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EC number: 243-869-3 | CAS number: 20544-37-0
- 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
Link to relevant study record(s)
Description of key information
Key value for chemical safety assessment
- Absorption rate - oral (%):
- 100
- Absorption rate - dermal (%):
- 10
- Absorption rate - inhalation (%):
- 100
Additional information
Assessment of the Toxicokinetic Behaviour
3,9-dibenzyl-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane 3,9-dioxide(EC 243-869-3; CAS-No.20544-37 -0)
There were no studies available in which the toxicokinetic properties of3,9-dibenzyl-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane 3,9-dioxidewere investigated.
Therefore, in accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012), assessment of the toxicokinetic behaviour of the3,9-dibenzyl-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane 3,9-dioxidewas conducted based on the relevant available information.
This comprises a qualitative assessment of the available substance-specific data on physico-chemical and toxicological properties according to ‚Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance‘ (ECHA, 2012).
3,9-dibenzyl-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane 3,9-dioxide(molecular weight of 408,33 g/mol) is a white powder, which has a low water solubility(measured water solubility: 30.9 mg/l at 20 °C (key study, 2019-05-08; see chapter 4.8 water solubility)).The measured log Po/w is 1.5 at 40°C (key study, 2010-05-21, see chapter 4.7 partition coefficient), indicating a low lipophilie and that a general accumulation of3,9-dibenzyl-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane 3,9-dioxideis low.
The vapour pressure of 9.5E-6 Pa at 25°C (key study, 2019-04-26; see chapter 4.6 vapour pressure) is very low.
Absorption
Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2012).
- Oral
The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 g/mol are favourable for oral absorption (ECHA, 2012). As the molecular weight of3,9-dibenzyl-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane 3,9-dioxideis 408 g/mol absorption of these molecules in the gastrointestinal tract is possible.
In an acute oral toxicity study, rats were administered to3,9-dibenzyl-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane 3,9-dioxidewhich showed an LD50 value of > 2000 mg/kg bw (key study, 2019-06-17, see chapter 7.2.1 acute oral toxicity). A treatment-related effect of3,9-dibenzyl-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane 3,9-dioxideafter oral administration is not indicated.
In a 28-day repeated dose oral toxicity study in rats administered 0 (control), 100, 300 and 1,000 mg/kg all examination items, general clinical observation, functional observation examination, body weight, food consumption, hematological examination, blood biochemistry examination, urinalysis, organ weight, pathological anatomical examination and pathological examination, no changes were found due to the administration of the test substance. Therefore, the no observed effect level (NOEL) of 3,9-dibenzyl-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane 3,9-dioxide under this test condition was judged to be 1,000 mg/kg body weight for male and female each(key study, 2010-09-24;see chapter 7.5.1 Repeated dose toxicity: oral).
In a reproduction/developmental screening toxicity study according to OECD 421Spargue Dawley rats received 0, 100, 300 and 1000 mg/kg body weight of test-item by gavage. Considering all results overall there is no proof of any clear dose-dependency nor adverse test item effect.Therefore, it is concluded that the NOAEL of the test item is found to be 1000 mg/kg body weight.
No conclusion can be derived, whether low bioavailability and/or very low toxicity of the substance are the reasons for the findings.
However, an estimation of the absorption after ingestion can be based on the substance-specific physico-chemical properties.3,9-dibenzyl-2,4,8,10 -tetraoxa-3,9-diphosphaspiro[5.5]undecane 3,9-dioxideis a diester of a strong acid and an alcohol. Without assuming an ester cleavage, in view of its molecular weight and its low water solubility, it may be absorbed little through aqueous pores or by carriage of small molecules across membranes with the bulk passage of water. The low water solubility does not favour absorption by passive diffusion. The log Pow of 1,5 shows that the substance ismainly distributed to hydrophobic areas such aslipid bilayersof cells.
On the other side, in the gastrointestinal tract (GIT), metabolism prior to absorption via enzymes of the microflora may occur.
By applying the Lipinski's Rule of Five,3,9-dibenzyl-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane 3,9-dioxideis predicted to be orally bioavailable.
According to its physico-chemical properties3,9-dibenzyl-2,4,8,10-tetraoxa-3,9-diphosphaspiro [5.5]undecane 3,9-dioxideis predicted to be 100% bioavailable via the oral route.
