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EC number: 412-060-9 | CAS number: 136210-32-7 DESMOPHEN VP-LS 2973 E; DESMOPHEN VP-LS 2975 E; DESMOPHEN VP-LS 2985 E
- 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:
- 84 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):
- 21
- Modified dose descriptor starting point:
- LOAEC
- Value:
- 1 763 mg/m³
- Explanation for the modification of the dose descriptor starting point:
- A factor 2 is suggested by the Guidance Document R.8 (ECHA, 2010) for the oral-to-inhalation extrapolation, but justified deviations are possible. Concerning inhalation, rats are in general more sensitive compared to humans as the rat’s ventilation frequency is higher. Also anatomical differences as well as air flow patterns between rodents and humans are to be taken into account (e.g. in case of effects at the olfactory epithelium; see Frederick et. al., 1998, Harkema, 1991). Therefore a factor 1 is chosen for adjusting route extrapolation. This provides sufficient protection, taking additionally into account that the respiratory tract’s toxicity of the substance is characterised by a low potential for upper respiratory tract irritation and no systemic toxicity at all could be observed (Pauluhn, Bayer AG, 1998a/b) and that the acute studies that were performed with oral, dermal and inhalation route of exposure did not give evidence for a route specific systemic toxicity.
- AF for dose response relationship:
- 3
- Justification:
- A LOAEL (mild effects in male rats only) is used as point of departure.
- AF for differences in duration of exposure:
- 1.4
- Justification:
- For extrapolation of exposure duration subchronic to chronic: The suggested factor 2 for extrapolation of exposure duration subchronic (90 days) to chronic was corrected for difference in number of days of exposure per week (7 days/week in animal study versus 5 days/week for workers). Thus, the total AF is 2 * 0.7 = 1.4. Actually, the exposure duration in the study that leads to the PoD for DNEL derivation was at least for female animals more than 90-days, i.e. 120 days plus mating period, that is in total up to 141 days.
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- Already covered by correction of starting point. Correction was according to Figure R.8 in the Guidance Document R.8 (ECHA, 2010): Corrected inhalatory LOAEC = oral LOAEL * 1/0.38 kg/m³ * 6.7 m³/10 m³.
- AF for other interspecies differences:
- 1
- Justification:
- A factor 2.5 is suggested by the Guidance Document R.8 (ECHA, 2010) for remaining interspecies differences, but justified deviations are possible. The substance showed no evidence of systemic availability or toxicity in an acute oral, dermal or aerosol inhalation study and even up to the limit dose of 1000 mg/kg bw/day a subacute toxicity study did not reveal adverse effects; in a two generation reproductive toxicity study mild kidney effects were seen in males only at a dose of 1000 mg/kg bw/day. The basophilic tubules and focal tubular dilation/hyaline casts are common spontaneous findings in male rats of this age but as a worst case assumption these findings were concluded to be adverse, since they correlated with statistically significantly elevated absolute and/or relative kidney weights, evident for F0 and F1 rats at 1000 mg/kg. Overall, as the male rat is highly sensitive to such kidney responses the use of a LOAEL based on such effects as a point of departure for derivation of a human DNEL is regarded to be highly conservative, therefore there is no need for an additional interspecies extrapolation factor.
- AF for intraspecies differences:
- 5
- AF for the quality of the whole database:
- 1
- Justification:
- The database has a good quality, taking into account completeness, consistency and the standard information requirements, therefore the default factor of 1 applies.
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 672 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- DNEL extrapolated from long term DNEL
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:
- 11.9 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):
- 84
- Modified dose descriptor starting point:
- LOAEL
- Value:
- 1 000 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
- Absorption oral compared to dermal assumed to be identical.
