N-(2-ethylhexyl)-8,9,10-trinorborn-5-ene-2,3-dicarboximide

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:

1991

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

Test material information

Constituent 1

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

impurity 1

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

impurity 2

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

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.