Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 700-868-7 | CAS number: 54889-63-3
- 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
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:
- 0.73 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):
- 6
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 4.4 mg/m³
- Explanation for the modification of the dose descriptor starting point:
- There are no relevant experimental data on repeated exposure by inhalation. For details on calculations please refer to discussion.
- 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:
- 1
- Justification:
- Substance specific AF (please refer to "Discussion")
- AF for intraspecies differences:
- 3
- Justification:
- Substance specific AF (please refer to "Discussion")
- 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:
- 0.42 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):
- 24
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 10 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. For details on calculations please refer to discussion.
- 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:
- 1
- Justification:
- Substance specific AF (please refer to "Discussion")
- AF for intraspecies differences:
- 3
- Justification:
- Substance specific AF (please refer to "Discussion")
- 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:
- 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:
- no hazard identified
Additional information - workers
WORKER
General
DNEL derivation for the test substance is performed under consideration of the recommendations of ECHA. 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.
Substance specific assessment factor for remaining differences
Although ‘residual’ interspecies variability may remain following allometric scaling, this is largely accounted for in the assessment factors proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies assessment factors (Calabrese and Gilbert, 1993).
Furthermore, within the ERASM project, it was suggested that a factor of 2.5 for ‘remaining‘ interspecies differences may be questionable as a standard procedure (Escher and Mangelsdorf, 2009; Batkeet al, 2010; Bitsch et al, 2006). The comparison of rats and mice indicated an interspecies difference of 1.4 for these two species. This corresponds closely to an interspecies AF solely explained by allometry (7:4 = 1.75) without an additional factor of 2.5 for putative toxicodynamic differences.
Based on the availability of a sufficient toxicity dataset, the default assessment factors (acc. to ECHA GD R8) can be modified into substance specific assessment factors (AF) considering the intrinsic hazard properties of the registered substance. The following findings form the basis of the rationale for the substance specific AF:
In a subchronic gavage study in rats (acc. to OECD TG 415) adverse effects have been observed consisting of decreased foodconsumption and decreased body weight gain. No other adverse test substance-related effects on clinical examinations, clinical pathology and pathology were detected. Reproductive parameters and organs were not affected in the modified one-generation study. Slightly decreased pre-weaning pup body weights/pup weight gain were observed at the LOAEL (Lowest Observed Adverse Effect Level) of 50 mg/kg bw/day in the F1 offspring, secondary to decreased food consumption/body weight gain in the corresponding F0 parental females. Developmental effects do not occur in the absence of parental toxicity. No toxicologically relevant effects on viability, litter size or sex ratio were noted.
In the key study given above, the nature of effects observed are based on unspecific systemic adverse effects such as reduced food consumption and body weight changes. In order to add sufficient conservatism into the DNEL derivation, namely to cover for the uncertainty of an putative systemically toxic parent compound/metabolite being excreted dependent on the caloric demand, an AF of 4 for allometric scaling is included for oral/ dermal systemic long term DNELs.
No additional AFs covering toxicodynamic differences between rats and humans are considered necessary. In fact, an underestimation of interspecies differences between rats and humans beyond allometric scaling is unlikely due to the favorable toxicological profile of the registered substance.
It needs further to be pointed out, that the multiplicatory principle of different AFs used further adds to conservatism in the derivation of the respective DNELs, especially for the registered substance, which contains a toxicological profile, justifying a only a classification as skin irritant Cat 2 according to regulation (EU) 1272/2008.
Substance specific assessment factor for intraspecies extrapolation
Studies on the distribution of human data for various toxicokinetic and toxicodynamic parameters were taken into account, including ‘healthy adults’ of both sexes, young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. (Hattis 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998). Using the 95th percentile of the combined distribution of the toxicokinetic and -dynamic variability of datasets is a statistical approach to account for intraspecies variability based on toxicological datasets. On the basis of the above mentioned assessments and statistical approach, an AF of 5 for the general population and AF factor of 3 for the more homogenous worker population can be estimated to account for intraspecies variability.
It needs further to be pointed out, that the multiplicatory principle of AF used further adds to conservatism in the derivation of the respective DNELs, especially for the registered substance, which contains a toxicological profile, justifying a non-classification according to 67/548/EEC and regulation (EU) 1272/2008.