- AF for dose response relationship:
- 3
- Justification:
- A LOAEL (mild effects in male rats only) is used as point of departure
- AF for differences in duration of exposure:
- 1.4
- Justification:
- For extrapolation of exposure duration subchronic to chronic: The suggested factor 2 for extrapolation of exposure duration subchronic (90 days) to chronic was corrected for difference in number of days of exposure per week (7 days/week in animal study versus 5 days/week for workers). Thus, the total AF is 2 * 0.7 = 1.4. Actually, the exposure duration in the study that leads to the PoD for DNEL derivation was at least for female animals more than 90-days, i.e. 120 days plus mating period, that is in total up to 141 days.
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- Differences rat vs. human
- AF for other interspecies differences:
- 1
- Justification:
- A factor 2.5 is suggested by the Guidance Document R.8 (ECHA, 2010) for remaining interspecies differences, but justified deviations are possible. The substance showed no evidence of systemic availability or toxicity in an acute oral, dermal or aerosol inhalation study and even up to the limit dose of 1000 mg/kg bw/day a subacute toxicity study did not reveal adverse effects; in a two generation reproductive toxicity study mild kidney effects were seen in males only at a dose of 1000 mg/kg bw/day. The basophilic tubules and focal tubular dilation/hyaline casts are common spontaneous findings in male rats of this age but as a worst case assumption these findings were concluded to be adverse, since they correlated with statistically significantly elevated absolute and/or relative kidney weights, evident for F0 and F1 rats at 1000 mg/kg. Overall, as the male rat is highly sensitive to such kidney responses the use of a LOAEL based on such effects as a point of departure for derivation of a human DNEL is regarded to be highly conservative, therefore there is no need for an additional interspecies extrapolation factor.
- AF for intraspecies differences:
- 5
- AF for the quality of the whole database:
- 1
- Justification:
- The database has a good quality, taking into account completeness, consistency and the standard information requirements, therefore the default factor of 1 applies.
Acute/short term exposure
- Hazard assessment conclusion:
- no DNEL required: short term exposure controlled by conditions for long-term
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- medium hazard (no threshold derived)
- Most sensitive endpoint:
- sensitisation (skin)
Acute/short term exposure
- Hazard assessment conclusion:
- medium hazard (no threshold derived)
- Most sensitive endpoint:
- sensitisation (skin)
Workers - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- no hazard identified
Additional information - workers
DNEL derivation, Submission 2009, for actualization see below:
No systemic toxicity was observed after an acute oral and dermal toxicity study in rats (Bomhard, Bayer AG, 1990 and 1992a; both LD50 > 2000 mg/kg bw/day) with aspartic acid, N,N'-[methylenebis(2-methyl-4,1-cyclohexanediyl)]bis-, 1,1',4,4'-tetraethyl ester. A subacute oral toxicity study in rats (Bomhard, Bayer AG, 1992b) gave no evidence of a toxicological potential and reveals the NOAEL of 1000 mg/kg bw/day as the starting point for the delineation of the DNELlong-term, systemicfor workers.
Due to the low vapour pressure of the liquid substance an inhalation exposure via vapour is not assumed. An acute inhalation toxicity study in rats with exposure to a highly respirable aerosol (Pauluhn, Bayer AG, 1998a; LC50 (4h) >4224 mg/m³ air, NO(A)EL 1436 mg/m³ air) gave no mortality and also no evidence of a systemic toxicity.
The major signs in the acute aerosol inhalation study (Pauluhn, Bayer AG, 1998a) were only observed at the highest concentration (4224 mg/m³ air) and could be seen as a consequence of the local irritating properties of the substance. Consistent to that the test substance was described to have a low potential to elicit upper respiratory tract sensory irritation (Pauluhn, Bayer AG, 1998b; RD50:841 mg/m³ air). Furthermore, the substance was reported to be “slightly to moderately irritating to the skin" of rabbits (Maertins, Bayer AG, 1991).
