and humans, 4-Hydroxy TEMPO metabolism is most likely based on the rapid formation of hydroxylamine metabolites. Its low half life, which is based on the presumed rapid metabolic degradation and subsequent quick urinary excretion, indicates a generally low potential for bioaccumulation, which provides further support for similar kinetics and toxicodynamics (target organs) in rats and humans (please refer to section 7.1.1). Moreover, ECETOC (2010) considers that routine application of the factor 2.5 is unjustified as a default factor since there is evidence that association between intra- and interspecies assessment factors is conservative and that the inclusion of a remaining difference factor is unnecessary.

 

Relevant dose descriptor (LOAEL): 500 mg/kg bw

Modification of the starting point factor: 1

Assessment factor for LOAEL-NAEL extrapolation: 3

Exposure duration factor (no time extrapolation required): 1

Allometric scaling factor (rat-to-human): 4

Remaining interspecies differences (rat-to-human): 1

Assessment factor for intraspecies differences (worker): 5

 

Worker DNEL (acute/short-term dermal exposure)

= 500 mg/kg bw × 1 / (3 × 1 × 4 × 1 × 5)

= 8.3 mg/kg bw, rounded to 8 mg/kg bw

 

Inhalation exposure: No specific DNEL for systemic acute/short-term worker exposure via inhalative route is derived, since no high peaks of exposure are expected based on both the low volatility and the use pattern of 4 -OH-TEMPO. Thus, the DNEL dervived for systemic long-term worker exposure via inhalative route is considered sufficiently protective.

 

 

Acute/short-term and long-term exposure - local effects and sensitisation

 

Skin irritation/corrosion: The substance 4-Hydroxy TEMPO is not a skin irritant based on the key study results (Hüls AG, 1995; AH/95-0151),i.e.displays negligible potency for skin irritation. No DNEL for this local effect has to be established.

 

Eye irritation: Based on the key study results (Hüls AG, 1995; AA-95/0151), 4-Hydroxy TEMPO is subject to classification for eye irritancy with H318 “Causes serious eye damage” according to Regulation (EC) No 1272/2008. A quantitative assessment of eye irritation is not possible since only qualitative data are available. The potency of 4-Hydroxy TEMPO for induction of eye irritation is considered to be high with regard to the qualitative dataset.

 

Respiratory irritation: There are no data available.

 

Skin sensitisation: The substance 4-Hydroxy TEMPO is not considered to be a skin sensitiser according to key study results (Hüls AG, 1995; HS-95/0151) and thus no DNEL for a possible skin sensitising potential is derived. Qualitatively, there is no or negligible skin sensitising potency.

 

Respiratory sensitisation: There are no data available.

 

 

Long-term exposure – systemic effects

 

In the key repeated dose oral toxicity study in rats (Exxon Chem Co., 1992; 92-0574-FGT), liver and spleen were identified as target organs of repeated exposure to 4-Hydroxy TEMPO . The NOAEL was established at 40 mg/kg bw/d. On the basis of the results obtained, the test item 4-Hydroxy TEMPO is not considered to be subject to classification according to Regulation (EC) No 1272/2008.

 

Dermal exposure: In order to derive the worker DNEL (long-term dermal exposure), the NOAEL assessed in the key repeated dose oral toxicity study is identified as the relevant dose descriptor. Assuming identical values for oral and dermal absorption (worst case) and considering the appropriate modification and assessment factors, the worker DNEL (long-term dermal exposure) is calculated as follows:

 

Relevant dose descriptor (NOAEL): 40 mg/kg bw

Modification of the starting point factor: 1

Exposure duration factor (subacute-to-chronic): 6

Allometric scaling factor (rat-to-human): 4

Remaining interspecies differences (rat-to-human): 1

Assessment factor for intraspecies differences (worker): 5

 

Worker DNEL (long-term dermal exposure)

= 40 mg/kg bw/d × 1 / (6 × 4 × 1 × 5)

= 0.3 mg/kg bw/d

 

Inhalation exposure: 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). The NOAEL assessed in the key repeated dose oral toxicity study is identified as the relevant dose descriptor and starting point.

 

- Modification of the starting point

Relevant dose descriptor (NOAEL): 40 mg/kg bw

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

= 40 mg/kg bw/d × (1 / 0.38 m³/kg bw/d) × 0.5 × (6.7 m³/10 m³)

= 35.3 mg/m³

 

- Calculation of the worker DNEL

Corrected inhalatory NOAEC for workers: 35.3 mg/m³

Assessment factor for intraspecies differences: 5

Exposure duration factor (subacute-to-chronic): 6

 

Worker DNEL (long-term inhalation exposure)

= 35.3 mg/m³ / 5 × 6

= 1.18 mg/m³, rounded to 1.2 mg/m³

 

 

 

 

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.

 

- ECETOC (2010). Technical Report 110. Guidance on assessment factors to derive a DNEL.

 

 

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:
DNEL (Derived No Effect Level)
Value:
0.2 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):
240
Modified dose descriptor starting point:
NOAEL
Value:
40 mg/kg bw/day
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable.
AF for differences in duration of exposure:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for differences between rats and humans is used.
AF for other interspecies differences:
1
Justification:
There is no evidence for species differences in the general mode of action or kinetics.
AF for intraspecies differences:
10
Justification:
The default value for the relatively inhomogenous group "General Population" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole database is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factor is required. Please refer to the Discussion.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

General

 

There are only industrial uses for 4 -OH-TEMPO. This chemical substance is neither marketed to the general public nor intentionally added to consumer products. Also, consumer products do not contain substances from which 4 -OH-TEMPO is intended to be released. Thus, DNEL derivation is not required for effects induced by systemic exposure occurring via the inhalation and dermal route and is also not required for local effects. However; in order to enable quantitative risk assessment related to potential exposure of the general population via secondary poisoning, a general population DNEL (long-term oral exposure) is derived.

Long-term exposure – systemic effects

 

In the key repeated dose oral toxicity study in rats (Exxon Chem Co., 1992; 92-0574-FGT), liver and spleen were identified as target organs of repeated exposure to 4 -OH-TEMPO. The NOAEL was established at 40 mg/kg bw/d. On the basis of the results obtained, the test item 4-OH-TEMPO is not considered to be subject to classification according to Regulation (EC) No 1272/2008.

 

Oral exposure: For the derivation of the general population DNEL (long-term oral exposure), the NOAEL assessed in the key repeated dose oral toxicity study is identified as the relevant dose descriptor. Considering the appropriate modification and assessment factors, the worker DNEL (long-term oral exposure) is calculated as follows:

Relevant dose descriptor (NOAEL): 40 mg/kg bw

Modification of the starting point factor: 1

Exposure duration factor (subacute-to-chronic): 6

Allometric scaling factor (rat-to-human): 4

Remaining interspecies differences (rat-to-human): 1

Assessment factor for intraspecies differences (general population): 10

 

General population DNEL (long-term oral exposure)

= 40 mg/kg bw/d × 1 / (6 × 4 × 1 × 10)

= 0.17 mg/kg bw/d, rounded to 0.2 mg/kg bw/d

  

 

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.

 

- ECETOC (2010). Technical Report 110. Guidance on assessment factors to derive a DNEL.