Based on the availability of a sufficient toxicity dataset, the default assessment factors (acc. to ECHA GD R8) can be modified into substance specific assessment factors (AF) considering the intrinsic hazard properties of the registered substance. The following findings form the basis of the rationale for the substance specific AF:
Based on the availability of a sufficient toxicity dataset, the default assessment factors (acc. to ECHA GD R8) can be modified into substance specific assessment factors (AF) considering the intrinsic hazard properties of the registered substance. The following findings form the basis of the rationale for the substance specific AF:
In a subchronic gavage study in rats (acc. to OECD TG 415) adverse effects have been observed consisting of decreased foodconsumption and decreased body weight gain. No other adverse test substance-related effects on clinical examinations, clinical pathology and pathology were detected. Reproductive parameters and organs were not affected in the modified one-generation study. Slightly decreased pre-weaning pup body weights/pup weight gain were observed at the LOAEL (Lowest Observed Adverse Effect Level) of 50 mg/kg bw/day in the F1 offspring, secondary to decreased food consumption/body weight gain in the corresponding F0 parental females. Developmental effects do not occur in the absence of parental toxicity. No toxicologically relevant effects on viability, litter size or sex ratio were noted.
In the key study given above, the nature of effects observed are based on unspecific systemic adverse effects such as reduced food consumption and body weight changes. No human relevant organ specific toxicity is identified for the registered substance, which would justify a conservative default assessment factor for intraspecies variations in toxicokinetics or toxicodynamics. However, an AF of 3 or 5 has been included to cover for remaining uncertainties within a controlled subpopulation, i.e. healthy workers or the general population, respectively.
Workers – Hazard via inhalation route
Long term systemic inhalation DNEL, worker
The DNEL long-term, systemic (inhalation) is derived by route-to route.
Step 1: Selection of the relevant dose descriptor (starting point):
The toxicity to reproduction study 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 is 5 mg/kg bw/day.
Step 2: Modification into a correct starting point:
Using a conservative approach, a worker DNEL (long-term inhalation exposure) is derived considering a two times higher absorption via inhalation than oral absorption.
Relevant dose descriptor (NOAEL): 5 mg/kg bw/day
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
= 5 mg/kg bw/day× 0.5 × (1 / 0.38 m³/kg bw/day) × (6.7 m³/10 m³)
= 4.4 mg/m³
Step 3: Use of assessment factors: 6
Interspecies: no allometric scaling factor is applied because an oral-to-inhalation route extrapolation is performed.
Interspecies AF, remaining differences: 1
Intraspecies AF (worker): 3
Exposure duration AF: 2
Remaining uncertainties AF: 1
In conclusion, long-term systemic inhalation DNEL, workers = 0.73 mg/m3
Short term systemic inhalation DNEL, worker
The test material is not classified and labelled for acute systemic toxicity (inhalation), according to Regulation (EC) No 1272/2008 (CLP). Thus, no DNEL is required.
Acute/longterm, local effects, inhalation worker
No data on long-term local toxicity after inhalation is available. Data on acute local toxicity after inhalation is available and showed no specific local effects. The substance is not classified for acute inhalation, therefore no adverse effects on the respiratory system are expected (in accordance with "Guidance on information requirements and chemical safety assessment", chapter R8). Thus, no DNEL local, long-term and acute (inhalation) is required. In addition DNEL for local effects does also not need to be derived as no eye irritation (leading to classification) and in conclusion no indication of local mucosal membrane damage has been identified (in accordance with "Guidance on information requirements and chemical safety assessment", chapter R8).
Workers – Hazard via dermal route
Long term systemic dermal DNEL, worker
The DNEL long-term, systemic (dermal) is derived by route-to route extrapolation.
Step 1: Selection of the relevant dose descriptor (starting point):
The toxicity to reproduction study 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 is 5 mg/kg bw/day.
