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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Study period:
3 July 2002 to 26 Sept 2002
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002
Report date:
2002

Materials and methods

Objective of study:
absorption
distribution
excretion
metabolism
Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
425-950-7
EC Name:
-
Cas Number:
187393-00-6
Molecular formula:
C38-H49-N3-O5
IUPAC Name:
5-[(2-ethylhexyl)oxy]-2-(4-{4-[(2-ethylhexyl)oxy]-2-hydroxyphenyl}-6-(4-methoxyphenyl)-1,3,5-triazin-2-yl)phenol
Details on test material:
- Name of test material (as cited in study report): CGF-C1607
- Molecular weight: 627.8
- Physical state: Powder
- Analytical purity: >=98%
- Purity test date: 29 June 2000
- Lot/batch No.: 003630B8M
- Expiration date of the lot/batch: 31 Dec 2002
- Radiochemical purity (if radiolabelling): 99%
- Specific activity (if radiolabelling): 2.17 GBq/mMole
- Locations of the label (if radiolabelling): Phenoxymethyl carbon
Radiolabelling:
yes
Remarks:
14-C

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Biological Services Section, Alderley Park, Macclesfield, Cheshire
- Age at study initiation: no data
- Weight at study initiation: 254 - 286 (mean 272) grams for males; 224 - 254 (mean 239) grams for females
- Fasting period before study: no
- Housing: individual stainless steel metabolism cages (for excretion / distribution study) & stock cages for blood sampling study
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): Rat and Mouse #1 maintenance diet; Special Diet Services, Stepfield, Whitham; ad libitum
- Water (e.g. ad libitum): tap, ad libitum
- Acclimation period: 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +- 3
- Humidity (%): 30 - 70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 3 July 2002 To: 26 Sept 2002

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
PEG 400
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

The dose preparation was formulated as a suspension and comprised unlabelled CGF-C1607 and [14C]-radiolabelled CGF-C1607 homogeneously dispersed in the dose vehicle, polyethylene glycol (PEG 400). As the test substance was dosed as a suspension, the unlabelled CGF-C1607 and [14C]-radiolabelled CGF-C1607 were mixed and milled to a particle size comparable to that of the unlabelled CGF-C1607 supplied, nominally 10 gm, prior to dose preparation. The concentration of unlabelled and [14C]-radiolabelled CGF-C 1607 in the dose preparation was 11.0 mg CGF-C1607/g. The specific activity of the test substance in the dose preparation was 103.4 kBq/mg. When administered at a nominal dose level of 4 ml/kg, this represented a nominal dose level of 50 mg/kg and a mean radiochemical dose of 5.11 MBq/kg.
Duration and frequency of treatment / exposure:
Single dose
Doses / concentrations
Remarks:
Doses / Concentrations:
50 mg/kg-bw
No. of animals per sex per dose / concentration:
4 (for mass balance study)
9 (for blood sampling study)
Control animals:
no
Positive control reference chemical:
None
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)

Tissues and body fluids sampled: For rats 1-8, urine and faeces were collected and the following whole tissues were removed: brain, spleen, liver, kidneys, pituitary, thymus, adrenal glands, testes and epididymis or ovaries, uterus and mammary tissue as appropriate, together with a representative sample of peri-renal adipose tissue (fat). The gastrointestinal tract including contents was removed. For rats 9-26, serial blood samples were collected.

Time and frequency of sampling: For rats 1-8, urine and faeces were collected 24, 48, 72 and 96 hours after dosing and were terminated 96 hours after dosing. Following removal of each rat, the metabolism cages were washed with ethanol : water (1:1 v/v). Terminal blood sample were taken by cardiac puncture and divided between two pre-weighed heparinised tubes, which were weighed as a pair before one was centrifuged to separate plasma. For rats 9-26, serial blood samples were collected by tail venepuncture at 1, 2, 4, 6, 8 and 10 hours after dosing and were terminated 12, 18 or 24 hours after dosing at which time terminal blood samples were taken by cardiac puncture.

Termination method: Each rat was killed by exsanguination under terminal anaesthesia, using Halothane Ph Eur vapour.

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled (delete / add / specify): faeces
- Time and frequency of sampling: 0-24 hours, 24-48 hours, 48-72 hours, and 72-96 hours
- From how many animals: 8 males & 8 females
- Method type(s) for identification: HPLC-MS using a Finnigan MAT LCQ ion trap mass spectrometer equipped with an electrospray source.

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
negligable (blood samples below limit of detection at all time points)
Type:
excretion
Results:
94% in faeces and 0.1% in urine (males), 97% in faeces and 0.2% in urine (females)
Type:
distribution
Results:
<0.01% of dose remained in tissues. No specific target tissue could be identified. 0.26% of dose (males) and 0.1% of dose (females) remained in residual carcass.
Type:
metabolism
Results:
>99.6% of dose excreted as unchanged test substance. No metabolites could be identified.

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
No metabolites could be identified; >99.6% of dose was excreted as unchanged test substance.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Following a single oral dose of 50 mg [14C]-CGF-C1607/kg to male and female rats, excretion was rapid in both sexes, with 94-97% of the administered dose excreted directly in faeces within 96 hours as unchanged CGF-C1607. This is consistent with the measured concentrations of radioactivity in blood and plasma of less than the limit of detection. Quantitatively, no sex difference was observed. Urinary excretion accounted for 0.1-0.3% of the dose, and residual radioactivity in tissues and carcass accounted for 0.1-0.3% of the dose. Residues in individual tissues were all <0.01% of the dose. Following oral dosing, it is considered that absorption of [14C]-CGF-C1607 was very low.
Executive summary:

Groups of male and female rats were each given a single oral dose of 50 mg [14C]-CGF-C1607/kg to investigate systemic exposure, tissue distribution and metabolite profiles. The excretion of radioactivity in urine and faeces was monitored for 4 days after dosing. After this period, the rats were killed and residual radioactivity was measured in blood, selected tissues and the remaining carcasses. An additional group of nine male and nine female rats were each given a single oral dose of 50 mg [14C]CGF-C1607/kg and radioactivity was measured in blood and plasma over a 24 hour time course after dosing.

Excretion was rapid and extensive in both male and female rats. Urinary excretion accounted for mean totals of 0.1% and 0.2% of the dose and faecal excretion accounted for mean totals of 94% and 97% of the dose for males and females respectively. Only one component was found in the faecal extracts and this was identified as parent CGF-C1607. Unchanged CGF-C1607 therefore represented all of the dose excreted in faeces in both male and female rats. Residues in the tissues were very low and accounted for <0.01% of the dose in total in both males and females. The radioactivity remaining in the residual carcass accounted for 0.3% of the dose for males and 0.1% for females. The total recoveries of administered radioactivity were approximately 95% for males and 97% for females. The concentration of radioactivity in blood and plasma was below the limit of detection at all time points up to 24 hours after dosing. The mean limits of detection were <0.038 µg/g and <0.019 µg/g in blood and plasma respectively.