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Toxicological information

Basic toxicokinetics

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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:
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

Reference
Name:
Unnamed
Type:
Constituent
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 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:
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 parametersopen allclose all
Toxicokinetic parameters:
Cmax: Blood: o-xylene = 27 µg/mL
Toxicokinetic parameters:
Cmax: Brain: o-xylene = 101 µg/g
Toxicokinetic parameters:
half-life 1st: Blood: o-xylene = 181 min
Toxicokinetic parameters:
half-life 1st: Brain: o-xylene = 186 min
Toxicokinetic parameters:
AUC: Blood: o-xylene = 12960
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.