Step 2: Modification of the starting point:
The logPow of the test substance was determined to be in the range of 4.0 to 4.3. Therefore the dermal uptake is considered to be 50% of the oral uptake. Dermal NOAEL= 50% oral NOAEL = 10 mg/kg bw/day
Step 3: Use of assessment factors: 24
Interspecies AF, allometric scaling (rat to human): 4
Interspecies AF, remaining differences: 1
Intraspecies AF (worker): 3
Exposure duration AF: 2
Remaining uncertainties AF: 1
In conclusion, long term systemic dermal DNEL, workers = 0.42 mg/kg bw/day
Short-term systemic dermal DNEL, worker
The test material is not classified and labelled for acute systemic toxicity (dermal), according to Regulation (EC) No 1272/2008 (CLP). Thus, no DNEL is required.
Local effects, long and short term dermal exposure, worker
The test material is classified for skin irritation toxicity cat. 2, according to Regulation (EC) No 1272/2008 (CLP). Thus, a qualitative risk assessment is conducted (in accordance with "Guidance on information requirements and chemical safety assessment", Part E).
Worker – Hazard for the eyes
The test item is not classified for eye irritation or severe eye damage according to Regulation (EC) No 1272/2008 (CLP). Thus, no qualitative risk assessment is required.
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 2.1. November 2012.
- ECHA (2014). Guidance on information requirements and chemical safety assessment.Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. November 2014.
- ECHA (2012) Practical Guide 15: How to undertake a qualitative human health assessment and document it in a chemical safety report, November 2012.
- ECHA (2016). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterisation, Version 3.0, May 2016.General Population - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.22 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):
- 10
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 2.17 mg/m³
- Explanation for the modification of the dose descriptor starting point:
- There are no relevant experimental data on repeated exposure by inhalation. For details on calculations please refer to discussion.
- 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:
- No allometric scaling factor is applied because an oral-to-inhalation route extrapolation is performed.
- AF for other interspecies differences:
- 1
- Justification:
- Substance specific AF (please refer to "Discussion")
- AF for intraspecies differences:
- 5
- Justification:
- Substance specific AF (please refer to "Discussion")
- 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
General Population - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.25 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):
- 40
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 10 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. For details on calculations please refer to discussion.
- 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:
- 1
- Justification:
- Substance specific AF (please refer to "Discussion")
- AF for intraspecies differences:
- 5
- Justification:
- Substance specific AF (please refer to "Discussion")
- 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:
- low hazard (no threshold derived)
Acute/short term exposure
- Hazard assessment conclusion:
- low hazard (no threshold derived)
General Population - Hazard via oral route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.13 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):
- 40
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 5 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
- No route to route extrapolation was used as one repeated oral exposure study was available. For details on calculations please refer to discussion.
- 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:
- 1
- Justification:
- Substance specific AF (please refer to "Discussion")
- AF for intraspecies differences:
- 5
- Justification:
- Substance specific AF (please refer to "Discussion")
- 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
General Population - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- no hazard identified
Additional information - General Population
General Population
General
DNEL derivation for the test substance is performed under consideration of the recommendations of ECHA. 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.
Substance specific assessment factor for remaining differences
Although ‘residual’ interspecies variability may remain following allometric scaling, this is largely accounted for in the assessment factors proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies assessment factors (Calabrese and Gilbert, 1993).
Furthermore, within the ERASM project, it was suggested that a factor of 2.5 for ‘remaining‘ interspecies differences may be questionable as a standard procedure (Escher and Mangelsdorf, 2009; Batkeet al, 2010; Bitsch et al, 2006). The comparison of rats and mice indicated an interspecies difference of 1.4 for these two species. This corresponds closely to an interspecies AF solely explained by allometry (7:4 = 1.75) without an additional factor of 2.5 for putative toxicodynamic differences.
Based on the availability of a sufficient toxicity dataset, the default assessment factors (acc. to ECHA GD R8) can be modified into substance specific assessment factors (AF) considering the intrinsic hazard properties of the registered substance. The following findings form the basis of the rationale for the substance specific AF:
In a subchronic gavage study in rats (acc. to OECD TG 415) adverse effects have been observed consisting of decreased foodconsumption and decreased body weight gain. No other adverse test substance-related effects on clinical examinations, clinical pathology and pathology were detected. Reproductive parameters and organs were not affected in the modified one-generation study. Slightly decreased pre-weaning pup body weights/pup weight gain were observed at the LOAEL (Lowest Observed Adverse Effect Level) of 50 mg/kg bw/day in the F1 offspring, secondary to decreased food consumption/body weight gain in the corresponding F0 parental females. Developmental effects do not occur in the absence of parental toxicity. No toxicologically relevant effects on viability, litter size or sex ratio were noted.
