Distillates (petroleum), hydrotreated light paraffinic

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

2011

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Human study in compliance with ICH Guideline for Good Clinical Practice, 1997

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

2011

Report date:

2011

Reference 2

Reference Type:

publication

Title:

Unnamed

Year:

2012

Materials and methods

Objective of study:

absorption

Test guideline

Guideline:

other: Non guideline – human testing but in compliance with ICH Guideline for Good Clinical Practice, 1997

Test material

Test material information

Constituent 1

Reference substance name:

8042-47-5

Cas Number:

8042-47-5

IUPAC Name:

8042-47-5

Constituent 2

Reference substance name:

15 cSt Paraffinic Hydrotreated White Oil (P15H)

IUPAC Name:

15 cSt Paraffinic Hydrotreated White Oil (P15H)

Test material form:

other: Oily liquid

Details on test material:

-Name of test material (as cited in study report): 15 cSt Paraffinic Hydrotreated White Oil (P15H)
-Type: Low viscosity oil
-Physical state: Liquid
- Storage condition of test material: Room temperature
- Certificate of analysis available
- Meets the purity requirements of the European Pharmacopoeia, US Pharmacopoeia, Food and Drug Administration, 21 CFR 178.3620 (a) and 21 CFR 172.878

Test animals

Species:

human

Sex:

female

Details on test animals or test system and environmental conditions:

Age: 18-35 years of age
Body weight: 55-85 kilograms

Alcohol consumption > 2l units/week
Not pregnant or lactating, not planning to conceive during the period of the study and using acceptable contraception.
No history of medical or endocrine diseases or surgical events that may significantly affect the study outcome.
No prescribed medication (except paracetamol occasionally)
No use of specific cosmetics (e.g. body lotion, baby oils, lipstick or pomade) prior to and during study period.

Administration / exposure

Route of administration:

oral: capsule

Details on exposure:

One single oral dose of Pl5H oil was given in a gelatin capsule, followed by blood sampling at pre-determined time points up to 168 hours post administration. Capsules contained on average 71.2 mg (min 70 mg, max 74 mg) p15H -tetracosane mix

Duration and frequency of treatment / exposure:

Single administration

Doses / concentrations

Remarks:

Doses / Concentrations:
The capsules contained on average 71.2 mg (min 70 mg, max 74 mg) P15H oil - tetracosane mix. The capsules were ranked according to weight and were given to the subjects based on their body weight. The actual dosing was therefore on average 1.09 +/- 0.12 mg mix/kg BW. After correction for the 8% tetracosane present, the P15H oil dose was on average 1.00 +/- 0.11 mg/kg BW.

No. of animals per sex per dose / concentration:

9

Control animals:

no

Details on study design:

One single oral dose of Pl5H oil was given in a gelatin capsule, followed by blood sampling at pre-determined time points up to 168 hours post administration. Capsules contained on average 71.2 mg (min 70 mg, max 74 mg) p15H -tetracosane mix. The study consisted of 7 days (168 h). Blood samples were taken at predose and at 1 , 2, 4, 8, 24, 48, 72, 96 and 168 h after dosing. The samples were extracted with hexane followed by analysis using two-dimensional gas chromotography-mass spectrometry (GCxGC-MS).

Details on dosing and sampling:

One single controlled oral dose of P15H oil was given in a capsule spiked with C24D50 (tetracosane-d50) as a marker. The intended dose P15H-oil was set at 1 mg/kg BW. Each capsule contained on average 71.2 mg mix containing 65.8 mg P15H white oil and 5.6 mg tetracosane-d50. The white mineral oil was already delivered at TNO in two glass containers at the start of the rat study in 2009. For preparing the doses for the current human volunteer study the sealed container was opened and this content was used for the preparation of the doses. The spiking of the P15H white oil and the subsequent filling of the capsules was performed by TNO in the sterile flow cupboard at Test Material Administration. The mix was prepared by mixing 0.0799 mg C24D50 in 0.9242 mg P15H oil. To avoid any potential dissolving of the gelatine capsule prior to consumption, they were filled in the early morning, about 1 h prior to consumption. The mix was prepared a few days earlier, to allow an even distribution of the intemal marker in the P15H oil. After inclusion of all subjects, the subjects received an entry number based on order of arrival on the first study day. Entry numbers consisted of the TNO study number (9051), followed by a slash ('/'), followed by a 2-digit number (01-09).

Statistics:

No statistical analysis was performed. For data analysis pharmacokinetic analysis was planned using WinNonlin® Version 6.1. (Phoenix).

Results and discussion

Preliminary studies:

No

Main ADME results

Type:

other:

Results:

The concentration of P15H in blood was below the limit of detection (0.163 ug/ml) in all samples from all subjects, hence no kinetic parameters could be derived.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): other: no appreciable absorption of P15H oil at a dose 2-4 fold greater than the estimated human daily intake
It was concluded that a dose of 1 mg/kg BW P15H oil in female human volunteers resulted in blood levels below the limit of detection. This suggests that there was no appreciable absorption of P15H oil at a dose that was 2-4 fold greater than the estimated human daily intake. In contrast, toxicokinetic studies conducted in Fischer 344 and Sprague- Dawley rats, showed higher bioavailability in both rat species than in humans.

Executive summary:

The absorption and kinetics of a sample of P15H white oil was investigated in nine female volunteers (age 18 -35 years) following single oral administration. The white oil was administered in a gelatine capsule, with each capsule containing on average 71.2 mg (min 70 mg, max 74 mg) P15H - tetracosane mix. After adjustment for body weight, the subjects received on average 1.09 +/- 0.12 mg mix/kg BW. After correction for the tetracosane content of the mixture (8%), the dose of P15H oil was on average 1.00 +/- 0.11 mg/kg BW. Blood samples were taken prior to treatment, and then at regular intervals over 7 days (that is: 1, 2, 4, 8, 24, 48, 72, 96 and 168 hours post-dose). The samples wereextracted with hexane followed by analysis using two-dimensional gas chromatography-mass spectrometry (GCxGC-MS). No clinical signs or adverse symptoms were reported by the volunteers. Results of blood analyses showed that the concentration of P15H white oil in the blood was below the average within laboratory detection limit (0.163 ug/mL) at all timepoints, hence no kinetic analyses were possible. At a dose 2-4 times that estimate daily intake, no appreciable absorption of P15H oil occurred.