Methylphosphonic acid

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics

Type of information:

other: Evaluation of toxicokinetic behaviour based on structure and physico-chemical and toxicological properties of the substance.

Adequacy of study:

key study

Study period:

2012-06-29

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Evaluation of toxicokinetic behaviour based on structure and physico-chemical and toxicological properties of the substance.

Objective of study:

toxicokinetics

Qualifier:

no guideline followed

Principles of method if other than guideline:

assessment of toxicokinetic behaviour

GLP compliance:

no

Conclusions:

MPAAU is expected to have good bioavailability after uptake via the oral and inhalation route. Based on data of an in-vitro dermal penetration test the bioavailability via the dermal route is low (<5%). MPAAU as well as so far unidentified 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.
There are indications from available toxicity studies that MPAAU was absorbed and distributed systemically when administered orally. Short-term toxicity studies with relatively large doses of MPAAU suggest that absorbed MPAAU and potential metabolites are rapidly eliminated without impact to the test animals. MPAAU and its potential metabolites do not present a genotoxic hazard and do not cause significant toxicity in animals.
Bioaccumulation is not expected because of the low log Pow.

Reference 2

Endpoint:

dermal absorption in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

12/1995-03/1996

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Pre-guideline method, but data are comprehensible and scientifically acceptable. (GLP: Yes)

Qualifier:

no guideline available

Principles of method if other than guideline:

Skin Permeability In vitro Absorption Through Porcine Ear Skin with MPAAU according to:
Bronaugh, R.L., R.F. Stewart and E. R. Congdon (1982) Methods for in vitro percutaneous absorption studies II. Animal Models for Human Skin Toxicology and Applied Pharmacology 62, 481-488

GLP compliance:

yes (incl. QA statement)

Radiolabelling:

no

Species:

other: porcine ears

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

Porcine ears were obtained from a local slaughter-house on the day of slaughter and before the pigs were steam-cleaned. The outer ear region was washed and cleaned with cold water. After carefully shaving, the skin was removed by dissection. The thickness of the dissected skin was 2-3 millimetre. The surface of the skin which was in contact with the test substance during the permeation-assay was 1.13 cm2.

For the determination of the absorption of the test article the skin was mounted in glass diffusion chambers with an area of 1.13 cm2 (area of skin) and a volume of 7 ml. These chambers are subdivided in an upper part (donor chamber) and in a lower part (receptor chamber). A volume of 7 ml physiological saline (0.9 % NaCl-solution) was placed in the receptor chamber of each diffusion cell, followed by the application of 226 pi of the test article dissolved in water (2 mg/ml) to the donor chambers. The top of the donor chamber was covered with parafilm. The diffusion chambers were placed in an incubator at 37° C. Samples (0.5 ml) were drawn from the receptor chamber after 0, 0.5, 1, 2, 4, 6, 8 and 24 hours and analysed. The volume of the fluid in the receptor chamber was kept constant by the addition of 0.5 ml of fresh receptor fluid to the receptor chamber immediately after removal of each sample.

Type of coverage:

other: pig skin inbetween donor chamber and acceptor chamber

Vehicle:

water

Duration of exposure:

Samples (0.5 ml) were drawn from the receptor chamber after 0, 0.5, 1, 2, 4, 6, 8 and 24 hours and analysed.

Doses:

226 µl of the test material dissolved in water (2 mg/ml) were applied to the donor chamber in the first and second experiment.

No. of animals per group:

2 Experiments, each using 4 glass diffusion chambers in parallel.

Control animals:

no

Details on study design:

No check of integrity of the skin preparations.
Acceptor fluid (0.9% NaCl) of sampling interval 0 hours (blank) showed no detector signal within the retention time of the substance.

Signs and symptoms of toxicity:

not examined

Dermal irritation:

not examined

Dose:

2mg ai/ml

Parameter:

percentage

Absorption:

<= 0 %

Remarks on result:

other: 8 hours

Remarks:

The concentration (receptor fluid) did not exceed the lower limit of detection prior to 8 hours after start of experiments.

Dose:

2mg ai/ml

Parameter:

percentage

Absorption:

< 5 %

Remarks on result:

other: 24 hours

Remarks:

In the 24 hours specimens (receptor fluid) the concentration of the permeated test article varied in the range of 0 to 12.7 % of the amount applied and averaged to 4.6 % +/- 4.2 % (n=8).

