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EC number: 244-007-9 | CAS number: 20749-68-2
- 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
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:
- 97.95 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):
- 18
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 1 763.15 mg/m³
- Explanation for the modification of the dose descriptor starting point:
- There are no quantitative data on absorption rates for oral or inhalation route available. From the data generated in the sub-acute oral study it can be concluded that absorption via oral is low, as the substance is nearly unsoluble in water (below the detection limit of 0.00003 g/l). The absorption via inhalation route might be comparable low. Consequently, there is no need to introduce further default value for the extrapolation from oral route to inhalation route. Corrected inhalatory NOAEC= oral NOAEL(1000 mg/kg bw/day) x 1/0.38 x 6.7/10 X 1 Corrected NOAEC (worker) = 1763.15 mg/m³
- AF for dose response relationship:
- 1
- Justification:
- There are no effects up to the limit dose
- AF for differences in duration of exposure:
- 6
- Justification:
- subacute to chronic exposure
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- Allometric scaling rat versus human: the AF of 4 is already included in the route to route extrapolation
- AF for other interspecies differences:
- 1
- Justification:
- The rats tolerated the dosing up to and including the limit dose of 1000 mg/kg bw/day, Consequently it is considered to be a conservative starting point for DNEL calculation and the real NOAEL in rats is probably much higher. In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor 2.5 is scientifically unjustified as a defaut factor. This view is supported by ERASM project (Barke et al 2010)
- AF for intraspecies differences:
- 3
- Justification:
- Based on the considerations by ECETOC Report TR 110 2010. Oral treatment with up to 1000 mg/kg bw/day for a period of 4 weeks as well as short term inhalation exposure against the highest technical attainable concentration of 2868 mg/m³ for 4 hours was tolerated by rats without mortalitity or any impairment. In addition, taking into account that the test item is a solid with a molecular weight of 408, melting point of >300 °C, log Pow >7 and water solubility below the detection limit, this indicates that hazard for worker from exposure against Macrolex Rot EG might be unlikely. Consequently the default factor will be lowered taking into account compound specific data
- AF for the quality of the whole database:
- 1
- Justification:
- There is information available to cover all relevant toxicological endpoints. The available studies are at most performed according to guideline and GLP. No adverse effects were observed in a guideline sub-acute toxicity study indicating that Macrolex Rot EG has a low toxicological potential and the starting point for the DNEL derivation is conservative
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 97.95 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:
- 13.89 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):
- 72
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 1 000 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
- There is no long term study available using dermal application as exposure route. Therefore the available subacute oral toxicity study in rats has to be considered and the respective NOAEL of 1000 mg/kg bw has to be used as starting point for DNEL calculation. As it can be assumed that dermal absorption would not be higher than the oral absorption ECHA proposed in the Guidance Document R8 not to introduce an additional default factor for the extrapolation from oral to dermal exposure route. NOAEL (oral, rat, subacute) = NOAEL (dermal, rat, subacute) = 1000 mg/kg bw/day
- AF for dose response relationship:
- 1
- Justification:
- There is no effect up to the limit dose
- AF for differences in duration of exposure:
- 6
- Justification:
- Subacute to chronic exposure
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- Allometric scaling: rat versus human
- AF for other interspecies differences:
- 1
- Justification:
- The rats tolerated the dosing up to and including the limit dose of 1000 mg/kg bw/day. Consequently it is considered to be a conservative starting point for DNEL calculation and the real NOAEL in rats is probably much higher. In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor 2.5 as a default factor is scientifically unjustified. This view is supported by ERASM project (Barke et al 2010).
- AF for intraspecies differences:
- 3
- Justification:
- Based on the considerations by ECETOC Report TR 110 2010. Oral treatment with up to 1000 mg/kg bw/day for a period of 4 weeks was tolerated by rats without mortalitity or any impairment. In addition, taking into account that the test item is a solid with a molecular weight of 408, melting point of >300 °C, log Pow >7 and water solubility below the detection limit, this indicates that hazard for worker from exposure against Macrolex Rot EG might be low. Consequently the default factor will be lowered taking into account compound specific data
- AF for the quality of the whole database:
- 1
- Justification:
- There is information available to cover all relevant toxicological endpoints. The available studies are at most performed according to guideline and GLP. No adverse effects were observed in a guideline sub-acute toxicity study indicating that Macrolex Rot EG has a low toxicological potential and the starting point for the DNEL derivation is conservative.
