2-chloroacetamide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics 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 oral 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

Objective of study:

excretion

toxicokinetics

other: residues in organs & tissues

Principles of method if other than guideline:

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

GLP compliance:

no

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-14C

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

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

oral gavage (intragastral) using a pharyngal tube

Duration and frequency of treatment / exposure:

1x

Doses / concentrations

Remarks:

Doses / Concentrations:
0.4 mg/mL; 2 mg/kg bw

No. of animals per sex per dose / concentration:

10

Control animals:

no

Details on dosing and sampling:

Blood samples were taken from retrobulbous veins.
Spontaneous urine and feces were collected within the sampling periods.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

30 min after dosage, blood levels were 1.17+- 0.20 µg equivalent/ml, i.e. 84 % of max. blood levels.
The latter were 1.39+-0.06 µg equivalent/ml and were observed bewtween 1 and 3 h after dosage.

Details on distribution in tissues:

Residues were calculated from the remaining radioactivities.
7 d after oral dose, altogether 8.96 + 0.68 % of the dose was found in the tissues and organs, mainly in the blood (2.3 %) and
the remaining body (4.2 %), further in the skeletal muscles (1.0%), the liver (0.4 %) and the skin (0.5 %).

Details on excretion:

Radioactivity was predominantly excreted in the urine. Within 7 days after dosage, 90.8 +- 2.1 % of the dose had been renally eliminated. In the feces and in the cages’ rinsing water 3.0 % and 0.6 % were found, respectively. Altogether, 94.4 +- 2.3 % of the dose was recovered within 7 days.
Renal elimination took place with half lives of 6 h (early phase) and 46 h (terminal phase). Since fecal elimination was much lower, half life could only be given for the terminal phase. Its half life of 32 h was in the same range as determined for renal excretion.
Elimination were practically the same as observed after i.v. dose.

Toxicokinetic parameters

Toxicokinetic parameters 1

Toxicokinetic parameters:

C(time): blood: 1 - 3 h p.appl.

Toxicokinetic parameters 2

Toxicokinetic parameters:

Cmax: blood: 1.39 +- 0.06 µg equivalent/ml

Toxicokinetic parameters 3

Toxicokinetic parameters:

half-life 1st: blood: 5.6 +- 0.9 h

Toxicokinetic parameters 4

Toxicokinetic parameters:

half-life 2nd: blood: ca. 520 h

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results At study termination after 7 d, radioactivity could still be detected in plasma. Remaining total body radioactivity after 7 days was 9% of the administered radioactivity.
After oral administration, maximal plasma levels were observed 1-3 hrs after administration. Two elimination half-lives of 5.6 and 520 hrs were determined for blood. Within 7 days after administration, 90% of radioactivity was excreted via urine, whereasradioactivity in faeces and cage wash amounted to 3.6%. At study termination after 7 d, radioactivity could still be detected in plasma. Remaining total body radioactivity after 7 days was 9% of the administered radioactivity. Highest amounts were found in blood, heart, lungs, liver and spleen.

Executive summary:

Groups of 10 animals received single doses of (1-14C)-chloroacteamide by the oral pathway. Parameters studied were absorption (blood analysis), tissue distribution) and excretion in urine and faeces. Termination was after 7 days. Radioactivity was determined by liquid scintillation and whole-body autoradiography. After oral administration, maximal plasma levels were observed 1-3 hrs after administration. Two elimination half-lives of 5.6 and 520 hrs were determined for blood. Within 7 days after administration, 90% of radioactivity was excreted via urine, whereas radioactivity in faeces and cage wash amounted to 3.6%. At study termination after 7 d, radioactivity could still be detected in plasma. Remaining total body radioactivity after 7 days was 9% of the administered radioactivity. Highest amounts were found in blood, heart, lungs, liver and spleen.