Petrolatum (petroleum), oxidized, calcium salt

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: This study is classified as reliable with restrictions and is an acceptable, well-documented study report that followed sound scientific principles.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2002

Report date:

2002

Materials and methods

Principles of method if other than guideline:

The method did not strictly follow the guideline but is deemed appropriate as utilized in this report.

A high dose and low dose of radiolabeled mineral hydrocarbons (MHCs) was administered via oral gavage to two rat strains in an elimination study. Urine, faeces, and exhaled air were collected at different time point and analyzed for radioactivity. Animals were killed after 96 hours and blood, liver, mesenteric lymph nodes, and content of bladder and intestine were collected and analyzed.

In the pharmacokinetic and disposition studies, female rats of two strains with indwelling jugular vein cannulas were orally administered a low and high dose of test material. During the study urine and faeces were collected and blood samples were taken. Also, three rats were killed at each time point and blood, liver, mesenteric lymph nodes, and the contents of the bladder and intestines were collected and analyzed.

In the metabolite identification study, male rats were orally administered a high dose of MHCs and urine samples were collected and analyzed for metabolite profile and major urinary metabolites.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

[14C]1-eicosanylcyclohexane radiolabeled mineral hydrocarbon

IUPAC Name:

[14C]1-eicosanylcyclohexane radiolabeled mineral hydrocarbon

Details on test material:

Read across to Highly Refined Base Oils
- Name of test material (as cited in study report): [1-14C]1-eicosanylcyclohexane ([14C]EICO)
- Substance type: white oils or waxes (mineral hydrocarbons a class of highly refined petroleum products) with substantial levels of saturated hydrocarbons in the range of C18 to C32
- Physical state: liquid
- Analytical purity: 99.9%
- Composition of test material, percentage of components:
- Isomers composition: not provided
- Purity test date: not provided
- Lot/batch No.: not provided
- Expiration date of the lot/batch: not provided
- Radiochemical purity (if radiolabelling): 99.9%
- Specific activity (if radiolabelling): 17 mCi/mmol
- Locations of the label (if radiolabelling): 1-14C
- Expiration date of radiochemical substance (if radiolabelling): not provided
- Stability under test conditions: not provided
- Storage condition of test material: not provided

Radiolabelling:

yes

Remarks:

14C

Test animals

Species:

rat

Strain:

other: Sprague-Dawley and F-344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hilltop Laboratory Animals, Inc. (Scottdale, PA)
- Age at study initiation: not provided
- Weight at study initiation: 175 to 199 grams
- Fasting period before study: yes, animals were fasted for 18 hours before test material administration in the elimination study.
- Housing: animals were individually housed in sealed glass cages
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): teklad 4% mouse-rat diet was provided ad libitum
- Water (e.g. ad libitum): water was provided ad-libitum
- Acclimation period: five to seven days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 22°C
- Humidity (%): not provided
- Air changes (per hr): there was a constant inflow of ambient air during the testing procedures
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark


IN-LIFE DATES: not provided

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

olive oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: approximately 400 µl of [14C]EICO in hexane was added to 1.6 ml of white oil and warmed slightly to remove hexane volume and facilitate dissolution. 6.4 ml of olive oil was then added to the white oil [14C]EICO mixture without further warming and thoroughly mixed. The resulting 8.0 ml mixture was allowed to cool to room temperature before dosing.

DIET PREPARATION
- Rate of preparation of diet (frequency): N/A
- Mixing appropriate amounts with (Type of food): N/A
- Storage temperature of food: N/A

VEHICLE
- Justification for use and choice of vehicle (if other than water): not provided
- Concentration in vehicle: 1:4 v/v
- Amount of vehicle (if gavage): 6.4 ml of olive oil
- Lot/batch no. (if required): not provided
- Purity: not provided


HOMOGENEITY AND STABILITY OF TEST MATERIAL: not provided

Duration and frequency of treatment / exposure:

In the routes of elimination study, oral pharmacokinetic and disposition studies, and metabolite identification study, each rat was administered a single oral gavage dose of test material.

Doses / concentrations

Remarks:

Doses / Concentrations:
In the routes of elimination study, each rat was administered a single oral gavage dose of 1.80 g/kg. In the oral pharmacokinetic and disposition studies rats were orally administered either a high dose of 1.80 g/kg or a low dose of .18 g/kg of [14C]EICO tracer, mineral hydrocarbons, and olive oil. In this same. Female rats of both strains were administered a single high dose (1.80 g/kg) of eicosanylcyclohexane (unlabeled), [14C]EICO tracer, and olive oil. In a metabolite identification study, male Sprague-Dawley rats were orally administered a single high dose of 1.80 g/kg of eicosanylcyclohexane (unlabeled), olive oil, and the [14C]EICO tracer.

