Extracts (petroleum), heavy naphtha solvent

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:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-GLP, non-guideline animal experimental study, published in peer reviewed literature, minor restrictions in reporting but otherwise adequate for assessment.

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

publication

Title:

The role of toxicokinetics in xylene-induced ototoxicity in the rat and guinea pig

Author:

Gagnaire F, Marignac B, Blachere V, Grossman S and Langlais C

Year:

2007

Bibliographic source:

Toxicology 231, 147-158

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline followed

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

o-xylene

EC Number:

202-422-2

EC Name:

o-xylene

Cas Number:

95-47-6

Molecular formula:

C8H10

IUPAC Name:

o-xylene

Details on test material:

- Source: Acros, Geel, Belgium
- Purity: 99% (for all)

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Iffa Credo, Saint-Germain-sur-l'Arbresle, France
- Age at study initiation: approx. 7 wk
- Housing: group housed, 4/cage in polypropylene cages with woodchip bedding
- Diet : UAR-Alimentation, Epinay-sur Orge, France, sterilised by gamma irradiation ad libitum
- Water : filtered tap water ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22°C
- Humidity: 50-60%
- Photoperiod (lights on): 07.00 - 19.00 hr

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

olive oil

Details on exposure:

Each isomer administered to 48 rats by gavage at 8.47 mmol/kg (in olive oil, 4 mL/kg bw) 5 d/wk for 2 wk.

Duration and frequency of treatment / exposure:

daily, 5 d/wk for 2 wk

Doses / concentrations

Remarks:

Doses / Concentrations:
8.47 mmol/kg (899 mg/kg)

No. of animals per sex per dose / concentration:

48

Control animals:

no

Details on study design:

Blood and brain concentrations of ortho, meta and para-xylene (one isomer per experiment) were determined in SD rats following sub-acute oral administration at 8.47 mmol/kg bw, 5 d/wk for 2 wk. Results for o-xylene only are reported here to permit comparison of toxicokinetics. Comment: 8.47 mmol p-xylene / kg bw shown previously to cause histological lesions of the organ of Corti in rats whereas m- and o-xylenes ineffective (see Gagnaire and Langlais (2005) Arch. Toxicol. 79, 346-354).

Details on dosing and sampling:

- Tissues and body fluids sampled: blood (abdominal aorta) and brain sampled on last day of treatment
- From how many animals: 6-8 per timepoint
- Time and frequency of sampling: 0.5, 1, 2, 5, 8, 11, 15 and 24 hr after final treatment
- Other: samples taken under deep anaesthesia (sodium pentobarbital) and stored frozen until analysis
- Method type(s) for identification: GC-FID

Statistics:

Elimination half-life was estimated during the linear phase post-treatment. Maximum blood and brain concentrations were compared by one-way ANOVA followed by Scheffe's multiple range test if results were significant.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Toxicokinetic parameters

Toxicokinetic parameters 1

Toxicokinetic parameters:

Cmax: Blood: o-xylene = 27 µg/mL

Toxicokinetic parameters 2

Toxicokinetic parameters:

Cmax: Brain: o-xylene = 101 µg/g

Toxicokinetic parameters 3

Toxicokinetic parameters:

half-life 1st: Blood: o-xylene = 181 min

Toxicokinetic parameters 4

Toxicokinetic parameters:

half-life 1st: Brain: o-xylene = 186 min

Toxicokinetic parameters 5

Toxicokinetic parameters:

AUC: Blood: o-xylene = 12960

Toxicokinetic parameters 6

Toxicokinetic parameters:

AUC: Brain: o-xylene = 43560

Any other information on results incl. tables

Graphical data revealed that concentrations of o-xylene peaked in blood and brain after 2 hr and then declined steadily over time. Levels in brain (Cmax, AUC) were 3-4 fold higher than in blood.

Applicant's summary and conclusion

Conclusions:

Blood and brain concentrations of o-xylene were determined in young adult male Sprague-Dawley rats following sub-acute oral gavage administration (8.47 mmol/kg bw/d, 5 d/wk for 2 wk). Levels of o-xylene in brain (Cmax, AUC) were 3-4 fold higher than in blood. Concentrations of peaked in blood and brain after 2 hr and then declined steadily over time.

Executive summary:

Blood and brain concentrations of o-xylene were determined in young adult male Sprague-Dawley rats following sub-acute oral gavage administration (8.47 mmol/kg bw/d, 5 d/wk for 2 wk). Levels of o-xylene in brain (Cmax, AUC) were 3-4 fold higher than in blood. Concentrations of o-xylene peaked in blood and brain after 2 hr and then declined steadily over time.