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EC number: 204-029-1 | CAS number: 113-48-4
- 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
Dermal absorption
Administrative data
- Endpoint:
- dermal absorption, other
- Remarks:
- Extent of dermal absorption and metabolic profile study in human volunteers
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1991
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 991
- Report date:
- 1992
Materials and methods
Test guideline
- Qualifier:
- no guideline available
- Principles of method if other than guideline:
- The objective of the study was to determine the extent of dermal absorption and the route and rate of excretion and metabolic profile of MGK 264 in human volunteers after a single dermal application of 14C-MGK 264 to the forearm for eight (8) hours.
Clinical study involving 4 male volunteers that were dermally adminisitered 5 mg 14C labelled N-octylbicycloheptene dicarboximide (MGK 264) to a 4 cm x 6 cm area of the volar aspect of one forearm. Blood samples were collected from both forearms (ipsilateral or application arm and contralateral or non-application arm) at the same time intervals and the radioactivity in plasma was determined over time.
Eight hours after dose administration, the dose was removed by wiping the dosed area with isopropyl alcohol swabs and rinsing the area with isopropyl alcohol. The skin was stripped (tape stripping) with 3M tape 1, 23 and 45 hours after removal of the dosage. Urine and feces samples were collected when available for 5 consecutive days.
Urine samples were analysed by HPLC to investigate the metabolism of MGK 264 prior to elimination. - GLP compliance:
- yes
Test material
- Reference substance name:
- N-(2-ethylhexyl)-8,9,10-trinorborn-5-ene-2,3-dicarboximide
- EC Number:
- 204-029-1
- EC Name:
- N-(2-ethylhexyl)-8,9,10-trinorborn-5-ene-2,3-dicarboximide
- Cas Number:
- 113-48-4
- Molecular formula:
- C17H25NO2
- IUPAC Name:
- N-(2-ethylhexyl)-8,9,10-trinorborn-5-ene-2,3-dicarboximide
- Reference substance name:
- (E)-1,4-Bis(2-ethylhexylamino)-2-butene-1,4-dione
- Molecular formula:
- C20H38N2O2
- IUPAC Name:
- (E)-1,4-Bis(2-ethylhexylamino)-2-butene-1,4-dione
- Reference substance name:
- 1-(2-ethylhexyl)-1H-pyrrole-2,5-dione
- Molecular formula:
- C12H19NO2
- IUPAC Name:
- 1-(2-ethylhexyl)-1H-pyrrole-2,5-dione
- Test material form:
- liquid
- Details on test material:
- Purity and characterisation analysis conducted on the following sample; Supplier: McLaughlin Gormley King ; Batch Number: AB9500
Constituent 1
impurity 1
impurity 2
- Specific details on test material used for the study:
- The test substance was [Hexyl-l- 14C] MGK 264. The radiolabeled test anicle was supplied by Amersham Corp. (Arlington Heights, IL; Code CFQ.6188). The structure and position of the label are shown in the frinal report attached to this end point record. The radiolabeled compound had a reported specific activity of 18.4 mCi/mmol and a reported radiochemical purity of 98%.
- Radiolabelling:
- yes
Test animals
- Species:
- other: human
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- Not allowed to bath/shower until last tape stripping on day 3. Kept at centre for 6 day after dosing.
Subjects not allowed medication/methylxanthine containing products/alcohol 48 hours before the start of the study.
Administration / exposure
- Type of coverage:
- semiocclusive
- Vehicle:
- other: isopropanol
- Duration of exposure:
- 8 hours
- Doses:
- 0.055 mg/kg bw (nominal)
5.0 mg MGK 264 in 100 microL: dosing solution - No. of animals per group:
- 4 males in study
- Control animals:
- no
- Details on study design:
- The application area on the volar aspect of the right or left forearm was outlined by an adhesive template (Duoderm®, Convatec/Squibb. J. C. Van Markenlaan, Rijswijk, The Netherlands) from which a rectangle of 4 cm x 6 cm had been removed. The dose was administered at about 9:00 a.m. on day 1 using a 100 μL glass WiretroI• micropipette (Drummond Scientific Corp., Broomall, PA). The dosage was spread over the entire application area using the glass micropipette, which was saved for residual analysis of radioactivity. The application area was then covered by an aluminum dome in which holes were made to provide for a nonocclusive condition. The dosage was left in place for eight (8) hours, during which the volunteers were free to move around under close supervision.
