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EC number: 221-088-9 | CAS number: 3001-98-7
- 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

Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics, other
- Remarks:
- expert statement
- Type of information:
- other: expert statement based on QSAR
- Adequacy of study:
- key study
- Study period:
- 2018
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Theoretical assessment taking all currrently available relevant information into account, based on the REACH Guidance: Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c Endpoint specific guidance.
Data source
Reference
- Reference Type:
- other: expert statement
- Title:
- Unnamed
- Year:
- 2 018
- Report date:
- 2018
Materials and methods
- Objective of study:
- absorption
- distribution
- excretion
- metabolism
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other: Guidance for the implementation of REACH: Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance, European Chemical Agency, May 2008.
- GLP compliance:
- no
Test material
- Reference substance name:
- 3,9-dimethyl-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane 3,9-dioxide
- EC Number:
- 221-088-9
- EC Name:
- 3,9-dimethyl-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane 3,9-dioxide
- Cas Number:
- 3001-98-7
- Molecular formula:
- C7H14O6P2
- IUPAC Name:
- 3,9-dimethyl-2,4,8,10-tetraoxa-3λ⁵,9λ⁵-diphosphaspiro[5.5]undecane-3,9-dione
- Test material form:
- solid: particulate/powder
- Details on test material:
- AFLAMMIT® PCO 962
Constituent 1
Results and discussion
Any other information on results incl. tables
No studies are available regarding the absorption, distribution, metabolism or excretion properties of Spirophosphonate in animals or humans following dermal, oral or inhalation exposure. Thus, the toxicokinetic behaviour of Spirophosphonate was assessed from the physico-chemical properties and available toxicological studies on the substance.
3.1. Absorption
3.1.1. Oral route
The acute oral LD50 for Spirophosphonate is greater than 5000 mg/kg rat (Mátyás 2016, OECD 425). No mortality was observed and all animals were symptom free during the entire study. Body weight and body weight gain of the animals showed no indication of a treatment-related effect. No external/internal macroscopic findings were noted at necropsy on Day 14.
Further, in a 14-day range-finding oral gavage study in rats, doses of up to 1000 mg/kg bw/day in distilled water did not result in clinical signs of toxicity or mortality or in any other treatment related effect. In a 28-day Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test in the Rats (Hargitai J 2018, OECD 422) the NOAEL for the female and male parental/adult generation, and also for the F1/pups generation is considered to be 1000 mg/kg/day .
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. Spirophosphonate is a diester of a strong acid and an alcohol. Even without assumption of cleavage of the ester, in view of its low molecular weight, 255 g/mol, it may be absorbed through aqueous pores or by carriage of small molecules across membranes with the bulk passage of water. The high water solubility and the calculated log Pow below -1 favour absorption by passive diffusion. In addition, applying of Lipinski's Rule of Five , Spirophosphonate was predicted to be orally bioavailable. Further, the human intestinal absorption (simple equation) was predicted in-silico to be to 56% according to Zhao, Abraham et al. (J.Pharm. Sci. 90:749-784).
According to its physico-chemical properties Spirophosphonate was predicted to be 100% bioavailable via the oral route.
3.1.2. Inhalation route
Absorption after inhalation is estimated based on the substance-specific physico-chemical properties.
As soon as aerosol particles of aerodynamic diameters of 3 μm are generated (usually done in an acute inhalation study) the substance can reach the alveolar region of the respiratory tract. As a hydrophilic molecule with high water-solubility, Spirophosphonate is regarded to readily diffuse/dissolve into the mucus lining of the respiratory tract. Alike, the substance would be readily soluble in blood.
Crossing of the respiratory tract epithelium membranes is considered to be limited due to the relatively low lipophilicity of Spirophosphonate. However, with a molecular weight of around 259 g/mol, it is very likely that it will be available for absorption through aqueous pores.
Absorption of the substance following inhalation exposure is predicted to be 100%.
3.1.3. Dermal route
Percutaneous penetration of Spirophosphonate has not been assessed.
The acute dermal LD50 of Spirophosphonate in the rat was > 2000 mg/kg bw (OECD 402). The results indicate limited toxicity after dermal exposure, which is further confirmed by the absence of irritation in an in vitro skin irritation study (OECD 439) and the absence of sensitization in a skin sensitization study (OECD 429).
