2-chloroacetamide

Dermal absorption

Administrative data

Endpoint:

dermal absorption in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1985

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The dermal route is relevant for human exposure; current study can add valuable information on absorption, distribution and excretion.

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1985

Report date:

1985

Materials and methods

Principles of method if other than guideline:

14C analysis: absorption, elimination, residues of 14C-chloroacetamide following dermal application

Test material

Test material information

Constituent 1

Reference substance name:

2-chloroacetamide

EC Number:

201-174-2

EC Name:

2-chloroacetamide

Cas Number:

79-07-2

Molecular formula:

C2H4ClNO

IUPAC Name:

2-chloroacetamide

Details on test material:

Own synthesis of lots RCL-No. 12059 I, 4.5 GBq/g (121 mCi/g) & No. 12059 II, 1.7 GBq/g (46.6 mCi/g); melting points 120°C.
Identity established by IR spectra in comparison to unlabelled standard.
Radiochemical purity >= 98% established by TLC & radioactivity scans.
Synthesis based on Ba 14C-Carbonat using a Grignard reaction to form 14C-acetic acid, chlorination, methylation & preparative
GLC to obtain 14C- methyl monochloroacetate, amidation to 14C-chloroacetamide,
purification by sublimation under reduced pressure.

Radiolabelling:

yes

Remarks:

1C-C14

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

Healthy male SPF-Wistar rats (stock: Winkelmann, Kirchborchen, Germany)
weight range: 190 – 280 g

Temperature 21+- 1 °C, relative humidity 45-55 %; single cages (excretions, autoradiography) or cages for two animals (blood
levels, exhalation) with separation devices for urine and faces collection. Feed (Altromin(R) 1324, milled, from Altrogge,
Lage/Lippe, Germany) & drinking water ad libitum.

Administration / exposure

Type of coverage:

occlusive

Vehicle:

water

Duration of exposure:

6 h

Doses:

2.9 or 6.2 mg/mL solution - 2 mg/kg bw

No. of animals per group:

5

Details on study design:

A 1 mL tuberculin syringe was used. The calculated application volume was given dropwise to & distributed evenly on the shaven skin area.
After 6 h, the application area was cleaned several times with a wet swap. The latter had been wettened with tap water & some drops of a tenside .(pricol(R), Henkel, Düsseldorf, Germany).

Results and discussion

Signs and symptoms of toxicity:

not examined

Dermal irritation:

not examined

Total recovery:

77.5 +- 5.0 %

Percutaneous absorption

Parameter:

percentage

Absorption:

14 - 39 %

Remarks on result:

other: 6 h p.appl

Any other information on results incl. tables

Max. blood concentrations of 0.58 +- 0.22 µg equivalent/ml between 2 and 6 h ( 4.4 +- 1.7 h) p. appl.

2-phase elimination from the blood with half-lives of 5.7+-2.1 h (2-8h p. appl.) and 180+-35 h (up to 5 d p. appl.)

Applicant's summary and conclusion

Conclusions:

After dermal administration, maximal plasma levels were observed between 2 and 6 hrs after application. Two elimination half-lives of approximately 6 and 180 hrs were determined for blood. Within 24 hrs, 43% of the administered radioactivity was excreted via
urine, whereas 0.7% of the administered radioactivity was excreted via faeces. At study termination after 24 hrs radioactivity (33% of the applied amount) was still present in organs, tissues, site of application and remaining body. Autoradiography revealed that radioactivity was present in blood, liver, kidneys and also in skin areas that had not been treated. At study termination, 43.4% and 0.68% of the applied radioactivity had been excreted via urine and faeces, respectively. 11.8% of the applied radioactivity was determined in tissues and body compartments excluding treated skin areas, 21.1% of the applied radioactivity was detected in skin of the application site. In total, 77.5% of the applied radioactivity was recovered. Thus, from the percentages of radioactivity excreted and radioactivity present in body compartments different from the application site, 56% of the applied radioactivity is taken as amount absorbed.

Executive summary:

Groups of animals received single doses of (1-14C)-chloroacteamide by the dermal pathway (onto shaved skin of the back; oral intake from treated skin was prevented by fixing a vessel onto the treated skin area). Treated skin areas were washed of 6 hrs after substance administration. Parameters studied were absorption (blood analysis), tissue distribution and excretion in urine and faeces. Termination was after 24 hrs for dermal application. Radioactivity was determined by liquid scintillation and whole-body autoradiography.

After dermal administration, maximal plasma levels were observed between 2 and 6 hrs after application. Two elimination half-lives of approximately 6 and 180 hrs were determined for blood. Within 24 hrs, 43% of the administered radioactivity was excreted via urine, whereas 0.7% of the administered radioactivity was excreted via faeces. At study termination after 24 hrs radioactivity (33% of the applied amount) was still present in organs, tissues, site of application and remaining body. Autoradiography revealed that radioactivity was present in blood, liver, kidneys and also in skin areas that had not been treated. However, at 6 hours there was also clear radioactivity in urinary tract, testes, lung and spleen. At study termination, 43.4% and 0.68% of the applied radioactivity had been excreted via urine and faeces, respectively. 11.8% of the applied radioactivity was determined in tissues and body compartments excluding treated skin areas, 21.1% of the applied radioactivity was detected in skin of the application site. In total, 77.5% of the applied radioactivity was recovered. Thus, from the percentages of radioactivity excreted and radioactivity present in body compartments different from the application site, 56% of the applied radioactivity is taken as amount absorbed.