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 13.89 mg/kg bw/day
- 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
Workers - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- no hazard identified
Additional information - workers
Macrolex Rot EG
CAS-Nr. 20749-68-2
DNEL- Derivation: Worker
I. Introduction
The substance is not classified legally. There is no German or European OEL available which can be used as starting point for the DNEL derivation.
II. Derivation of Worker-DNEL (systemic)
Basis for DNEL Derivation
Macrolex Rot EG was administered by gavage to 5 male and 5 female Wistar rats per dose group indayily doses of 0, 100, 300, 1000 mg/kg bw/day suspended in polyethylene glycol 400 (vehicle) for a period of 28 days. The study was conducted in compliance with OECD TG 407 under GLP conditions.
Survival was not affected by treatment with Macrolex Rot EG and no clinical signs were observed. The observed decreased alkaline phosphatase in females was not considered relevant because neither all other clinical chemistry data nor hematology gave evidence for treatment related effects up to 1000 mg/kg bw. Starting at the mid dose of 300 mg/kg bw,. all animals of both sexes showed changes in feces color (reddish particles), which is a consequence of the strong red color of the test item and thus is not considered as adverse effect. Histopathology revealed minimally to slightly reduced secretion in the seminal vesicles in 3 out of 5 males at 1000 mg/kg bw which was not associated with degeneration of seminal vesicles. Changes in other male genital organs (testes, epididymides, prostate or coagulation glands) could not be found up to and including 1000 mg/kg bw.. Therefore, reduced secretion is regarded as unspecific and possibly stress-related. An adverse effect is not assumed. Female reproductive organs were not affected up to 1000 mg/kg bw/day.
In conclusion, under the conditions described above, the no-adverse-effect-level (NOAEL) for male and female rats after 4 -week daily oral treatment by gavage with Macrolex Rot EG is 1000 mg/kg bw/day.
In an OECD 414 study, one group of 20 females received Macrolex Rot EG at a dose of 1000 mg/kg/day by oral gavage administration, from Day 6 to 19 after mating. A similarly constituted control group received the vehicle, polyethylene glycol 400 (PEG 400) at the same volume dose as the treated group. Animals were killed on Day 20 after mating for reproductive assessment and fetal examination.
Clinical observations, body weight and food consumption were recorded. Adult females were examined macroscopically at necropsy on Day 20 after mating and the gravid uterine weight recorded and all fetuses were examined macroscopically at necropsy and subsequently by detailed internal visceral examination or skeletal examination.
Based on the results of this study, it is concluded that in the absence of any evidence for general systemic toxicity or adverse effects on embryo-fetal survival, growth and development, that the no (NOAEL) observed adverse effect level was 1000 mg/kg/day (highest dose tested).
Therefore, the calculation of a separate DNEL for toxicity to reproduction is not necessary, because the NOAEL of the repeated dose subacute toxicity study and the NOAEL of the OECD TG 414 study is identical.
1.) DNEL long-term, inhalation route –Systemic effects
NOAEL (rat) from a sub-acute oral toxicity study 1000 mg/kg bw/day
Correction of the starting point according to ECHA Guidance Chapter R8
There are no quantitative data on absorption rates for oral or inhalation route available. From the data generated in the sub-acute oral study it can be concluded that absorption via oral is low, as the substance is nearly unsoluble in water (below the detection limit of 0.00003 g/l). The absorption via inhalation route might be comparable low. Consequently, there is no need to introduce further default value for the extrapolation from oral route to inhalation route.