The DNELlong-term, systemicfor workers for oral/dermal exposure and for inhalative exposure is derived as follows:
DNELlong-term, systemic for workers for oral/dermal exposure using default extrapolation factors1:
Oral NOAEL (rat) from a subacute toxicity study: 1000 mg/kg bw/day
Absorption oral compared to dermal assumed to be identical 1
For interspecies differences rat vs. human (allometric scaling): 4
2For remaining interspecies differences: 1
For intraspecies differences in workers: 5
3For extrapolation of exposure duration subacute to chronic: 4.2
For reliability of dose-response: 1
For quality of whole database: 1
Overall factor: 84
Worker DNELlong-term, systemicfor oral/dermal exposure: 11.9 mg/kg bw/day
DNELlong-term, systemicfor workers for inhalative exposure using default extrapolation factors1:
Oral NOAEL (rat) from a subacute toxicity study: 1000 mg/kg bw/day
Correction of the starting point according to Figure R.8 in the Guidance Document R.8 (ECHA, 2008c)
Corrected inhalatory NOAEL = oral NOAEL * 1/0.38 m³/kg * 6.7m³/10m³
Corrected inhalatory NOAEL for workers = 1763 mg/m³
4Absorption oral compared to inhalative 1
For interspecies differences rat vs. human (allometric scaling): 1 (already covered by correction of starting point)
2For remaining interspecies differences: 1
For intraspecies differences in workers: 5
3For extrapolation of exposure duration subacute to chronic: 4.2
For reliability of dose-response: 1
For quality of whole database: 1
Overall factor: 21
Worker DNELlong-term, systemicfor inhalative exposure: 84.0 mg/m³ air
1: default factors according to the Guidance Document R.8 (ECHA, 2008c)
2: A factor 2.5 is suggested by the Guidance Document R.8 (ECHA, 2008c) for remaining interspecies differences, but justified deviations are possible. The substance showed no evidence of systemic availability or toxicity in an acute oral, dermal or aerosol inhalation study and even up to the limit dose of 1000 mg/kg bw/day a subacute toxicity study did not reveal adverse effects. The DNEL derivation based on a NOAEL with no LOAEL, is already very conservative, therefore no correction for remaining interspecies differences has to be done → factor 1.
3: The suggested factor 6 for extrapolation of exposure duration subacute to chronic was corrected for difference in number of days of exposure per week (7 days/week in animal study versus 5 days/week for workers). Thus, the total AF is 6 * 0.7 = 4.2.
4: A factor 2 is suggested by the Guidance Document R.8 (ECHA, 2008c) for the oral-to-inhalation extrapolation, but justified deviations are possible. Concerning inhalation, rats are in general more sensitive compared to humans as the rat’s ventilation frequency is higher. Also anatomical differences as well as air flow patterns between rodents and humans are to be taken into account (e.g. in case of effects at the olfactory epithelium; see Frederick et. al., 1998, Harkema, 1991). Therefore a factor 1 is chosen for adjusting route extrapolation. This provides sufficient protection, taking additionally into account that the respiratory tract’s toxicity of the substance is characterised by a low potential for upper respiratory tract irritation and no systemic toxicity at all could be observed (Pauluhn, Bayer AG, 1998a/b) and that the acute studies that were performed with oral, dermal and inhalation route of exposure did not give evidence for a route specific systemic toxicity.
Due to the low sensory irritation potential of the substance (RD50: 841 mg/m³) there is no need to derive an acute DNEL for local toxicity. As there is no evidence of toxicity up to the highest dose tested in the repeated dose toxicity study it is proposed to limit exposure peaks to a factor of 8. This approach is in line with the regulatory procedure in Germany (see Technical Rule for Hazardous Substances 900, published by the German Federal Ministry of Labour and Social Affairs).
According to the potency categorisation approach, the substance is classified as a moderate skin sensitiser (category 1), based on a guinea pig maximisation test (5% intradermal concentration during induction; 85% incidence of sensitisation).
DNEL-derivation, additional remarks for submission 2012:
The justification for DNELs above was part of the data submission for aspartic acid, N,N'-[methylenebis(2 -methyl-4,1 -cyclohexanediyl)]bis-, 1,1',4,4'-tetraethyl ester according to REACH in 2009. Meanwhile, results of a two-generation reproduction toxicity study for the substance reveal a NOAEL of 200 mg/kg (Doses 0, 40, 200 and 1000 mg/kg) for general toxicity (for reproduction toxicity 1000 mg/kg) due to signs of kidney damage in F0 males and indications of changes in kidney function in F0 females and F1 rats both at 1000 mg/kg.