No. of animals per sex per dose / concentration:

No information provided

Control animals:

no

Positive control reference chemical:

No information provided

Details on study design:

- Dose selection rationale: not provided
- Rationale for animal assignment (if not random): not provided

Details on dosing and sampling:

ROUTES OF ELIMINATION STUDY
During this study, rats were fasted for 18 hours prior to oral administration of test material, but water was provided ad libitum. Each rat was dosed with 1.80 g/mg of test material and immediately placed in individually sealed glass metabolism cages with a constant flow of ambient air. Food was reintroduced two hours after dosing. At 8, 16, 24, 48, and 72 hours, urine, faeces, and exhaled organics and carbon dioxide were collected. All exhaled solvents were collected and measured for total radioactivity by direct liquid scintillation counting. At 96-hours rats were killed and blood was collected from the inferior vena cava, and the liver, mesenteric lymph nodes, kidneys, lungs, heart, spleen, and subcutaneous fat were excised. All samples were analyzed for radioactivity by liquid scintillation counting.

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, blood, liver, and mesenteric lymph nodes, and contents of the intestine and bladder samples were taken
- Time and frequency of sampling: three rats per strain were killed and sampling occurred at 4, 8, 16, 32, 48, 72, and 96 hours in the high dose animals. Six rats were killed and sampling occurred at 96 hours in the low dose animals.
- Other: rats with indwelling jugular vein cannula were orally administered either a high dose (1.80 g/kg) or a low dose (.18 g/kg) of the test material. Rats were placed in Nalgene metabolism cages for collection of urine and faeces. Serial blood samples were collected through the jugular vein cannula at selected times and radioactivity was measured by direct liquid scintillation counting.


METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine
- Time and frequency of sampling: urine was collected once from cages, 16 hours into the study.
- From how many animals: information not provided
- Method type(s) for identification: urine samples were analyzed using high-performance liquid chromatography (HPLC) to determine the metabolite profile and by liquid chromatography with tandem mass spectrometry (LC-MS/MS) to identify the major urinary metabolites.
- Limits of detection and quantification: not provided
- Other: male rats were orally administered a high dose of MHCs and urine samples were collected and analyzed for metabolite profile and major urinary metabolites.


TREATMENT FOR CLEAVAGE OF CONJUGATES: N/A

Statistics:

Statistical evaluations between F-334 and Sprague-Dawley rats were conducted using parametric and nonparametric procedures at the 5% level of significance. For the parametric procedures, a one-way analysis of variance program to assess significance was used. In nonparametric procedures, the Kruskal-Wallis one-way analysis of variance on ranks was applied. Statistical analysis on the urinary and faecal excretion data between the two rat strains were based on the individual amounts of 14C equivalents recovered during the sample collection periods and not on the cumulative percentage of dose values (displayed in the graphs in the study report).

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Blood kinetics data shows that, after administration of the high dose to F-344 rats, the maximum blood concentration of [14C]EICO was 110 ng/ml at 16 hours. In contrast, the maximum blood concentration after administration of the high dose to Sprague-Dawley rats was 41 ng/ml at 6 hours. After administration of the low dose, Sprague-Dawley rats had a maximum blood concentration of 27 ng/ml at 5 hours, whereas F-344 rats displayed a triphasic blood-concentration time profile, with peaks at 44 ng/ml at 2 hours and 34 ng/ml and 6 hours.

Details on distribution in tissues:

Livers of F-344 rats retained a greater percentage of the test material than did Sprague-Dawley rats, after administered the high dose. In F-344 rats,maximum hepatic concentrations occurred at 24 and 48 hours, they were 4 and 5% of the administered dose, respectively. Three percent of the dose was still present within the livers of these rats at 96 hours. In Sprague-Dawley rats, maximum hepatic concentrations of 2% occurred at 16 and 24 hours. Only 0.1% remained in the livers of these rats at 96 hours. After the low dose, 3% of the dose was recovered in the livers of F-344 rats by 96 hours, compared to 0.5% in Sprague-Dawley rats. Thus, livers of F-344 retained more of the absorbed dose of the test material than did the Sprague-Dawley rats.

The mesenteric lymph nodes of F-344 retained approximately 0.01% of the administered dose at 96 hours, compared to 0.003% in Sprague-Dawley rats after exposure to the high dose. At 96 hours after the administration of the low dose, 0.02% and 0.009% of the radioactivity was present in F-344 and Sprague-Dawley rats, respectively.

The remaining 0.9% of the radioactivity was associated with the kidney (0.2%), lung (0.1%), heart (0.03%), spleen (0.04%), and subcutaneous fat (0.5%) at 96 hours post-administration in female F-344 rats

Details on excretion:

Faecal excretion was the major route of elimination of radioactive material for both rat strains in the high and low dose studies. In the high dose study, 92% and 88% of administered radioactivity was recovered by 96 hours in the F-344 and Sprague-Dawley rats, respectively. In the low dose study, 76% and 70% was recovered by 96 hours in the F-344 and Sprague-Dawley rats, respectively. Fecal elimination was more rapid in Sprague-Dawley rats. By 16 hours the bulk of the radioactivity was excreted by the Sprague Dawley rats, whereas the majority of the administered radioactivity was found in the intestine of the of the F-344 rats at 16 hours.