Corrected inhalatory NOAEC= oral NOAEL(1000 mg/kg bw/day) x 1/0.38 x 6.7/10 X 1
Corrected NOAEC (worker) = 1763.15 mg/m³
Overall factor 18
Worker DNEL (long term, systemic for inhalation route) 97.95 mg/m³
2.) DNEL short-term, inhalation route –Systemic effects
There is a reliable study available in which is performed according to OECD TG 403 under GLP conditions. Rats were exposed to the maximum technically attainable concentration of 2868 mg/m³ for 4 hours. No animal died and the exposure was tolerated without any pathodiagnostic effects suggestive of portal of entry or systemic toxicity. Thus, no hazard was identified in this animal experiment. Therefore, it is proposed not to define a special DNEL (short term for inhalation route but to take the DNEL (long term, systemic for inhalation route as surrogate.
Thus, Worker DNEL (long term and short term, systemic for inhalation route) is 97.95 mg/m³
General dust limit:
For insoluble particles, the general threshold value for dust has to be taken into account:
For general dust in Germany the current binding national Occupational Exposure Limit is 10 mg/m³ for inhalable and 3 mg/m³ for respirable dust (TRGS900; http://www.baua.de/cae/servlet/contentblob/666764/publicationFile/55580/TRGS-900.doc).
The use of the official national German value for general dust is in line with the proposal in ECHA Guidance document R8 Version 2.1. dated November 2012. Here it is stated that the general dust limits of 10 mg/m3 for the inhalable airborne fraction and 3 mg/m3 for the respirable airborne fraction used in setting Occupational Exposure Limits in many countries should be considered in combination with nature of the dust. It is stated in the ECHA Guidance document that for non-soluble inert dusts if the derived DNEL for inhalation is above these dust limits, the general dust limits should apply for exposure scenarios with exposure to dust (see chapter 8.7.1, page 48 of ECHA guidance document R.8, Version 2.1 dated November 2012).
For the respirable and inhalable fraction of Macrolex Rot EG the general dust limit has to be considered.
3.) DNEL (long term, systemic , dermal route)
There is no long term study available using dermal application as exposure route. Therefore the available subacute oral toxicity study in rats has to be considered and the respective NOAEL of 1000 mg/kg bw has to be used as starting point for DNEL calculation. As it can be assumed that dermal absorption would not be higher than the oral absorption ECHA proposed in the Guidance Document R8 not to introduce an additional default factor for the extrapolation from oral to dermal exposure route.
NOAEL (oral, rat, subacute) = NOAEL (dermal, rat, subacute) = 1000 mg/kg bw/day
Overall factor 72
Thus, worker DNEL (long term, systemic for dermal route) is 13.89 mg/kg bw/day
4.) DNEL (short term, systemic , dermal route)
There is no acute study available using dermal application to determine acute systemic toxicity after dermal application. Thus, no probable toxic hazard was identified. In addition, in the available study on skin irritation in animals or in the animal study on skin sensitization no systemic toxicity or mortality was observed. Therefore it is proposed to take the Worker long term DNEL for dermal application as surrogate:
Thus, Worker DNEL (long term and short term, systemic for dermal route) is 13.89 mg/kg bw/day
III. Derivation of DNELs (local)
Basis for DNEL derivation
In the available tests on skin irritation and eye irritation Macrolex Rot EG is not irritating to the skin nor to the mucous membranes of rabbits. The modified Local Lymph Node Assay (IMDS) was performed according to OECD Guidelines No. 429 and No. 406. The results show that there is no indication for a skin sensitizing effect after administration Macrolex Rot EG in this test system.
Based on these results no DNELs (local) need to be derived because no hazard was identified
IV. Conclusion (systemic and local)
The systemic DNELs for long term include the short term hazard.
Therefore, the relevant DNELs are
Worker DNEL (systemic, dermal route): 13.89 mg/kg bw/day
Worker DNEL (systemic, inhalation route): 97.95 mg/m³
For the respirable and inhalable fraction of Macrolex Rot EG the general dust limit has to be considered.
With respect to local effects no DNELs are needed because no hazard was identified.
