Isopropyl myristate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

5 in. to 168 hours post dosing

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Remarks:

no guideline available

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2006

Report date:

2006

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Rats were orally administered 14C-IPM (carbonyl-14C). Then blood, expirated air, urine and feces were collected at certain intervalls and analysed for parent IPM by GC/MS and profiled for the presence of other radioactive labelled metabolites by LC/RAM/MS. At the end of the study liver, fat and carcass homogenates were analysed too.

GLP compliance:

yes

Remarks:

no certificate attached

Test material

Test material information

Constituent 1

Test material form:

liquid

Specific details on test material used for the study:

Isopropyl myristate (carbonyl -14C)
supplied by Moravek Biochemicals Inc., Brea, California
radiochemical and chemical purity: > 99%, analysed by HPLC
specific radioactivity: 52 mCi/mmol

Radiolabelling:

yes

Remarks:

Carbonyl-14C

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

selection because of their relatively large size, their general suitability and the availability of historical background data

Sex:

male

Details on test animals or test system and environmental conditions:

Jugular and portal vein cannulated rats (dual cannalae) were obtained from Taconic (Germantown, New York
age: 8-12 weeks, healty, identification by metal ear tags
Housing: Singly in glass Roth-type metabolism cages (designed fror the collection of urine, feces, CO2 and organic volatiles)
air was drwn through the cages at ca. 500 ml/min., ralative humidity: 40-70%, room temperature (22°C +/- 3°C), 12-hour light/dark cycle
Feed (Lab Diet in pelleted form) and municipal water ad libitum, but no access to feed 16h before and 4h after dosing
In accordance with the U.S. Department of Agriculture animal welfare regulations the study was reviewed and approved by the Institutional Animal Care and Use Committee (IACUC).

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: PEG-400

Details on exposure:

No access to feed and water 16h before and 4h after oral admnistration of C14-IPM

Duration and frequency of treatment / exposure:

single dose

Doses / concentrations

Dose / conc.:

1 mg/kg bw (total dose)

Remarks:

The dose solution was administered at a target volume of 5g/kg body weight (target radioactivity: 196 µCi/kg bw)

No. of animals per sex per dose / concentration:

4 male rats

Control animals:

yes

yes, concurrent no treatment

Positive control reference chemical:

no

Details on study design:

Potential exposure to IPM will be via the oral route from food that comes into contact with food-contact films. The dose of 1mg/lg bw used in this study is about 12-fold higher than the amount of IPM that could potentially leach from the food contact material in a worst case scenario.

Details on dosing and sampling:

Blood from portal and jugular vein was collected at 5, 10, 15 and 30 minutes and 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours post dosing and analysed fpo IPM, metabolites and radioactivity.
The expired air was passed through a solution of monoethanolamine-1-methoxy-2-propanol to trap expired CO2 and analysed for radioactivity. The CO2 trap was changed at 3, 6, 9, 12, 24 and 48 hours post-dosing.
All urine voided was collected in dry-ice cooled traps at 12, 24, 48, 72, 96, 120, 144 and 168 hours post-dosing and anaylsed for radioactivity and chemicals.
Feces were collected in dry-iced chilled containers during the course of the study in 24h intervals and quantified for radioactivity. A fecal homogenate of one rat from 0-24h sample was chemically analysed.
168 hours after dosing the animals were killed. The Roth cages were washed and the cage wash was analysed for radioactivity.
The following tissues were collected from each animal after sacrifice at 168 hours post-dosing: Blood, liver, skin, kidney, gastro-intestinal tract with contents, fat, residuel carcass and analysed for radioactivity and chemical contents.

Statistics:

desriptive statistics (mean standard deviation) were used and conducted by using Microsoft Excel spreadsheets and databases in full precision mode (15 digits of accuracy).
Certain pharmacokinetic parameters were estimated inboth portal and jugular blood using a pharmacokinetic modeling program (WinNolin, Pharsight Corp., Mountain view; California)

Results and discussion

Preliminary studies:

A probe study was conducted in one jugular vein cannulated male Fischer 344 rat dosed with radiolabelled IPM. Blood, expired volatiles (in a charcoal trap), CO2, urine and feces (only 0-24h and 24-48h samples to cover the transit time through the gastro-intestinal tract of ca. 21h for rats) were collected and analysed for radioactivity. Blood was analysed for parent IPM and metabolites too. The radioactivity of the expired volatiles was <1% and therefore the charcoal trap was removed. The recovery of the radioactivity was low (ca. 50%).

Main ADME results

Type:

metabolism

Results:

It was considered that ester hydrolysis of the 14C-IPM with release of myristic acid that served as a substrate for beta oxidation of the fatty acids to 2-carbon fragments, which are convicted to CO2 and expired.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

14C-labelled material was rapidly absorbed from the gastro-intestinal tract with 2-3fold higher radioactivity appearing inthe portal vein blood than in the jugular vein blood during the rapid absorption period of

Details on distribution in tissues:

No parent IPM was detected in any of the tissues (liver, fat, carcass) and 0-12h urine. Only one minor radioactive peak was observed in the urine sample, which was more polar than the parent IPM. A small 14C-IPM peak was observed in the 0-24h fecal extract, representing unabsorbed dose. At later time points, the relative amount of radioactivity found in the jugular vein blood was slightly higher than that in the portal vein blood. This was considered to be due to lymphatic transport to the systemic circulation through the thoracic duct.
The majority of the recovered 14C-IPM derived radioactivity was found in the CO2 trap (29% of the administered dose over 168h). Urinary and fecel elimination were negligiable (2.1 +/- 0.3 and 3.5 +/- 1.4% of radioactivity). 10% of the radioactivity was found in the carcass (probably in fat), 10 % in the skin, 2% in the gastro-intestinal tract (probably in the mesenteric fat), in liver and kidney below 1% of the administered dose. The total recovery of the radioactivity was 55% +/- 7%. The loss may result by additional CO2 (repeated opening of the cages for sampling).

Transfer into organs

Key result

Observation:

no transfer detectable

Remarks:

most radiolabelled 14C exhaled

Details on excretion:

Urinary and fecel elimination negligiable. The majority of the rcovered 14C-IPM derived radioactivity was exhaled as CO2 within 168hours post-dosing.

Toxicokinetic parameters

Key result

Toxicokinetic parameters:

Tmax: 148-165 h

Remarks:

mean residue time of the radioactivity

Metabolite characterisation studies

Metabolites identified:

no

Remarks:

only radioactive labeled exhaled CO2 detected

Details on metabolites:

No parent compound was detected in blood or other tissue, although the radioctivity was high enough for quantification. Thus it was suggested, that IPM was hydrolyzed prior to its absorption and/or metabolized prior to reaching the blood circulation. This assumption is supported by the fact that no parent compound was found in other tissues homogenates.
Refering other studies, it was discussed that esterases occuring in most mammalian tissues including the gut lumen and intestinal wall give rise to rapid hydrolysis of esters in vivo.

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

not found

Applicant's summary and conclusion

Conclusions:

In this study radioactive labelled IPM (14C-carbonyl) was administered to rats. Parent IPM was not found in blood, feces, urine or other tissues. Radioactivity was found mostly in exhaled CO2. It was suggested, that IPM was hydrolized soon after oral administration.