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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-GLP, non-guideline animal experimental investigation, 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 dosed by gavage - single dose of 8.47 mmol/kg, dissolved in olive oil (dose volume 4 mL/kg bw).
Duration and frequency of treatment / exposure:
Single dose
Doses / concentrations
Remarks:
Doses / Concentrations:
8.47 mmol/kg (899 mg/kg)
No. of animals per sex per dose:
60
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 oral administration of a single dose of 8.47 mmol/kg bw. Results for m-xylene only are reported here. Comment: 8.47 mmol p-xylene / kg bw shown previously to cause histological lesions in 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), brain
- From how many animals: 6-8 per timepoint
- Time and frequency of sampling: 10, 20 and 30 min; 1, 2, 5, 8, 11, 15 and 24 hr
- Other: samples taken under deep anaesthesia (sodium pentobarbital) and stored frozen until analysis
- Method type(s) for identification: GC-FID
Statistics:
Elimination half-life estimated during the linear phase post-treatment. Maximum blood and brain concentrations 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: m-xylene = 48 µg/mL
Toxicokinetic parameters:
Cmax: Brain: m-xylene = 115 µg/g
Toxicokinetic parameters:
half-life 1st: Blood: m-xylene = 143 min
Toxicokinetic parameters:
half-life 1st: Brain: m-xylene = 145 min
Toxicokinetic parameters:
AUC: Blood: m-xylene = 42258
Toxicokinetic parameters:
AUC: Brain: m-xylene = 97203

Any other information on results incl. tables

Graphical data showed that m-xylene appeared rapidly in blood and was maximal 30 min after administration. It then remained steady for 11 hr before decreasing. Concentrations in brain paralleled those in the blood but with two peaks, at 30 min and 5 hr. Levels in brain (Cmax, AUC) were around 2-fold greater than those for blood.

Applicant's summary and conclusion

Conclusions:
Blood and brain concentrations of m-xylene were determined in young adult male Sprague-Dawley rats following oral gavage administration of 8.47 mmol/kg. m-xylene appeared rapidly in blood and was maximal 30 min after administration. It then remained steady for 11 hr before decreasing. Concentrations in brain paralleled those in the blood but with two peaks, at 30 min and 5 hr. Levels of m-xylene in brain (Cmax, AUC) were around 2-fold greater than those for blood.
Executive summary:

Blood and brain concentrations of m-xylene were determined in young adult male Sprague-Dawley rats following oral gavage administration of 8.47 mmol/kg. m-xylene appeared rapidly in blood and was maximal 30 min after administration. It then remained steady for 11 hr before decreasing. Concentrations in brain paralleled those in the blood but with two peaks, at 30 min and 5 hr. Levels of m-xylene in brain (Cmax, AUC) were around 2-fold greater than those for blood.