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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Similar to guideline, but with acceptable deviations; considered adequate for assessment.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
2005
Reference Type:
secondary source
Title:
Unnamed
Year:
2008

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
Remarks:
small group size, low mass-balance recovery
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): [8-14C] MCCPs mixed with Cereclor S52
- Substance type: technical product
- Physical state: liquid
- Analytical purity: no data
- Impurities (identity and concentrations): no data on presence/absence of stabiliser
- Composition of test material, percentage of components: C14-17 chlorinated paraffins; 52% chlorinated
- Purity test date: no data
- Lot/batch No.: 9695/1 (Cereclor S52); 02BLY0137 (8-14C MCCPs)
- Expiration date of the lot/batch: no data
- Radiochemical purity (if radiolabelling): no data
- Specific activity (if radiolabelling): 1.06 mCi/g
- Locations of the label (if radiolabelling): 8-14C
- Expiration date of radiochemical substance (if radiolabelling): no data
- Stability under test conditions: no data
- Storage condition of test material: formulation stored at -20oC
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS- Source: Harlan UK- Age at study initiation: 6-7 weeks plus 2-5 days- Weight at study initiation: 191-244 g- Fasting period before study: no data- Housing: - Individual metabolism cages: yes- Diet (e.g. ad libitum): ad libitum- Water (e.g. ad libitum): ad libitum- Acclimation period: 2-5 daysENVIRONMENTAL CONDITIONS- Temperature (°C): 19-23- Humidity (%): 40-70- Air changes (per hr): 15- Photoperiod (hrs dark / hrs light): 12/12IN-LIFE DATES: From: 1 MAR 2004 to 24 JUN 2004

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: 1 g of 14C-MCCP plus 1.20833 g of unlabelled Cereclor S52 were made up to a total volume of 42 ml with corn oil, giving a dosing solution of 52.5 mg/ml.VEHICLE- Justification for use and choice of vehicle (if other than water): test material solubility- Concentration in vehicle: 52.5 mg/ml- Amount of vehicle (if gavage): 10 ml/kg bwHOMOGENEITY AND STABILITY OF TEST MATERIAL: 4 samples analysed by LSC
Duration and frequency of treatment / exposure:
Single dose on Day 1; groups of 3 animals killed on days 2, 5, 12, 26, 54 and 89
Doses / concentrations
Remarks:
Doses / Concentrations:525 mg/kg bw
No. of animals per sex per dose:
18
Control animals:
no
Positive control:
no
Details on study design:
- Dose selection rationale: no data
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)- Tissues and body fluids sampled: urine, faeces, blood, plasma, liver, kidneys, lungs, heart, brain, testes, spleen, muscle, fat, skin and fur, residual carcass- Time and frequency of sampling: - urine/faeces on days 1, 2, 3, 4, 8, 9, 10, 11, 22, 23, 24, 25, 50, 51, 52, 53, 85, 86, 87 and 88 days post-dosing- blood/plasma /tissues on days 2, 5, 12, 26, 54 and 89
Statistics:
None

Results and discussion

Preliminary studies:
None
Main ADME resultsopen allclose all
Type:
absorption
Results:
Only about 30% of the orally administered dose of a C14 -17 chlorinated paraffin (52% chlorination) was absorbed by day 4 from the GI tract
Type:
distribution
Results:
Twenty-four hours after dosing, the liver, kidney, fat and skin/fur contained the highest concentrations of radioactivity
Type:
excretion
Results:
Approximately 50% of the administered dose was eliminated in the faeces in the first 24 hours. At day 4, about 71% of the administered dose was excreted via the faeces and 6% in the urine.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
At 96 hours post dosing, 71.4% of the dose was eliminated in faeces, suggesting that only about 30% of the orally administered dose was absorbed by day 4.
Details on distribution in tissues:
Twenty-four hours after dosing, the liver, kidney, fat and skin/fur contained the highest concentrations of radioactivity (1.6, 0.07, 0.78 and 2.7% of the administered dose respectively). Thereafter, concentrations of radioactivity declined in all tissues except for the fat and the skin/fur, with the highest levels seen on days 5 and 12. The amount of the administered dose recovered from body tissues including blood remained at approximately 7% until day 12, but it declined to approximately 2% by day 89. Elimination of radioactivity from body tissues occurred with an elimination half-life of approximately 2-5 days (well perfused tissues such as liver and kidney) or approximately 2 weeks (poorly perfused tissues such as white fat).
Details on excretion:
Excretion via the faeces was the major route of elimination of radiolabelled material, with approximately 50% of the administered dose accounted for within the first 24 hours after dosing and 71% by 96 hours post dosing. Elimination in urine accounted for approximately 6% of the administered dose after 4 days. Radioactivity remained measurable in the urine and faeces for the 13 week duration of the study.

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
no data

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study resultsThe results of this study indicate that, in the male F344 rat, approximately 30% of a single dose of an [8-14C]-labelled C14-17 chlorinated paraffin of 525 mg/kg bw was absorbed from the GI tract and this was widely distributed in tissues. The faeces were the major route of elimination of the radiolabelled material. The elimination half-life of a single dose in well-perfused tissues such as the liver and kidneys was 2-5 days whilst in poorly-perfused tissues such as white adipose tissue, it was about 2 weeks.
Executive summary:

The absorption, tissue distribution and elimination of a14C-labelled C14 -17 chlorinated paraffin (52% chlorinated) after a single oral gavage administration at a dose level of 525 mg/kg bw was investigated in male rats. Radioactivity in blood and plasma, urine and faeces, selected tissues (but not gastrointestinal tract) and residual carcass was determined for up to 89 days post dosing.

In animals kept in metabolism cages until termination, the average total recovery of radioactivity from urine, faeces and those tissues and organs sampled was 83.6% of the administered dose. Residual activity in the gastrointestinal tract and bladder and in cage washings was not determined.

Excretion via the faeces was the major route of elimination of radiolabelled material. Approximately 71% of the dose was recovered in the faeces and approximately 6% in the urine in the first 4 days after administration. Radioactivity was still detectable in urine and faeces at the end of the study.

Distribution of radioactivity into the liver and kidney was rapid, with highest levels (1.6 and 0.07% of the dose respectively) seen 24 hours after dosing; whereas distribution into fat and skin-and-fur was slower with the highest levels (2.5 and 3.7% respectively) seen on day 12 post-dosing. After reaching a peak, elimination of radioactivity from the tissues occurred with a half-life of approximately 2-5 days (well perfused tissues such as the liver and kidneys) or approximately 2 weeks (poorly perfused tissues such as white adipose tissue).

Only about 30% of the orally administered dose was absorbed by day 4 from the GI tract, the majority being excreted in the faeces. On completion of the study (88 days) approximately 2% of the administered radioactivity remained in the tissues, primarily in the skin and fur.