Results and discussion
- Signs and symptoms of toxicity:
- not specified
- Dermal irritation:
- not specified
- Total recovery:
- The total mean recovery of radioactivity administered was 91.71 %
Percutaneous absorption
- Key result
- Time point:
- 8 h
- Dose:
- 0.055 mg/kg bw
- Parameter:
- percentage
- Absorption:
- 1.67 %
- Remarks on result:
- other: Based on a combination of radiolabelled material present in the urine and unaccounted for radioactivity (about 9%), a conservative dermal absorption value of 10% may be used for risk assessment purposes.
Any other information on results incl. tables
Radioactivity in Tape Strippings: the amount of radioactivity was the highest in the early strips and quickly decreased in the later strips, for each of the three days sampled. These data clearly showed that the radioactivity was present on the outer layers of the skin and did not accumulate in the skin.
Urine and faeces: The volunteers excreted a mean of 1.67% of the dosed radioactivity in the urine. The majority of the urinary radioactivity was present in the first 24 hour sample. The volunteers excreted none of the dosed radioactivity in the feces.
External recovery: The results clearly show that 88.72% of the dosed radioactivity remained on the surface of the skin 8 hours after dose administration.
Total recovery: The total recovery of radioactivity included radioactivity recovered from the urine, the feces, the external recovery (dome, swab and skin ri_nse), the glass micropipet, the tape strips and the gauze. The mean of the total recovery for the study was 91.71 %.
Distribution of 14C-Radioactivity in Urine: The distribution of metabolites in volunteer urine composites was summarized as a percent of radioactivity and the chromatograms showed the 14C radioactivity distributed between 2 predominant and several minor metabolites.
The distribution of urinary metabolites representing the percentage of total dose was calculated. Unmetabolized MGK 264 was only detected in Volunteer 02 BO urine where it accounted for 1.04% of the radioactivity in the urine and 0.02 % of the administered dose.
A comparison of the rat metabolic profile to human profile showed that four human metabolites had similar retention times to previously identified rat metabolites. The two predominant human metabolites had similar retention times to rat metabolites C and D. Metabolites C and D are isomers formed by 11-oxidation of the side chain to a carboxylic acid and oxidation of the norbornene double bond producing a stable epoxide. Together Metabolites C and D represented 54.51 % to 68.08% of the radioactivity in volunteer urine or 0.69% to 1.273% of the administered
dose. Human metabolites with the same retention times as rat metabolites A and B were also observed. Metabolites A and B are also isomers formed by P-oxidation of the side chain to a carboxylic acid and oxidation of the norbornene ring double bond producing a stable epoxide. Metabolites A and B combined represent 7.92% to 23.86% of the radioactivity in the urine and 0.09% to 0.55% of the administered dose.
Applicant's summary and conclusion
- Conclusions:
- The total mean recovery of radioactivity administered was 91.71 %. A mean of 1.67% of the administered radioactivity was excreted in the urine and no measurable amount was excreted in the feces. The results obtained from tape stripping the skin clearly showed that the radioactivity did not accumulate in the skin.
It is therefore concluded that based on a combination of radiolabelled material present in the urine (about 1%) and unaccounted for radioactivity (about 9%), a conservative dermal absorption value of 10% may be used for risk assessment purposes. - Executive summary:
Four healthy male volunteers were dermally administered 5 mg 14C labelled N-octylbicycloheptene dicarboximide (MGK 264) to a 4 cm x 6 cm area of the volar aspect of the forearm. The radioactive dose applied was approximately 50 μCi. The application area was covered by a protective dome under nonocclusive conditions. Blood samples were collected from both forearms (ipsilateral and contralateral) at the same time intervals and the radioactivity in plasma was determined over time.
Eight hours after dose administration, the dose was removed by wiping the dosed area with isopropyl alcohol swabs and rinsing the area with isopropyl alcohol. The skin was stripped (tape stripping) with 3M tape 1, 23 and 45 hours after removal of the dosage. Urine and feces samples were collected when available for 5 consecutive days.
The total mean recovery of radioactivity administered was 91.71 %. A mean of 1.67% of the administered radioactivity was excreted in the urine and no measurable amount was excreted in the feces. The mean external recovery of radioactivity (dome, gauze, skin rinse and swabs) was 88. 72 % of the administered radioactivity. The results obtained from tape stripping the skin clearly showed that the radioactivity did not accumulate in the skin.
It is therefore concluded that based on a combination of radiolabelled material present in the urine (about 1%) and unaccounted for radioactivity (about 9%), a conservative dermal absorption value of 10% may be used for risk assessment purposes.
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