Conversion factor human vs. animal skin:

In vitro dermal absorption studies are preferably carried out with human skin preparations; pig skin is considered a suitable alternative (EHC 235: Dermal Absorption, page 109). No interspecies conversion of animal data is necessary.
Percutaneous penetration refers to in vitro experiments and represents the amount of topically applied test substance that is found in the receptor fluid - this quantity is taken as systemically available (R.7C p.156). No conversion of in vitro data is necessary.

Since permeation of the test article through porcine skin was very low a graphical evaluation of the analytical data was impossible. The concentration of the permeated test article did not exceed the lower limit of detection prior to 8 hours after start of experiments.

The permeation rates (slope) and permeation constants (Kp) could not be determined since no measurable penetration of the skin occurred prior to 8 hours.

Conclusions:

MPAAU showed very low penetration through the skin of porcine ears. Within 8 hours no MPAAU were detected in the receptor chamber. Within 24 hours less than 5 % (mean value) of the amount of MPAAUN applied to the test system penetrated.

Executive summary:

The test article MPAAU was assessed for its potential to permeate through porcine skin.

The assay was performed in two independent experiments over a time scale of 0 to 24 hours. The test article was tested at the following concentration (a.i):

Experiment I and II: 0.94 mg/ml in water. Samples were drawn from the receptor chambers following a fixed schedule:

Exp. I and II: 0.0; 0.5; 1.0; 2.0; 4.0, 6.0; 8.0 and 24 hours following the application of the test article.

The samples (0.5 ml each) were labelled and transferred to the sponsor's facilities for subsequent analysis.

Specimens of a pig ear skin penetration study were separated by reversed phase HPLC followed by UV-detection at 200 nm. The separated and detected MPAAU a.i. was quantified by an external calibration function. The bottom quantification limit of the practical work amounted to 1.28 µg/mL MPAAU a.i. in aqueous solution. By means of a serial connection of two analytical HPLC-columns penetrated MPAAU a.i. in the specimens of the 24 h sampling interval were quantified. Within 24 hours less than 5 % (mean value) of the amount of FLOVAN CGN applied to the test system penetrated*. Within 8 hours no MPAAU were detected in the receptor chamber.

*) test substance applied to the test system: 212.44 µg MPAAU a.i.; 452.00 µg MPAAU

5 % of the test substance: 10.62 ug MPAAU a.i.; 22.60 ug MPAAU

Discussion: Since permeation of the test article through porcine skin was very low a graphical evaluation of the analytical data was impossible. The concentration of the permeated test article did not exceed the lower limit of detection prior to 8 hours after start of experiments.

In conclusion, it can be stated that MPAAU showed very low penetration through the skin of porcine ears. Within 8 hours no MPAAU were detected in the receptor chamber. Within 24 hours less than 5 % (mean value) of the amount of MPAAUN applied to the test system penetrated.

Description of key information

MPA is expected to have good bioavailability when exposed via the oral and inhalation route. Based on data of an in vitro dermal penetration test with MPAAU the bioavailability via the dermal route is low (<5 %). Bioaccumulation is not expected because of the low log Pow. There is no indication of metabolism. Excretion via urine is regarded to be the preferred way of elimination.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

5

Absorption rate - inhalation (%):

100

Additional information

There is evidence from available toxicity studies with MPA and MPAAU and physico-chemical properties that MPA was absorbed and distributed systemically when administered orally. Short-term toxicity studies with relatively large doses of MPAAU suggest that absorbed MPAAU and potential metabolites are rapidly eliminated without impact to the test animals. MPAAU and its potential metabolites do not present a genotoxic hazard and do not cause significant local or systemic toxicity in animals. Bioaccumulation is not expected because of the low log Pow. MPAAU showed very low penetration through the skin of porcine ears. Within 8 hours no percutaneous penetration was detected. Within 24 hours less than 5 % (mean value) of the amount of substance applied to the test system penetrated. Since bioavailability, dermal penetration, bioaccumulation and elimination are factors mainly driven by physical-chemical properties of the test item (especially water solubility) the test results of MPAAU and MPA are well comparable in vivo. MPAAU is expected to dissolve rapidly into its ionic components in ionic solvents like water or main body fluids like saliva, gastric and intestinal fluid or blood. Therefore, the test results obtained with MPAAU may also mirror the intrinsic biochemical and metabolic fate of MPA alone.