- Dermal
In an acute dermal toxicity study with Sprague-Dawley rats the LD50 was determined to be > 2000 mg/kg3,9-dibenzyl-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane 3,9-dioxide(key study, 2019-03-12, see chapter 7.2.3 acute dermal toxicity). Due to the experimental non acute oral and non-dermal toxicity, it appears that3,9-dibenzyl-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane 3,9-dioxideis less absorbed through gastrointestinal tract and skin.
The results indicate no toxicity after dermal exposure, which is further confirmed by the absence of irritation and the absence of sensitization in skin sensitization studies (OECD 442B, 442D).
No conclusion can be derived, whether low bioavailability and/or no toxicity of the substance are the reasons for the findings.
However, an estimation of the dermal absorption can be based on the substance-specific physico-chemical properties. The molecular weight (408,33) and the partition coefficient (logP 1.5) indicate dermal absorption through the stratum corneum. But because of its low water solubility it is maybe too water-insoluble to pass through the remaining epidermis sub-layers to enter the blood stream. Calculation with DERMWIN v2.02 shows a very low permeability constant (Kp) of 9.95E-5 cm/h.
In conclusion, it can be supposed that3,9-dibenzyl-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5] un-decane 3,9-dioxidepenetrates very low through the skin. The dermal absorption default is therefore set to 10%.
- Inhalation
3,9-dibenzyl-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5] undecane 3,9-dioxidehas a very low vapour pressure (9.5E-6 Pa at 25˚C). The particle size distribution report indicates a range of 0.122μm to 704μm (D(10): 8.0275μm, D(50): 18.702μm, D(95): 43.351μm). This indicates that 95% of the particles are available in the inhalable fractions of air (<100μm). Particles with aerodynamic diameters of above 1-5μm have the greatest probability of settling in the nasopharyngeal region whereas particles with aerodynamic diameters below 1-5μm are most likely to settle in the tracheo-bronchial or pulmonary regions. As there are fractions in both categories, the substance is likely to be distributed throughout the respiratory tract upon inhalation. As a water-insoluble dust, the substance could be coughed or sneezed out of the body or swallowed (refer to oral absorption). Based on the low water solubility (30.9 mg/L at 20°C) and slight lipophilicity (1.5 at 40°C), it is likely that absorption will be low and occur via micellular solubilisation and the lymphatic system.
As no inhalational toxicity study data is available for chemical safety assessment purposes, an inhalation absorption rate of 100% is accepted, using a conservative approach.
Distribution
Distribution of3,9-dibenzyl-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5] undecane 3,9-dioxide is estimated based on the substance-specific physico-chemical properties.
As the substance has a moderate molecular weight, distribution is expected to be relatively wide.
After ingestion, the material might be stable in the acidic stomach. At neutral or basic pH it mainly hydrolyzes moderate to benzyl[2-({[benzyl(hydroxy)phosphoryl]oxy}methyl)-3-hydroxy-2-hydroxymethyl) propoxy] phosphinic acid. Further cleavage by biotransformation is assumed. Passive diffusion as well as active transport are possible for transformation products. Repeated dose studies on3,9-dibenzyl-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]un-decane 3,9 -dioxide do not give any information on bioavailability as nochanges were found due to the administration of the test substance.
Metabolism:
In a 28-day repeated dose oral toxicity study in rats administered 0 (control), 100, 300 and 1,000 mg/kg all examination items, general clinical observation, functional observation examination, body weight, food consumption, hematological examination, blood biochemistry examination, urinalysis, organ weight, pathological anatomical examination and pathological examination, no changes were found due to the administration of the test substance. Therefore, the no observed effect level (NOEL) of 3,9-dibenzyl-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane 3,9-dioxide under this test condition was judged to be 1,000 mg/kg body weight for male and female each(key study, 2010-09-24;see chapter 7.5.1 Repeated dose toxicity: oral).
3,9-dibenzyl-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane 3,9-dioxide shows no potential for genetic toxicity in three in vitro test systems (OECD 471, 473, 476) both, in the presence and absence of metabolic activation (rat liver S9 mix). Apparently, neither the substance nor its potential metabolites are reactive from the genotoxic point of view.
Hydroxylation by Phase I- Enzymes followed by conjugation with glucuronic acid which results in excretion via the kidneys or via bile is conceivable.
In conclusion, metabolism of3,9-dibenzyl-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane 3,9-dioxide is expected, but also not of concern.
Excretion:
Conjugation with activated glucuronic acid increases the molecular weight of the compound for 200 g/mol to approximately 600 g/mol which supports renal excretion. Bioaccumulation of the test item or the hydrolysis products is not expected.
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