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Toxicological information

Basic toxicokinetics

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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:
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

Reference
Name:
Unnamed
Type:
Constituent
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 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:
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 parametersopen allclose all
Toxicokinetic parameters:
C(time): blood: 1 - 3 h p.appl.
Toxicokinetic parameters:
Cmax: blood: 1.39 +- 0.06 µg equivalent/ml
Toxicokinetic parameters:
half-life 1st: blood: 5.6 +- 0.9 h
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.