In the key study given above, the nature of effects observed are based on unspecific systemic adverse effects such as reduced food consumption and body weight changes. In order to add sufficient conservatism into the DNEL derivation, namely to cover for the uncertainty of an putative systemically toxic parent compound/metabolite being excreted dependent on the caloric demand, an AF of 4 for allometric scaling is included for oral/ dermal systemic long term DNELs.
No additional AFs covering toxicodynamic differences between rats and humans are considered necessary. In fact, an underestimation of interspecies differences between rats and humans beyond allometric scaling is unlikely due to the favorable toxicological profile of the registered substance.
It needs further to be pointed out, that the multiplicatory principle of different AFs used further adds to conservatism in the derivation of the respective DNELs, especially for the registered substance, which contains a toxicological profile, justifying a only a classification as skin irritant Cat 2 according to regulation (EU) 1272/2008.
Substance specific assessment factor for intraspecies extrapolation
Studies on the distribution of human data for various toxicokinetic and toxicodynamic parameters were taken into account, including ‘healthy adults’ of both sexes, young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. (Hattis 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998). Using the 95th percentile of the combined distribution of the toxicokinetic and -dynamic variability of datasets is a statistical approach to account for intraspecies variability based on toxicological datasets. On the basis of the above mentioned assessments and statistical approach, an AF of 5 for the general population and AF factor of 3 for the more homogenous worker population can be estimated to account for intraspecies variability.
It needs further to be pointed out, that the multiplicatory principle of AF used further adds to conservatism in the derivation of the respective DNELs, especially for the registered substance, which contains a toxicological profile, justifying a non-classification according to 67/548/EEC and regulation (EU) 1272/2008.
Based on the availability of a sufficient toxicity dataset, the default assessment factors (acc. to ECHA GD R8) can be modified into substance specific assessment factors (AF) considering the intrinsic hazard properties of the registered substance. The following findings form the basis of the rationale for the substance specific AF:
Based on the availability of a sufficient toxicity dataset, the default assessment factors (acc. to ECHA GD R8) can be modified into substance specific assessment factors (AF) considering the intrinsic hazard properties of the registered substance. The following findings form the basis of the rationale for the substance specific AF:
In a subchronic gavage study in rats (acc. to OECD TG 415) adverse effects have been observed consisting of decreased foodconsumption and decreased body weight gain. No other adverse test substance-related effects on clinical examinations, clinical pathology and pathology were detected. Reproductive parameters and organs were not affected in the modified one-generation study. Slightly decreased pre-weaning pup body weights/pup weight gain were observed at the LOAEL (Lowest Observed Adverse Effect Level) of 50 mg/kg bw/day in the F1 offspring, secondary to decreased food consumption/body weight gain in the corresponding F0 parental females. Developmental effects do not occur in the absence of parental toxicity. No toxicologically relevant effects on viability, litter size or sex ratio were noted.
In the key study given above, the nature of effects observed are based on unspecific systemic adverse effects such as reduced food consumption and body weight changes. No human relevant organ specific toxicity is identified for the registered substance, which would justify a conservative default assessment factor for intraspecies variations in toxicokinetics or toxicodynamics. However, an AF of 3 or 5 has been included to cover for remaining uncertainties within a controlled subpopulation, i.e. healthy workers or the general population, respectively.
General population – Hazard via inhalation route
Long term systemic inhalation DNEL, General population
The DNEL long-term, systemic (inhalation) is derived by route-to route extrapolation.
Step 1: Selection of the relevant dose descriptor (starting point):
The toxicity to reproduction study 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 is 5 mg/kg bw/day.
Step 2: Modification into a correct starting point:
Using a conservative approach, a general population DNEL (long-term inhalation exposure) is derived considering a two times higher absorption via inhalation than oral absorption.
