[nitrilotris(methylene)]trisphosphonic acid, sodium salt

Dermal absorption

Administrative data

Endpoint:

dermal absorption in vivo

Type of information:

experimental study

Adequacy of study:

key study

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:

1983

Report date:

1983

Materials and methods

Principles of method if other than guideline:

Application of radiolabelled substance and observation of absorption and excretion in urine.

GLP compliance:

no

Remarks:

pre-GLP

Test material

Test material information

Constituent 1

Reference substance name:

Nitrilotrimethylenetris(phosphonic acid)

EC Number:

229-146-5

EC Name:

Nitrilotrimethylenetris(phosphonic acid)

Cas Number:

6419-19-8

Molecular formula:

C3H12NO9P3

IUPAC Name:

[nitrilotris(methylene)]tris(phosphonic acid)

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

5 male (208-222 grams) and 5 female (171-215 grams) Wistar rats

Administration / exposure

Type of coverage:

occlusive

Vehicle:

water

Duration of exposure:

48 hours

Doses:

200 µl (0.2 mL) of a 0.88% aqueous solution (pH 7) of 14C-ATMP (equivalent to 1.76 mg ATMP/ rat; 27.1 µCi/rat) was applied to 10 cm² area of shaved skin (24 hours prior to application) under occlusion for 48 hours.
The doses were based upon a mean body weight of 216.4 g for males and 186.4 g for females, equivalent to 8.1 or 9.4 mg/kg bw, respectively.

No. of animals per group:

5 males, 5 females

Details on study design:

PREPARATION OF DOSING SOLUTION
The test sample was prepared by custom synthesis 8.50 mg 14C-ATMP (540 µCi) was mixed with 26.0 mg unlabelled material and 3954 mg double distilled water. The final concentration of ATMP in the dosing solution appears to be 0.89% and not 0.88% as stated in the report.

It is unclear how the solution was neutralised to pH 7.0; use of NaOH may have resulted in the formation of the sodium salt.

SAMPLE COLLECTION
Radioactivity present in urine, faeces, exhaled air (14C-carbon dioxide), skin (application site), carcass and cage wash was quantified over a 48 hours post-application period.

Results presented as mean and SD.

Results and discussion

Absorption in different matrices:

The majority of the dose remained at the application site 48 hours after application, with trace amounts excreted in urine, faeces and as 14C-carbon dioxide or remaining in the carcass:
- Urine: 0.2-0.5%
- Faeces: 0.087-0.03%
- CO2: 0.087-0.061%
- Skin (application site): 76.3-60.2%
- Carcass: 0.22-0.35% (Mean data for males or females, respectively). The total absorbed over 48 hours was 0.603% of the dose in males, and 0.940% of the dose in females.
Of the material absorbed:
- urinary excretion was virtually complete during the first 24 hours post-treatment (93-95% of total present in urine) with negligible excretion between 24-48 hours;
- faecal elimination was comparable over 0-24 hours and 24-48 hours (approximately 50% of total excreted present at each time point);
- slightly more 14C-CO2 was exhaled over 0-8 hours (40-50% of total excreted) than over 8-24 hours or 24-48 hours.

Percutaneous absorption

Percutaneous absorption 1

Time point:

48 h

Dose:

200 µl of a 0.88% aqueous solution (pH 7) of 14C-ATMP

Parameter:

percentage

Remarks:

male rats

Absorption:

0.603 %

Percutaneous absorption 2

Time point:

48 h

Dose:

200 µl of a 0.88% aqueous solution (pH 7) of 14C-ATMP

Parameter:

percentage

Remarks:

female rats

Absorption:

0.94 %

Any other information on results incl. tables

Absorption: 0.603% (male); 0.94% (female)

Excretion: the majority of the absorbed radiolabelled ATMP was excreted in the urine within 24 hours of treatment.

Applicant's summary and conclusion

Conclusions:

In a dermal absorption study, not conducted according to any OECD Test Guideline and pre-GLP (Reliability 2), the cutaneous absorption of radiolabelled ATMP over 48 hours was 0.603% in male rats and 0.94% in females. 60-75% of the applied material was recovered from the application site at 48 hours. Radioactivity was excreted mainly in urine over the first 24 hours following application.