More detailed, in males of F0 -generation basophilic tubules were slightly increased by severity at 1000 mg/kg and minimal focal tubular dilation/casts were slightly more frequent at 1000 mg/kg.
|
0 mg/kg |
40 mg/kg |
200 mg/kg* |
1000 mg/kg |
|
Male animals without kidney findings |
3 |
- |
1 |
- |
|
Male animals with Basophilic Tubules |
Grade 1 |
18 |
18 |
18 |
6 |
Grade 2 |
4 |
6 |
5 |
16 |
|
Grade 3 |
- |
- |
- |
2 |
|
Grade 4 |
- |
1 |
- |
- |
|
Male animals with Foc. Tub. Dil./Casts |
Grade 1 |
8 |
7 |
10 |
13 |
Grade 2 |
1 |
- |
- |
3 |
*in total kidneys of 24 animals examined
Although basophilic tubules and focal tubular dilation/hyaline casts are common spontaneous findings in male rats of this age these findings were concluded to be adverse, since they correlated with statistically significantly elevated absolute and/or relative kidney weights, evident for F0 and F1 rats at 1000 mg/kg. For F0 females slightly more frequent slight non-adverse tubular change of inner renal cortex were found at 1000 mg/kg and for F1 rats kidney histopathology was inconspicuous.
Taking into account the large spacing between the NOAEC and LOAEC in the two-generation reproduction toxicity study of 5 – instead of typically a factor of 3, and the mild response at the LOAEC, which revealed adverse effects for male F0 -animals only, a DNEL based on the NOAEL of this study would overestimate the risk. By comparison starting with the LOAEC of 1000 mg/kg of this two-generation (subchronic) study and setting an extrapolation factor of 3 for reliability of dose-response would result exactly in the initial derived DNEL of 11.9 mg/kg.
Oral LOAEL (rat) from a 2 -Gen.- study: 1000 mg/kg bw/day
1Absorption oral compared to dermal assumed to be identical 1
For interspecies differences rat vs. human (allometric scaling): 4
2For remaining interspecies differences: 1
For intraspecies differences in workers: 5
3For
extrapolation of exposure duration subchronic to
chronic: 1.4
(2
* 0.7 = 1.4)
4For reliability of dose-response: 3
5For quality of whole database: 1
Overall factor: 84
Worker DNELlong-term, systemicfor oral/dermal exposure: 11.9 mg/kg bw/day
Due to the moderate skin sensitization potential the risk management measures and operational conditions set for the substance lead to avoidance of exposure, anyway.
Overall it was concluded not to deviate from the initial DNELs.
1:A factor 2 is suggested by the Guidance Document R.8 (ECHA, 2008c) for the oral-to-inhalation extrapolation, but justified deviations are possible. Concerning inhalation, rats are in general more sensitive compared to humans as the rat’s ventilation frequency is higher. Also anatomical differences as well as air flow patterns between rodents and humans are to be taken into account (e.g. in case of effects at the olfactory epithelium; see Frederick et. al., Toxicol.Appl. Pharmacol. 152, 211 -231, 1998; Harkema, Toxicol. Pathol. 19, 4, 321 -336, 1991). Therefore a factor 1 is chosen for adjusting route extrapolation. This provides sufficient protection, taking additionally into account that the respiratory tract’s toxicity of the substance is characterized by a low potential for upper respiratory tract irritation and no systemic toxicity at all could be observed (Pauluhn, Bayer AG, 1998a/b) and that the acute studies that were performed with oral, dermal and inhalation route of exposure did not give evidence for a route specific systemic toxicity.
