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Diss Factsheets
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EC number: 218-760-9 | CAS number: 2226-96-2
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
![](https://poisoncentres.echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Toxicological Summary
- Administrative data
- Workers - Hazard via inhalation route
- Workers - Hazard via dermal route
- Workers - Hazard for the eyes
- Additional information - workers
- General Population - Hazard via inhalation route
- General Population - Hazard via dermal route
- General Population - Hazard via oral route
- General Population - Hazard for the eyes
- Additional information - General Population
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.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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