General Population - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 29 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:
- 870 mg/m³
- Explanation for the modification of the dose descriptor starting point:
- NOAEL (rat) from a sub-acute oral toxicity study 1000 mg/kg bw/day Correction of the starting point according to ECHA Guidance Chapter R8 There are no quantitative data on absorption rates for oral or inhalation route available. From the data generated in the sub-acute oral study it can be concluded that absorption via oral is low. As the substance is nearly unsoluble in water (below the detection limit of 0.00003 g/l). The absorption via inhalation route might be comparable low. Consequently, there is no need to introduce further default value for the extrapolation from oral route to inhalation route. Corrected inhalatory NOAEC= oral NOAEL(1000 mg/kg bw/day) x 1/1.15 x 1 Corrected NOAEC (general population) = 870 mg/m³
- AF for dose response relationship:
- 1
- Justification:
- There are no effects up to the limit dose
- AF for differences in duration of exposure:
- 6
- Justification:
- Sub-acute to chronic exposure
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- Allometric scaling rat versus human: the AF of 4 is already included in the route to route extrapolation
- AF for other interspecies differences:
- 1
- Justification:
- The rats tolerated the dosing up to and including the limit dose of 1000 mg/kg bw/day, Consequently it is considered to be a conservative starting point for DNEL calculation and the real NOAEL in rats is probably much higher. In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor 2.5 is scientifically unjustified as a defaut factor. This view is supported by ERASM project (Barke et al 2010)
- AF for intraspecies differences:
- 5
- Justification:
- Based on the considerations by ECETOC Report TR 110 2010. Oral treatment with up to 1000 mg/kg bw/day for a period of 4 weeks as well as short term inhalation exposure against the highest technical attainable concentration of 2868 mg/m³ for 4 hours was tolerated by rats without mortalitity or any impairment. In addition, taking into account that the test item is a solid with a molecular weight of 408, melting point of >300 °C, log Pow >7 and water solubility below the detection limit, this indicates that hazard for general population from exposure against Macrolex Rot EG might be unlikely. Consequently the default factor will be lowered taking into account compound specific data.
- AF for the quality of the whole database:
- 1
- Justification:
- There is information available to cover all relevant toxicological endpoints. The available studies are at most performed according to guideline and GLP. No adverse effects were observed in a guideline sub-acute toxicity study indicating that Macrolex Rot EG has a low toxicological potential and the starting point for the DNEL derivation is conservative.
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 29 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
General Population - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 8.33 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:
- 1 000 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
- There is no long term study available using dermal application as exposure route. Therefore the available sub-acute oral toxicity study in rats has to be considered and the respective NOAEL of 1000 mg/kg bw has to be used as starting point for DNEL calculation. As it can be assumed that dermal absorption would not be higher than the oral absorption ECHA proposed in the Guidance Document R8 not to introduce an additional default factor for the extrapolation from oral to dermal exposure
- AF for dose response relationship:
- 1
- Justification:
- There are no effects up to the limit dose
- AF for differences in duration of exposure:
- 6
- Justification:
- Sub-acute to chronic exposure
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- Allometric scaling rat versus human
- AF for other interspecies differences:
- 1
- Justification:
- The rats tolerated the dosing up to and including the limit dose of 1000 mg/kg bw/day, Consequently it is considered to be a conservative starting point for DNEL calculation and the real NOAEL in rats is probably much higher. In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor 2.5 is scientifically unjustified as a defaut factor. This view is supported by ERASM project (Barke et al 2010)
- AF for intraspecies differences:
- 5
- Justification:
- Based on the considerations by ECETOC Report TR 110 2010. Oral treatment with up to 1000 mg/kg bw/day for a period of 4 weeks was tolerated by rats without mortality or any impairment. In addition, taking into account that the test item is a solid with a molecular weight of 408, melting point of >300 °C, log Pow >7 and water solubility below the detection limit, this indicates that hazard for general population from exposure against Macrolex Rot EG might be low. Consequently the default factor will be lowered taking into account compound specific data.
- AF for the quality of the whole database:
- 1
- Justification:
- There is information available to cover all relevant toxicological endpoints. The available studies are at most performed according to guideline and GLP. No adverse effects were observed in a guideline sub-acute toxicity study indicating that Macrolex Rot EG has a low toxicological potential and the starting point for the DNEL derivation is conservative.