2: A factor 2.5 is suggested by the Guidance Document R.8 (ECHA, 2008c) for remaining interspecies differences, but justified deviations are possible. The substance showed no evidence of systemic availability or toxicity in an acute oral, dermal or aerosol inhalation study and even up to the limit dose of 1000 mg/kg bw/day a subacute toxicity study did not reveal adverse effects; in a two generation reproductive toxicity study mild kidney effects were seen in males only at a dose of 1000 mg/kg bw/day. The basophilic tubules and focal tubular dilation/hyaline casts are common spontaneous findings in male rats of this age but as a worst case assumption these findings were concluded to be adverse, since they correlated with statistically significantly elevated absolute and/or relative kidney weights, evident for F0 and F1 rats at 1000 mg/kg. Overall, as the male rat is highly sensitive to such kidney responses the use of a LOAEL based on such effects as a point of departure for derivation of a human DNEL is regarded to be highly conservative, therefore there is no need for an additional interspecies extrapolation factor.
3: The suggested factor 2 for extrapolation of exposure duration subchronic (90 days) to chronic was corrected for difference in number of days of exposure per week (7 days/week in animal study versus 5 days/week for workers). Thus, the total AF is 2 * 0.7 = 1.4. Actually, the exposure duration was at least for female animals more than 90 -days, i.e.120 days plus mating period, that is in total up to 141 days.
4: A LOAEL (mild effects in male rats only) is used as point of departure.
5: The database has a good quality, taking into account completeness, consistency and the standard information requirements, therefore the default factor of 1 applies.
General Population - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 14.5 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):
- 60
- Modified dose descriptor starting point:
- LOAEC
- Value:
- 870 mg/m³
- Explanation for the modification of the dose descriptor starting point:
- A factor 2 is suggested by the Guidance Document R.8 (ECHA, 2008c) for the oral-to-inhalation extrapolation, but justified deviations are possible. Concerning inhalation, rats are in general more sensitive compared to humans as the rat’s ventilation frequency is higher. Also anatomical differences as well as air flow patterns between rodents and humans are to be taken into account (e.g. in case of effects at the olfactory epithelium; see Frederick et. al., 1998, Harkema, 1991). Therefore a factor 1 is chosen for adjusting route extrapolation. This provides sufficient protection, taking additionally into account that the respiratory tract’s toxicity of the substance is characterised by a low potential for upper respiratory tract irritation and no systemic toxicity at all could be observed (Pauluhn, Bayer AG, 1998a/b) and that the acute studies that were performed with oral, dermal and inhalation route of exposure did not give evidence for a route specific systemic toxicity.
- AF for dose response relationship:
- 3
- Justification:
- A LOAEL (mild effects in male rats only) is used as point of departure
- AF for differences in duration of exposure:
- 2
- Justification:
- For extrapolation of exposure duration subchronic to chronic.
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- Already covered by correction of starting point. Correction was according to Figure R.8 in the Guidance Document R.8 (ECHA, 2010): Corrected inhalatory LOAEC = oral LOAEL * 1/1.15 m³/kg.
- AF for other interspecies differences:
- 1
- Justification:
- A factor 2.5 is suggested by the Guidance Document R.8 (ECHA, 2010) for remaining interspecies differences, but justified deviations are possible. The substance showed no evidence of systemic availability or toxicity in an acute oral, dermal or aerosol inhalation study and even up to the limit dose of 1000 mg/kg bw/day a subacute toxicity study did not reveal adverse effects; in a two generation reproductive toxicity study mild kidney effects were seen in males only at a dose of 1000 mg/kg bw/day. The basophilic tubules and focal tubular dilation/hyaline casts are common spontaneous findings in male rats of this age but as a worst case assumption these findings were concluded to be adverse, since they correlated with statistically significantly elevated absolute and/or relative kidney weights, evident for F0 and F1 rats at 1000 mg/kg. Overall, as the male rat is highly sensitive to such kidney responses the use of a LOAEL based on such effects as a point of departure for derivation of a human DNEL is regarded to be highly conservative, therefore there is no need for an additional interspecies extrapolation factor.
