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Diss Factsheets
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EC number: - | CAS number: -
- 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
Endpoint summary
Administrative data
Description of key information
The following modeling approaches and methods will be used in the analysis:
• OASIS TIMES (AMES, CA, ER, AR) and Catalogic (301C) modeling approach
• Toolbox 4.2 (TB) for searching of analogues and read-across analysis
• Available documented data and expert evaluation
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- repeated dose toxicity: oral, other
- Type of information:
- (Q)SAR
- Adequacy of study:
- weight of evidence
- Study period:
- 2018
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification
- Justification for type of information:
- The following modeling approaches and methods will be used in the analysis:
• OASIS TIMES (AMES, CA, ER, AR) and Catalogic (301C) modeling approach
• Toolbox 4.2 (TB) for searching of analogues and read-across analysis
• Available documented data and expert evaluation - Principles of method if other than guideline:
- QSAR modelling
- GLP compliance:
- no
- Key result
- Dose descriptor:
- other:
- Effect level:
- 0 other: QSAR qualitative data
- Based on:
- other: QSAR qualitative dat
- Remarks:
- QSAR qualitative dat
- Sex:
- not specified
- Basis for effect level:
- other: QSAR qualitative dat
- Remarks on result:
- other: QSAR qualitative dat
- Key result
- Critical effects observed:
- not specified
- Lowest effective dose / conc.:
- 0 other: QSAR qualitative data
- System:
- other: QSAR qualitative data
- Organ:
- not specified
- Conclusions:
- • Oral repeated dose administration of some organophosphorus esters could lead to neurotoxic effects associated with inhibition of AChE.
• Phosphinates could interact with AChE, but they are not able to finish the inhibition process including additional reaction of dealkylation (“ageing” mechanism)
due to the lack of second ester group.
• It could be assumed that both constituents of E17-194T will not cause neurotoxicity, i.e. will be non toxic in RDT tests. - Executive summary:
Repeated dose toxicity
Repeated dose toxicity (RDT) is a hazard associated with toxicological effects occurring as a result of repeated daily dosing with/ or exposure to a substance for a specified period up to the expected lifespan of the test species [37]. Currently, there is no existing OASIS model for predicting RDT.
The possible RDT effect of many organophosphorus esters is associated with inducing neurotoxicity by the inhibition of acetylcholinesterase activity [11-13, 38]. In the synaptic cleft OP esters bind to the serine hydroxyl group of AChE and inhibit its activity. The mechanism of AChE inhibition is discussed in sectionIII.3.Toxicological effects of phosphates, phosphonates and phosphinates Mechanistic considerations. As it is mentioned in the same section, the phosphinates are capable to bind covalently with the active site of the enzyme, but cannot continue the inhibition process by aging due to the lack of second ester group (Scheme 3). Moreover, studies with hens showed that the phosphinates protect them from neurotoxic effects because the enzyme was no more available for attack by subsequent doses of neurotoxic organophosphorus compounds (phosphates/phosphonates) [38]. Therefore, it is assumed that both analyzed chemicalswill not cause neurotoxicityafter prolonged exposure.
Experimental repeated dose toxicity data for organophosphorus compounds is searched in literature sources and Toolbox databases.Despite exact RDT data values for phosphinatesarenot found, Johnson reports thatnoneofthescreenedphosphinatesare known to cause delayed neurotoxic effect [38].
Oral RDT data (rat) is available for some phosphonates and phosphates in Toolbox (Table 5).However, these chemicals could not be used as analogues of the target chemicals due to different type of activity with respect to AChE inhibition (presence of second ester group in phosphonates and phosphates undergoing “aging” mechanism –Scheme 2).
Table 5. RDT data for organophosphorus esters
#
Structure
Experimental RDT data
(oral, rat)
Source
(Toolbox database)
1.
Dimethyl phosphinate
CAS 868-85-9
NOEL = < 25 mg/kg bdwt/d
NOEL = 50 mg/kg bdwt/d
Repeated Dose Toxicity HESS
2.
dimethyl methylphosphonate
CAS 756-79-6
NOEL = < 250 mg/kg bdwt/d
Repeated Dose Toxicity HESS
3.
NOAEL = 20 mg/kg bw/day
NOAEL = 100 mg/kg bw/day;
ECHA Chem
4.
trimethyl phosphate
CAS 512-56-1
NOEL = <40 mg/kg bdwt/d
Repeated Dose Toxicity HESS
5
triethyl phosphate
CAS 78-40-0
NOAEL = 1000 mg/kg bdwt/d
NOAEL = ca. 335 mg/kg bdwt/d
ECHA Chem
6.
dibutyl phosphate
CAS 107-66-4
NOEL = 30 mg/kg bw/day
Repeated Dose Toxicity HESS
Conclusions on RDT:
· Oral repeated dose administration of some organophosphorus esters could lead to neurotoxic effects associated with inhibition of AChE.
· Phosphinates could interact with AChE, but they are not able to finish the inhibition process including additional reaction of dealkylation (“ageing” mechanism) due to the lack of second ester group.
· It could be assumed that both constituents of E17-194T will not cause neurotoxicity, i.e. will benon toxicin RDT tests.
Reference
Endpoint conclusion
- Study duration:
- subchronic
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Justification for classification or non-classification
No adverse effects are predicted based on the QSAR model.
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