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 8.33 mg/kg bw/day
- 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
General Population - Hazard via oral route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 8.33 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:
- 1 000 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
- Route to rote extrapolation needs not to be performed
- AF for dose response relationship:
- 1
- Justification:
- There are no effects up to the limit dose
- AF for differences in duration of exposure:
- 6
- Justification:
- Sub-acute to chronic exposure
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- Allometric scaling rat versus human
- AF for other interspecies differences:
- 1
- Justification:
- The rats tolerated the dosing up to and including the limit dose of 1000 mg/kg bw/day, Consequently it is considered to be a conservative starting point for DNEL calculation and the real NOAEL in rats is probably much higher. In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor 2.5 is scientifically unjustified as a defaut factor. This view is supported by ERASM project (Barke et al 2010)
- AF for intraspecies differences:
- 5
- Justification:
- Based on the considerations by ECETOC Report TR 110 2010. Oral treatment with up to 1000 mg/kg bw/day for a period of 4 weeks was tolerated by rats without mortality or any impairment. In addition, taking into account that the test item is a solid with a molecular weight of 408, melting point of >300 °C, log Pow >7 and water solubility below the detection limit, this indicates that hazard for general population from exposure against Macrolex Rot EG might be low. Consequently the default factor will be lowered taking into account compound specific data.
- AF for the quality of the whole database:
- 1
- Justification:
- There is information available to cover all relevant toxicological endpoints. The available studies are at most performed according to guideline and GLP. No adverse effects were observed in a guideline sub-acute toxicity study indicating that Macrolex Rot EG has a low toxicological potential and the starting point for the DNEL derivation is conservative.
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 8.33 mg/kg bw/day
- 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
General Population - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- no hazard identified
Additional information - General Population
Macrolex Rot EG
CAS-Nr. 20749-68-2
DNEL- Derivation: General Population
I. Introduction
The substance is not classified legally.
II. Derivation of General Population-DNEL (systemic)
Basis for DNEL Derivation
Macrolex Rot EG was administered by gavage to 5 male and 5 female Wistar rats per dose group indayily doses of 0, 100, 300, 1000 mg/kg bw/day suspended in polyethylene glycol 400 (vehicle) for a period of 28 days. The study was conducted in compliance with OECD TG 407 under GLP conditions.
Survival was not affected by treatment with Macrolex Rot EG and no clinical signs were observed. The observed decreased alkaline phosphatase in females was not considered relevant because neither all other clinical chemistry data nor hematology gave evidence for treatment related effects up to 1000 mg/kg bw. Starting at the mid dose of 300 mg/kg bw, all animals of both sexes showed changes in feces color (reddish particles), which is a consequence of the strong red color of the test item and thus is not considered as adverse effect. Histopathology revealed minimally to slightly reduced secretion in the seminal vesicles in 3 out of 5 males at 1000 mg/kg bw which was not associated with degeneration of seminal vesicles. Changes in other male genital organs (testes, epididymides, prostate or coagulation glands) could not be found up to and including 1000 mg/kg bw.. Therefore, reduced secretion is regarded as unspecific and possibly stress-related. An adverse effect is not assumed. Female reproductive organs were not affected up to 1000 mg/kg bw/day.
In conclusion, under the conditions described above, the no-adverse-effect-level (NOAEL) for male and female rats after 4 -week daily oral treatment by gavage with Macrolex Rot EG is 1000 mg/kg bw/day.
In an OECD 414 study, one group of 20 females received Macrolex Rot EG at a dose of 1000 mg/kg/day by oral gavage administration, from Day 6 to 19 after mating. A similarly constituted control group received the vehicle, polyethylene glycol 400 (PEG 400) at the same volume dose as the treated group. Animals were killed on Day 20 after mating for reproductive assessment and fetal examination.
Clinical observations, body weight and food consumption were recorded. Adult females were examined macroscopically at necropsy on Day 20 after mating and the gravid uterine weight recorded and all fetuses were examined macroscopically at necropsy and subsequently by detailed internal visceral examination or skeletal examination.
Based on the results of this study, it is concluded that in the absence of any evidence for general systemic toxicity or adverse effects on embryo-fetal survival, growth and development, that the no (NOAEL) observed adverse effect level was 1000 mg/kg/day (limit dose; highest dose tested).