The amount of radioactivity excreted in the urine was dose-dependent in both strains. At 96 hours, 11% of the high dose and 22% of the low dose were eliminated in the urine of F-344 rats. by 96 hours, 11% and 27% was eliminated in the urine of the Sprague-Dawley rats in the high and low dose, respectively . Sprague-Dawley rats excreted nearly all of the radioactivity recovered in the urine by 16 hours, regardless of the dose. F-344 rats maintained relatively linear urination elimination rates throughout the 96 hour study.

Total recovery in faeces and urine ranged from 97 to 103%.

No radioactivity was recovered in expired in carbon dioxide or organic vapours

Toxicokinetic parameters

Toxicokinetic parameters 1

Test no.:

#1

Toxicokinetic parameters:

Cmax: 110 ng/ml at 16 hours in F-433/high dose

Toxicokinetic parameters 2

Test no.:

#1

Toxicokinetic parameters:

Cmax: 41 ng/ml at 6 hours in Sprague-Dawley/high dose

Toxicokinetic parameters 3

Test no.:

#2

Toxicokinetic parameters:

Cmax: 34 ng/ml at 16 hours in F-433/low dose

Toxicokinetic parameters 4

Test no.:

#2

Toxicokinetic parameters:

Cmax: 44 ng/ml at 2 hours in F-433/low dose

Toxicokinetic parameters 5

Test no.:

#2

Toxicokinetic parameters:

Cmax: 27 ng/ml at 5 hours in Sprague-Dawley/low dose

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

The major urinary metabolite identified in both rat strains was 12-cyclohexyldodecanoic acid. Urinary metabolite 10-cyclohexyldodecanoic acid was also identified.

HPLC analysis of both rat strains treated with the high dose of revealed that only metabolites of EICO were excreted. Sprague-Dawley rats eliminated the great bulk of these metabolites by 16 hours , and F-433 rats excreted them much more slowly.

Applicant's summary and conclusion

Conclusions:

The results of this report demonstrate that inherent differences of the pharmacokinetic activity and disposition of [14C]EICO exists between female F-344 and Sprague-Dawley rat strains. F-344 rats are systematically exposed to higher blood concentrations of the test material; excrete metabolites in urine in a slower, time-dependent manner, and retain a significant amount of radioactivity in the livers at 96 hours. Based on this hepatic retention in F-344, a difference in the ability of the livers to metabolize the test material most likely explains the pharmacokinetic/dispositional differences observed in the two strains.

Executive summary:

Read across justification

No toxicokinetic studies have been conducted with petrolatums specifically. Toxicokinetic studies of paraffin and microcrystalline waxes and highly refined base oils (white mineral oils) which are similar to petrolatum constituents have been conducted and are summarized for reference to the primary components of petrolatums.

In a basic toxicokinetics study, female Sprague-Dawley and F-344 rats were administered either a high dose of 1.8 g/kg or a low dose of 0.18 g/kg of [1 -14C]1-eicosanylcyclohexane ([14C]EICO) in olive oil by oral gavage. Blood, urine, feces, liver, and mesenteric lymph nodes were analyzed for [14C]EICO and its metabolites.

Blood kinetics data shows that, after administration of the high dose to F-344 rats, the maximum blood concentration of [14C]EICO was 110 ng/ml at 16 hours. In contrast, the maximum blood concentration after administration of the high dose to sprague-dawley rats was 41 ng/ml at 6 hours. After administration of the low dose, sprague-dawley rats had a maximum blood concentration of 27 ng/ml at 5 hours, whereas F-344 rats displayed a triphasic blood-concentration time profile, with peaks at 44 ng/ml at 2 hours and 34 ng/ml and 6 hours. Livers and mesenteric lymph nodes of F-344 rats retained a greater percentage of the test material than did sprague-dawley rats. Faecal excretion was the major route of elimination of radioactive material for both rat strains in the high and low dose studies. The amount of radioactivity excreted in the urine was dose-dependent in both strains. The major urinary metabolite identified in both rat strains was 12-cyclohexyldodecanoic acid. Urinary metabolite 10-cyclohexyldodecanoic acid was also identified.

The results of this report demonstrate that inherent differences of the pharmacokinetic activity and disposition of [14C]EICO exists between female F-433 and sprague-dawley rat strains. F-344 rats are systematically exposed to higher blood concentrations of the test material; excrete metabolites in urine in a slower, time-dependent manner, and retain a significant amount of radioactivity in the livers at 96 hours. Based on this hepatic retention in F-344, a difference in the ability of the livers to metabolize the test material most likely explains the pharmacokinetic/dispositional differences observed in the two strains.

This study received a Klimisch score of 2 and is classified as reliable with restrictions.