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Administrative data

Endpoint:
basic toxicokinetics, other
Remarks:
Assessment of toxico-kinetics from relevant available information
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed

Materials and methods

Objective of study:
absorption
excretion
Test guideline
Qualifier:
according to guideline
Guideline:
other: OECD 421-like
Principles of method if other than guideline:
Percutaneous Penetration with Mucaca Mulata (Monkeys)
GLP compliance:
not specified
Remarks:
Not applicable ( prior to 1981)

Test material

Constituent 1
Reference substance name:
Reaction mass of phosphonic acid, methyl-, bis[(5-ethyl-2-methyl-2,2-dioxido-1,3,2-dioxaphosphorinan-5-yl)methyl] ester with (5-ethyl-2-methyl-2-oxido-1,3,2-dioxaphosphorinan-5-yl)methyl methyl methylphosphonate
EC Number:
915-680-2
Molecular formula:
not applicable for UVCB
IUPAC Name:
Reaction mass of phosphonic acid, methyl-, bis[(5-ethyl-2-methyl-2,2-dioxido-1,3,2-dioxaphosphorinan-5-yl)methyl] ester with (5-ethyl-2-methyl-2-oxido-1,3,2-dioxaphosphorinan-5-yl)methyl methyl methylphosphonate

Test animals

Species:
monkey
Strain:
Mulatta arctoides
Sex:
not specified
Details on test animals or test system and environmental conditions:
Excretion: Three rhesus monkeys received the radioactive material (1mg/kg) via an intramuscular injection into the lower legs. The intramuscular administration was selected based on the experience of the lab and the known difficulties in Intra venous administration with rhesus monkeys
absorption: pregnant female rabbits

Administration / exposure

Route of administration:
not specified
Vehicle:
not specified
Duration and frequency of treatment / exposure:
( hours): 0-4,4-8,8-12,12-24,24-48,48-72,72-96,96-120,120-144,144-168,168,192 and 192-216
Doses / concentrationsopen allclose all
Dose / conc.:
300 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
Dose / conc.:
3 000 mg/kg bw/day
No. of animals per sex per dose / concentration:
Three Mucaca mulata were used for each approach
Details on study design:
The percutaneous study consists of a two-step process:
- Step 1 :Excretion kinetics of a substance are determined following a parental injection of the radiolabeled substance
- Step 2: The substance then is applied topically and the amount excreted is corrected for the previously determined parenteral excretion kinetics.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Absorption through the abdominal wall was very slow with only 0.856% of the dose recovered in the first 24 hours after application. This can be compared to the 63.84% recovered after the intra muscular route of administration. Total urinary recovery for this study was 7.91± 0.61% and using the correction factor determined from the 76.21% parenteral dose, which was 1.311, the actual penetration of radiolabeled substance would be 10.37±0.8%. The excretion rates showed prolonged but low level excretion of the radioactivity. Unlike the parenteral dose, the maximum excretion rate occurred during the 24-48hours collection period.
Details on distribution in tissues:
not mentioned
Details on excretion:
Step 1
Three rhesus monkeys received the radioactive material (1mg/kg) via an intramuscular injection into the lower legs. The intramuscular administration was selected based on the experience of the lab and the known difficulties in Intra venous administration with rhesus monkeys. Elimination via the kidney appears very rapid for the radiolabeled substance with 38.15% recovered in the urine in the first 4 hours and 63.854% total in the first 24 hours. After 48 hours only 5.92 was recovered the next 168 hours. Total urinary was 76.21± 7.94% of the parenteral dose. Plotted against time, the data are consistent with a two compartment open model. The most rapid elimination phase ( α) provides a half time of elimination k=4.5 h-1 while the secondary elimination phase (β) provides k= 11.0 h-1.

Step 2
Three Mucaca mulata were used for each approach. The first one involved rhesus monkeys with unwashed polyester fabrics containing 5.91% of radiolabeled substance and the second with scoured polyester fabric containing 2.5% radioactive chemical. Each patch was applied on the stomach of each monkey, wetted with human urine and left next to the skin for a 24-hour exposure period. These patches were not to be occluded in anyway. Urine samples were collected for a total period of 216 hours, and for a similar period for the feces. The purpose of this study was to determine the amount of radiolabeled substance that can be extracted from threated polyester fabric (unscoured and scoured) with human urine and then absorbed via percutaneous route on rhesus monkey. The radiolabeled substance had a specific activity of 1.84 mCi/mg. The exact radioactive load per 4” x5” patch was determined from a randomly selected patch prepared in a similar manner.

Metabolite characterisation studies

Metabolites identified:
not measured
Details on metabolites:
not mentioned

Applicant's summary and conclusion

Conclusions:
The excretion rates showed prolonged but low level excretion of the radioactivity