- AF for intraspecies differences:
- 10
- AF for the quality of the whole database:
- 1
- Justification:
- The database has a good quality, taking into account completeness, consistency and the standard information requirements, therefore the default factor of 1 applies.
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 14.5 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
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:
- 4.2 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:
- LOAEL
- Value:
- 1 000 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
- Absorption oral compared to dermal assumed to be identical
- AF for dose response relationship:
- 3
- Justification:
- A LOAEL (mild effects in male rats only) is used as point of departure.
- AF for differences in duration of exposure:
- 2
- Justification:
- A LOAEL (mild effects in male rats only) is used as point of departure.
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- Differences rat vs. human
- AF for other interspecies differences:
- 1
- Justification:
- A factor 2.5 is suggested by the Guidance Document R.8 (ECHA, 2010) for remaining interspecies differences, but justified deviations are possible. The substance showed no evidence of systemic availability or toxicity in an acute oral, dermal or aerosol inhalation study and even up to the limit dose of 1000 mg/kg bw/day a subacute toxicity study did not reveal adverse effects; in a two generation reproductive toxicity study mild kidney effects were seen in males only at a dose of 1000 mg/kg bw/day. The basophilic tubules and focal tubular dilation/hyaline casts are common spontaneous findings in male rats of this age but as a worst case assumption these findings were concluded to be adverse, since they correlated with statistically significantly elevated absolute and/or relative kidney weights, evident for F0 and F1 rats at 1000 mg/kg. Overall, as the male rat is highly sensitive to such kidney responses the use of a LOAEL based on such effects as a point of departure for derivation of a human DNEL is regarded to be highly conservative, therefore there is no need for an additional interspecies extrapolation factor.
- AF for intraspecies differences:
- 10
- AF for the quality of the whole database:
- 1
- Justification:
- The database has a good quality, taking into account completeness, consistency and the standard information requirements, therefore the default factor of 1 applies.
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 4.2 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
Local effects
Long term exposure
- Hazard assessment conclusion:
- medium hazard (no threshold derived)
- Most sensitive endpoint:
- sensitisation (skin)
Acute/short term exposure
- Hazard assessment conclusion:
- medium hazard (no threshold derived)
- Most sensitive endpoint:
- sensitisation (skin)
General Population - Hazard via oral route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 4.2 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:
- LOAEL
- Value:
- 1 000 mg/kg bw/day
- AF for dose response relationship:
- 3
- Justification:
- A LOAEL (mild effects in male rats only) is used as point of departure.
- AF for differences in duration of exposure:
- 2
- Justification:
- For extrapolation of exposure duration subchronic to chronic.
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- Differences rat vs. human
- AF for other interspecies differences:
- 1
- Justification:
- A factor 2.5 is suggested by the Guidance Document R.8 (ECHA, 2010) for remaining interspecies differences, but justified deviations are possible. The substance showed no evidence of systemic availability or toxicity in an acute oral, dermal or aerosol inhalation study and even up to the limit dose of 1000 mg/kg bw/day a subacute toxicity study did not reveal adverse effects; in a two generation reproductive toxicity study mild kidney effects were seen in males only at a dose of 1000 mg/kg bw/day. The basophilic tubules and focal tubular dilation/hyaline casts are common spontaneous findings in male rats of this age but as a worst case assumption these findings were concluded to be adverse, since they correlated with statistically significantly elevated absolute and/or relative kidney weights, evident for F0 and F1 rats at 1000 mg/kg. Overall, as the male rat is highly sensitive to such kidney responses the use of a LOAEL based on such effects as a point of departure for derivation of a human DNEL is regarded to be highly conservative, therefore there is no need for an additional interspecies extrapolation factor.
- AF for intraspecies differences:
- 10
- AF for the quality of the whole database:
- 1
- Justification:
- The database has a good quality, taking into account completeness, consistency and the standard information requirements, therefore the default factor of 1 applies.
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 4.2 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
General Population - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- no hazard identified
Additional information - General Population
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