Relevant dose descriptor (NOAEL): 5 mg/kg bw/day
Standard respiratory volume of the rat (sRVrat) for 24 hours: 1.15 m³/kg bw/d
Oral absorption of the rat / inhalation absorption of humans (ABSoral-rat / ABSinh-human): 0.5
Corrected inhalatory NOAEC for general population
= 5 mg/kg bw/day × 0.5 × (1 / 1.15 m³/kg bw/day)
= 2.17 mg/m³
Step 3: Use of assessment factors: 10
Interspecies: No allometric scaling factor is applied because an oral-to-inhalation route extrapolation is performed.
Interspecies AF, remaining differences: 1
Intraspecies AF (general population): 5
Exposure duration AF: 2
Remaining uncertainties AF: 1
In conclusion, long-term systemic inhalation DNEL, general population = 0.22 mg/m³
Short term systemic inhalation DNEL, General population
The test material is not classified and labelled for acute systemic toxicity (inhalation), according to Regulation (EC) No 1272/2008 (CLP). Thus, no DNEL is required.
Acute/longterm, local effects, General population (inhalation)
No data on long-term local toxicity after inhalation is available. Data on acute local toxicity after inhalation is available and showed no specific local effects. The substance is not classified for acute inhalation, therefore no adverse effects on the respiratory system are expected (in accordance with "Guidance on information requirements and chemical safety assessment", chapter R8). Thus, no DNEL local, long-term and acute (inhalation) is required. In addition DNEL for local effects does also not need to be derived as no eye irritation (leading to classification) and in conclusion no indication of local mucosal membrane damage has been identified (in accordance with "Guidance on information requirements and chemical safety assessment", chapter R8).
General population – Hazard via dermal route
Long term systemic dermal DNEL, General population
The DNEL long-term, systemic (dermal) is derived by route-to route extrapolation.
Step 1: Selection of the relevant dose descriptor (starting point):
The toxicity to reproduction study 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 is 5 mg/kg bw/day.
Step 2: Modification of the starting point:
The logPow of the test substance was determined to be in the range of 4.0 to 4.3. Therefore the dermal uptake is considered to be 50% of the oral uptake. Dermal NOAEL= 50% oral NOAEL = 10 mg/kg bw/day
Step 3: Use of assessment factors: 40
Interspecies AF, allometric scaling (rat to human): 4
Interspecies AF, remaining differences: 1
Intraspecies AF (general population): 5
Exposure duration AF: 2
Remaining uncertainties AF: 1
In conclusion, long term systemic dermal DNEL, general population = 0.25 mg/kg bw/day
Short-term systemic dermal DNEL, General population
The test material is not classified and labelled for acute systemic toxicity (dermal), according to Regulation (EC) No 1272/2008 (CLP). Thus, no DNEL is required.
Local effects, long and short term dermal exposure, General population
The test material is classified for skin irritation toxicity cat. 2, according to Regulation (EC) No 1272/2008 (CLP). Thus, a qualitative risk assessment is conducted (in accordance with "Guidance on information requirements and chemical safety assessment", Part E).
General population – Hazard via oral route
Long term systemic oral DNEL, General population
The DNEL long-term, systemic (oral) is derived from the toxicity to reproduction study (oral).
Step 1: Selection of the relevant dose descriptor (starting point):
The toxicity to reproduction study 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 is 5 mg/kg bw/day.
Step 2: Modification of the starting point:
No modification is used as the same exposure route is considered.
Step 3: Use of assessment factors: 40
Interspecies AF, allometric scaling (rat to human): 4
Interspecies AF, remaining differences: 1
Intraspecies AF (general population): 5
Exposure duration AF: 2
Remaining uncertainties AF: 1
In conclusion, long term systemic oral DNEL, general population = 0.13 mg/kg bw/day
Short-term systemic oral DNEL, General population
The test item is not classified for acute oral toxicity according to Regulation (EC) No 1272/2008 (CLP). Thus, no qualitative risk assessment is required.
General population – Hazard for the eyes
The test item is not classified for eye irritation or severe eye damage according to Regulation (EC) No 1272/2008 (CLP). Thus, no qualitative risk assessment is required.
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 2.1. November 2012.
- ECHA (2014). Guidance on information requirements and chemical safety assessment.Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. November 2014.
- ECHA (2012) Practical Guide 15: How to undertake a qualitative human health assessment and document it in a chemical safety report, November 2012.
- ECHA (2016). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterisation, Version 3.0, May 2016.
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.