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 dermal absorption can be based on the substance-specific physico-chemical properties.
The high water solubility and the low partition coefficient (logP below 1) indicate low dermal permeability. Alike, according to the Skin Permeation & Partition Model (Abraham and Martins, 2004) , predicting a skin permeability coefficient log Kp = -12.74 cm/s, the dermal absorption is calculated to be very low (Flux = Kp x C = 2.8 x 10-7 mg/cm²/event <<0.001 mg/cm²/event).
In conclusion, it can be predicted that Spirophosphonate shows very low penetration through the skin. The dermal absorption default is therefore set to 1%.
3.2. Distribution
Distribution of Spirophosphonate is estimated based on the substance-specific physico-chemical properties.
As the substance has a low to moderate molecular weight, distribution in the body is expected to be relatively wide. Due to the high water solubility of the substance, the molecules might diffuse through aqueous channels and pores. Alike, according to the Blood to Fat Distribution Model (Abraham and Ibrahim, 2006) , predicting a log Kfat/blood = -4.1, the partition from blood/plasma into fat is calculated to be low.
The human serum albumin binding log KHSA = -5.45 was predicted in-silico according to Valko et al. (J.Parm. Sci. 92: 22236-2248), corresponding to a very low affinity to HSA.
Thus, Spirophosphonate is expected to be rapidly distributed into organs and tissues However, as Spirophosphonate has a low lipophilicity, its diffusion rate across membranes and into cells is regarded to be limited and the intracellular concentration is expected to be lower than in extracellular compartments. Spirophosphonate is not expected to bioaccumulate.
3.3. Metabolism
Metabolism of Spirophosphonate is assessed from literature data and from genetic toxicity tests with/without metabolic activation.
Spirophosphonate is a diester of a strong acid and an alcohol. Both parts might be released by acidic cleavage in the stomach or by biotransformation. According to Arnot et al. the half-life biotransformation in fish was predicted to be 0.44 hours. Methyl phosphoric acid is expected to be resistant to metabolism. Compounds containing the C-P bond resist cleavage during metabolism in mammals and higher plants . Limited data is available regarding the metabolism of Pentaerythritol, but feeding studies in human volunteers revealed that about 85% of Pentaerythritol fed was eliminated unchanged in urine. Elimination was essentially complete in 30 hr .
Spirophosphonate shows no potential for genetic toxicity in three in vitro test systems (OECD 471, 487, 490) both, in the presence and in the absence of metabolic activation (rat liver S9 mix). Apparently, neither the substance nor its potential metabolites are reactive from the genotoxic point of view.
In conclusion, metabolism of Spirophosphonate is expected, but also not of concern.
3.4. Excretion
Prediction of excretion is based on physico-chemical properties of Spirophosphonate (parent and potential metabolites) and observations from repeated-dose toxicity tests in rats or rabbits. The major routes of excretion are renal excretion or biliary excretion.
The physico-chemical properties of Spirophosphonate suggest that parent molecules and potential metabolites are all water soluble and likely to be eliminated rapidly in urine. Biliary excretion cannot be excluded. No specific information is available facilitating estimation of the renal clearance or biliary clearance. Therefore, “non-metabolic clearance” is considered as a single first order rate excretion parameter (ECHA R.7C, p.200).
Absence of effects in short-term oral toxicity studies with relatively large doses of Spirophosphonate suggest that absorbed parent molecule and potential metabolites are rapidly eliminated without further impact to the test animals.
In conclusion, systemically available Spirophosphonate is expected to be excreted unchanged or in form of its potential metabolites Methyl phosphoric acid and Pentaerythritol.
4. Conclusion
Spirophosphonate is expected to have good bioavailability after uptake via the oral and inhalation route. Based on physico-chemical data and in-silico estimation the bioavailability via the dermal route is low (1%). Spirophosphonate as well as potential metabolites are expected to be widely distributed in the organism without potential of bioaccumulation. Excretion via urine is regarded to be the preferred way of elimination. Bioaccumulation is not expected because of the low log Pow.
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results: Bioaccumulation not to be espected based on the low log Kow and theoretical assessment
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