Therefore, the calculation of a separate DNEL for toxicity to reproduction is not necessary, because the NOAEL of the repeated dose subacute toxicity study and the NOAEL of the OECD TG 414 study is identical.
1.) DNEL long-term, inhalation route –Systemic effects
NOAEL (rat) from a sub-acute oral toxicity study 1000 mg/kg bw/day
Correction of the starting point according to ECHA Guidance Chapter R8
There are no quantitative data on absorption rates for oral or inhalation route available. From the data generated in the sub-acute oral study it can be concluded that absorption via oral is low. As the substance is nearly unsoluble in water (below the detection limit of 0.00003 g/l). The absorption via inhalation route might be comparable low. Consequently, there is no need to introduce further default value for the extrapolation from oral route to inhalation route.
Corrected inhalatory NOAEC= oral NOAEL(1000 mg/kg bw/day) x 1/1.15 x 1
Corrected NOAEC (general population) = 870 mg/m³
Overall factor 30
General Population DNEL (long term, systemic for inhalation route) is 29 mg/m³
2.) DNEL short-term, inhalation route –Systemic effects
There is a reliable study available in which is performed according to OECD TG 403 under GLP conditions .Rats were exposed to the maximum technically attainable concentration of 2868 mg/m³ for 4 hours. No animal died and the exposure was tolerated without any pathodiagnostic effects suggestive of portal of entry or systemic toxicity. Thus, no hazard was identified in this animal experiment. Therefore, it is proposed not to define a special DNEL (short term for inhalation route) but to take the DNEL (long term, systemic for inhalation route) as surrogate.
Thus, General Population DNEL (long term and short term, systemic for inhalation route) is 29 mg/m³
3.) DNEL (long term, systemic , oral route and dermal route)
There is no long term study available using dermal application as exposure route. Therefore the available sub-acute oral toxicity study in rats has to be considered and the respective NOAEL of 1000 mg/kg bw has to be used as starting point for DNEL calculation. As it can be assumed that dermal absorption would not be higher than the oral absorption ECHA proposed in the Guidance Document R8 not to introduce an additional default factor for the extrapolation from oral to dermal exposure route.
NOAEL (oral, rat, subacute) = NOAEL (dermal, rat, subacute) = 1000 mg/kg bw/day
Overall factor 120
Thus, the General Population DNEL (long term, systemic for oral route and for dermal route) is 8.33 mg/kg bw/day
4.) DNEL (short term, systemic , oral route and dermal route)
There is an oral study in rats available resulting in LD50 value of > 5000 mg/kg bw. No animal died, no animal showed signs of systemic poisoning and at sacrifice no gross pathological finding was detected.
Regarding dermal application there is no acute study available using dermal application to determine acute systemic toxicity after dermal application. In addition, in the available study on skin irritation in animals or in the animal study on skin sensitization no systemic toxicity or mortality was observed. Therefore it can be assumed that acute dermal toxicity is negligible.
Consequently, considering both application routes, it is proposed to take the General Publication long term DNEL for oral exposure and dermal application as surrogate:
Thus, General Population DNEL (long term and short term, systemic, for oral and for dermal route) is 8.33 mg/kg bw/day
III. Derivation of DNELs (local)
Basis for DNEL derivation
In the available tests on skin irritation and on eye irritation Macrolex Rot EG is not irritating to the skin nor to the mucous membranes of the eyes of rabbits.
The modified Local Lymph Node Assay (IMDS) was performed according to OECD Guidelines No. 429 and No. 406. The results show that there is no indication for a skin sensitizing effect after administration Macrolex Rot EG in this test system.
Based on these results no DNELs (local) need to be derived because no hazard was identified
IV. Conclusion (systemic and local)
The systemic DNELs for long term include the short term hazard.
Therefore, the relevant DNELs are
General Population DNEL (systemic, inhalation route): 29 mg/m³
General Population DNEL (systemic, oral route and dermal route): 8.33 mg/kg bw/day
With respect to local effects no DNELs are needed because no hazard was identified.
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