3-iodo-2-propynyl butylcarbamate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1995-03-01

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1995

Report date:

1995

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

EPA OPP 85-1 (Metabolism and Pharmacokinetics)

Deviations:

no

Test guideline 2

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

no

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

3-iodo-2-propynyl butylcarbamate

EC Number:

259-627-5

EC Name:

3-iodo-2-propynyl butylcarbamate

Cas Number:

55406-53-6

Molecular formula:

C8H12INO2

IUPAC Name:

3-iodoprop-2-yn-1-yl butylcarbamate

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
Radiolabelled
- Source and lot/batch No.of test material: ZC9383

Unlabelled:
- Batch: 9312-7356

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

other: Crl:CDBR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: 5 - 9 weeks
- Weight at arrival: Males: 182 - 297 g; females: 180 - 205 g
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature: 19 - 25 °C
- Humidity: 50 +/- 20 %
- Photoperiod: 12 / 12 hrs dark / hrs light

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: carboxymethylcellulose (CMC)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Radiolabeled dosing solutions were prepared by combining known amounts of radiolabeled test item, non-radiolabeled test item, and 0.5% (w/w) carboxymethylcellulose (CMC). The specific activity of the radiolabeled material was used to determine the mass of the 14C-test item in each dose. The amount of the non-radiolabeled test item and 0.5% CMC added to each dose and the total dose weight were measured gravimetrically. The components of the dose solutions were mixed at room temperature to ensure homogeneity. The 14C-dose solutions were prepared and verified for concentration and homogeneity either the day of or the day before dosing; they were stored in a refrigerator or at room temperature until use. The concentrations of the dosing solutions during dosing were determined by radioanalysis of pre- and post-dose aliquots of each solution. Results of the pre- and post-dose aliquot analyses were used to calculate the actual dose applied to each animal.

Duration and frequency of treatment / exposure:

Group A: single oral high dose (104 mg/kg bw actual received)
Group B: multiple oral low dose (14 daily doses of non labeled substance followed by a single radiolabeled dose on the 15th day; 20.4 mg/kg bw actual received)
Group C: single oral high dose (121 mg/kg bw actual received)
Group D: single oral low dose (19.1 mg/kg bw actual received)

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

20 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

125 mg/kg bw/day (nominal)

No. of animals per sex per dose / concentration:

Group A and B: 5 animals/sex
Group C and D: 9 animals/sex

Control animals:

no

Positive control reference chemical:

not applicable

Details on study design:

- Dose selection rationale: based on data of other toxicity studies
- Rationale for animal assignment: random

Details on dosing and sampling:

TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled:
Group A and B: urine, faeces, exhaled air (every 24 h), blood and residual carcass (terminal sacrifice),
Group C and D: urine, faeces (after 2 and 4 h for the 2- and 4-hour sacrifice animals, every 24 h for the 5-day sacrifice animals), bone marrow, eyes, heart, liver, muscle, spleen, thyroid, bone, brain, fat, kidneys, lungs, ovaries, skin, testes, uterus, and residual carcass at sacrifice
- Time and frequency of sampling:

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: see above
- Time and frequency of sampling: see above
- Method type for identification: Liquid scintillation counting

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

The test item is completely absorbed via the oral route

Main ADME results 2

Type:

distribution

Results:

The test item was completely distributed over the bodies of either dose and sex

Main ADME results 3

Type:

metabolism

Results:

The test item is exensively transformed in the rat

Main ADME results 4

Type:

excretion

Results:

Major elemination route was in the urine in all groups and sexes

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

The test item was extensively metabolised in the rat. It first underwent reductive dehalogenation to form PBC which is afterwards further metabolised by oxidative dealkylation. Major metabolites were the two stereo conformers of Propargyl-N-acetic acid carbamate and carbondioxide. Metabolites found in trace amounts included Methyl-N-butylcarbamate, 1-Hydroxybutamide and Propargyl-N-methylcarbamate. Several other trace metabolites could not be further characterised. Glucuronidation appeared to be the main secondary metabolism pathway.

Applicant's summary and conclusion

Conclusions:

14C-labelled test item was administered orally to four groups of rats. Total mean recoveries for the individual dose groups (Groups A and B) were 106% and 96.1% for males and 98.1% to 81.9% for females, respectively. The majority of the radioactivity was recovered in urine (57.3% to 70.7%), a smaller amount (18.3% to 24.0%) was recovered in CO2, 4.40% to 7.44% in feces, and less than 3.1% recovered in carcass and tissues combined. Urine was the primary elimination route, and the majority of the radioactivity was eliminated within 48 Hours postdose. The percent of recovered radioactivity in the tissues (Groups C and D) declined with time through 120 hours postdose. All of the examined tissues for both male and female animals had less than 0.9% (excluding carcass) of the total administered radioactivity at 120 hours postdose. The concentration of radioactivity declined in the tissues with time through the final 120 hour postdose collection, although detectable amounts of radioactivity were found for both male and female animals in all matrices.
The test item is extensively biotransformed in the rat. The parent compound was not detected in the urine suggesting complete detoxification. Among several radioactive components detected in the urine, the major and the only significant metabolites were two distereomeric conformers of propargyl-N-acetic acid carbamate which accounted for 56% to 72% of urinary radioactivity and 32% to 51% of total radioactivity administered to the rat. Through the interpretation of its chemical and spectral characteristics, including the use of 2-D NMR, the structure of this metabolite was unambigously established. Metabolites found in the urine in trace quantities include methyl-N-butylcarbamate, 1-Hydroxybutamide and propargyl-N-methylcarbamate. The remaining metabolites were characterized by their chemical and enzymatic properties. Glucuronidation appeared to be the main secondary metabolism pathway; five metabolites were characterized as glucuronides.
Percent and concentration distribution of these metabolites in blood, liver, and kidney were determined. For all tissues examined propargyl-N-methylcarbamate and propargyl-N-acid carbamate gave the highest percent and concentration values in the samples collected at 2 and 4 hours postdose. At 120 hours these metabolites were not quantifiable but traces of a group of highly polar but uncharacterized metabolites were found in the tissues.
Among the dose regimens, there were no apparent sex-related differences regarding the absorption, distribution, elimination, or metabolism of 14C-labelled test item in rats.

Executive summary:

The absorption, distribution, elimination, and biotransformation of the test item were studied in male and female rats dosed orally with 14C-labelled test item. A total of 56 animals (28/sex) were placed on test. The test animals were divided into four groups. There were ten animals per group (5 male, 5 female) in Groups A and B which were used for mass balance and metabolite identification. Groups C and D had 18 animals per group (9 male, 9 female) and were used for tissue metabolite identification. Test material administration was as follows: single oral high dose (104 mg/kg, Group A), multiple oral low dose (14 daily nonradiolabeled doses followed by a single radiolabeled dose on the 15th day, 20.4 mg/kg, Group B), single oral high dose, (121 mg/kg, Group C), and single oral low dose (19.1 mg/kg, Group D).

Expired organic volatiles and carbon dioxide were collected from Groups A and B. All treated groups had urine and feces collected at prescribed intervals. Animals in Groups A and B were sacrificed 14 days after administration of the radiolabeled dose. Animals in Groups C and D (3/sex) were sacrificed at 2-, 4-, and 120-hours after administration of the radiolabeled dose. Selected tissue samples from Groups C and D were collected, weighed, and analyzed for total radioactivity. Blood, liver and kidney samples were analyzed for parent compound and metabolites.

Among the dose regimens, there were no apparent sex-related differences regarding the absorption, distribution, elimination, or metabolism of 14C-test item in rats.

Total mean recoveries for the individual dose groups (Groups A and B) were 106 % and 96.1 % for males and 98.1 % to 81.9 % for females, respectively. Of the total radioactivity, 57.3 % to 70.7 % was recovered in urine, 18.3 % to 24.0 in CO2, 4.40 % to 7.44 % in feces, and less than 3.1 % in the carcass. Urine was the primary elimination route and the majority of the radioactivity was eliminated within 48 hours postdose. The percent of recovered radioactivity in the tissues (Groups C and D) declined with time through 120 hours postdose. All of the examined tissues for both male and female animals had less than 0.9% (excluding carcass) of the total administered radioactivity at 120 hours postdose. The concentration of radioactivity declined in the tissues with time through the final 120 hour postdose collection, although detectable amounts of radioactivity were found for both male and female animals in all matrices.

The test item is extensively biotransformed in the rat. The parent compound was not detected in the urine suggesting complete detoxification. Among several radioactive components detected in the urine, the major and the only significant metabolites were two distereomeric conformers of propargyl-N-acetic acid carbamate which accounted for 56 %-72 % of urinary radioactivity and 32 %-51 % of total radioactivity administered to the rat. Metabolites found in the urine in trace quantities include methyl-N-butylcarbamate, 1 -Hydroxybutamide and propargyl-N-methylcarbamate. Other metabolites were characterized by their chemical and enzymatic properties. Glucuronidation appeared to be the main secondary metabolism pathway; five metabolites were characterized as glucuronides. Percent and concentration distribution of these metabolites in blood, liver and kidney were determined. For all tissues examined propargyl-N-methylcarbamate and propargyl -N-acid carbamate gave the highest percent and concentration values in the samples collected at 2 and 4 hours postdose. At 120 hours these metabolites were not quantifiable but traces of a group of highly polar but uncharacterized metabolites were found in the tissues.