Registration Dossier

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
1999
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study is classified as reliable with restrictions because though a GLP compliance statement is not provided, the study is well conducted and provides some information regarding the absorption kinetics of the test material

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1999

Materials and methods

Objective of study:
other: Dermal penetration and systemic bioavailability
Test guideline
Qualifier:
no guideline followed
Deviations:
not applicable
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Residual Aromatic Extracts (RAE), C, D, and E
- Substance type: Residual Aromatic Extracts
- Kinematic viscosity at 35°C (calculated from dynamic viscosities):
sample C 5400
sample D 4800
sample E 5160
Radiolabelling:
yes
Remarks:
Spiked with 0.1% radiolabeled Benzo-a-pyrene (BaP) in experiment 1; Spiked with 2.1 Ci/mmol triated BaP in experiment 2

Test animals

Species:
mouse
Strain:
CF-1
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Data not reported
- Age at study initiation: Data not reported
- Weight at study initiation: Data not reported
- Fasting period before study: Data not reported
- Housing: Mice were housed individually on wood chip bedding in experiment 1; housed individually in mesh-bottomed cages
without bedding in experiment 2
- Individual metabolism cages: Data not reported
- Diet (e.g. ad libitum): Data not reported
- Water (e.g. ad libitum): Data not reported
- Acclimation period: Animals were acclimatised to the presence of a rectanglular piece of aluminium foil
held in place over the shaved area by polythene adhesive tape for 2
days (6 h/day) preceding the exposure.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Data not reported
- Humidity (%): Data not reported
- Air changes (per hr): Data not reported
- Photoperiod (hrs dark / hrs light): Data not reported

Administration / exposure

Route of administration:
dermal
Vehicle:
not specified
Details on exposure:
TEST SITE
- Area of exposure: Dorsal skin
- % coverage: Data not provided
- Type of wrap if used: Aluminium foil wrapping
- Time intervals for shavings or clipplings: Shaved once prior to treatment with test material(s)

REMOVAL OF TEST SUBSTANCE
- Washing (if done): No
- Time after start of exposure: Not applicable

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 80 ul in Experiment 1; 20 uL in Experiment 2
- concentration (if solution): 20.4 +/- 0.3 uCi for RAE C and 20.3 +/- 0.3 uCi for RAE D; RAE E concentration in Experiment 2 not provided

USE OF RESTRAINERS FOR PREVENTING INGESTION: Data not provided
Duration and frequency of treatment / exposure:
Test materials were applied at 10-min intervals, one from each dose group (dose groups not specified in succession; total exposure duration was 6 hours.
Doses / concentrations
Remarks:
Doses / Concentrations:
Doses for RAE C and D in experiment 1 were 20.4 +/- 0.3 uCi and 20.3 +/- 0.3 uCi, respectively; Doses for RAE E in experiment 2 not specified
No. of animals per sex per dose:
5 females/treatment group
Control animals:
not specified
Positive control:
No data
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: Radioactivity associated with skin DNA and in circulating blood measured
- Time and frequency of sampling: Samples collected 6 hours after initial treatment
Statistics:
The analysis of variance (ANOVA) method was used to check for differences in mean and variability. Significant differences between dosed groups was determined using Studentised range multiple comparison test. Differences in variability were determined using Hartley’s test. All tests were carried out at the 5% significance level.

Results and discussion

Main ADME resultsopen allclose all
Type:
other: Radioactivity in blood
Results:
RAE radioactivity in blood was five-fold lower compared to other polycyclic aromatic hydrocarbons
Type:
other: Radioactivity bound to skin
Results:
RAE radioactivity bound to skin was three-fold lower compared to other polycyclic aromatic hydrocarbons

Any other information on results incl. tables

RAE specific binding data was not provided following experiment 1. However, binding data from [14C]BaP spiked test materials, RAE C and D was very similar. Since binding data for other polycyclic aromatic compounds (PACs) were also examined, the results were reported in a comparative manner. The study authors reported that the amount of radioactivity found in the blood of mice treated with RAE C and D was five-fold lower compared to other PACs (specifically oil A). Similarly, the radioactivity in bound skin DNA in animals treated with RAE C and D was three-fold lower compared to other PACs (oil A). In experiment 2, again RAE specific biding data were not reported. The study authors stated that the DNA binding in skin was five-fold higher in animals treated with other PACs (specifically oil A) compared to animals treated with RAE E. Similarly binding in blood was seven-fold lower in animals treated with RAE E compared to those treated with other PACs (specifically oil A).

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
The study authors state that the determinations made both in blood and DNA strongly support the view that PACs in viscous oil products are less bio-available compared to lower viscosity oil products.
Executive summary:

In a dermal and systemic availability study, adult female CF1 mice were treated with various doses of Residual Aromatic Extracts (RAE) C, D, and E in two separate experiments. The dorsal skin of the mice was shaved and prior to treatment, the shaved skin was examined for hair growth or skin damage. Only animals with undamaged skin were used in both experiments. Mice were randomly allocated to 5 animals/treatment group (five treatment groups in experiment 1; six treatment groups in experiment 2; dose groups not specified for either experiment). Animals in experiment 1 were treated with 80 µL of the test materials (RAE C, and D) spiked with 0.1% [14C]BaP. In experiment 2, animals were treated with 20 µl RAE E spiked with 2.1 Ci/mmol [3h]BaP. Animals were dosed at 10 minute intervals, one for each dose group in succession in both experiments. Following treatment, aluminium foil along with polythene adhesive tape was placed over the shaved and treated area of the skin to prevent accidental ingestion of the test material. Mean doses for RAE C and D in experiment 1 were 20.4 ± 0.3 and 20.3 ±0.3 µCi per animal, respectively. Mean doses for RAE E in experiment 2 were not provided. Animals were sacrificed 6 hours after the last dose applied. The aluminium binding was left in place and the heart was exposed and blood samples were collected for DNA analysis of radiolabeled BaP. Similarly the aluminium bound skin was preserved after removal of the occlusive wrapping and later used for DNA analysis of radiolabeled BaP.

 

RAE specific binding data was not provided following experiment 1. However, binding data from [14C]BaP spiked test materials, RAE C and D was very similar. Since binding data for other polycyclic aromatic compounds (PACs) were also examined, the results were reported in a comparative manner. The study authors reported that the amount of radioactivity found in the blood of mice treated with RAE C and D was five-fold lower compared to other PACs (specifically oil A). Similarly, the radioactivity in bound skin DNA in animals treated with RAE C and D was three-fold lower compared to other PACs (oil A). In experiment 2, again RAE specific biding data were not reported. The study authors stated that the DNA binding in skin was five-fold higher in animals treated with other PACs (specifically oil A) compared to animals treated with RAE E. Similarly binding in blood was seven-fold lower in animals treated with RAE E compared to those treated with other PACs (specifically oil A).

 

The study authors state that the determinations made both in blood and DNA strongly support the view that PACs in viscous oil products are less bio-available compared to lower viscosity oil products.

 

This study received a Klimisch score of “reliable with restrictions” because though a GLP compliance statement was not provided, it is well conducted and provides some information regarding the absorption kinetics of the test material.