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Basic toxicokinetics

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basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
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.
Reason / purpose:
reference to other study

Data source

Reference Type:
The role of toxicokinetics in xylene-induced ototoxicity in the rat and guinea pig
Gagnaire F, Marignac B, Blachere V, Grossman S and Langlais C
Bibliographic source:
Toxicology 231, 147-158

Materials and methods

Objective of study:
Test guideline
no guideline followed
GLP compliance:
not specified

Test material

Details on test material:
- Source: Acros, Geel, Belgium
- Purity: 99% (for all)

Test animals

Details on test animals and environmental conditions:
- 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

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

Administration / exposure

Route of administration:
oral: gavage
olive oil
Details on exposure:
Each isomer was administered to 60 rats by gavage at a single dose of 8.47 mmol/kg, dissolved in olive oil and given at a volume of 4 mL/kg bw.
Duration and frequency of treatment / exposure:
Single dose
Doses / concentrations
Doses / Concentrations:
8.47 mmol/kg
No. of animals per sex per dose:
Control animals:
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 p-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
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: p-xylene = 73 µg/mL
Toxicokinetic parameters:
Cmax: Brain: p-xylene = 210 µg/g
Toxicokinetic parameters:
half-life 1st: Blood: p-xylene = 188 min
Toxicokinetic parameters:
half-life 1st: Brain: p-xylene = 142 min
Toxicokinetic parameters:
AUC: Blood: p-xylene = 45807
Toxicokinetic parameters:
AUC: Brain: p-xylene = 110589

Any other information on results incl. tables

Graphical data showed that all 3 isomers appeared rapidly in blood and the brain but there were notable differences in time-course:

- concentrations of o-xylene in both tissues peaked after 2 hr, remained steady for 3 hr and then declined steadily over time

- blood m-xylene was maximal 30 min after administration, remained steady for 11 hr then decreased. Concentrations in brain paralleled those in the blood but with two peaks at 30 min and 5 hr

- concentrations of p-xylene in blood and brain peaked after 30 min then decreased sharply at 1 hr followed by a more steady decline.

The maximal concentration in blood and brain differed significantly between the isomers, and was always greatest for p-xylene.

Applicant's summary and conclusion

All three isomers (o-, p-, m-) exhibited similar kinetics (Cmax, half-life, AUC) following gavage administration (8.47 mmol/kg bw) to young adult male rats although tissue concentrations of p-xylene were generally higher, and half-lives slightly shorter, than those of o-xylene and m-xylene. Levels of p-xylene in brain (Cmax, AUC) were around 2 to 3-fold greater than those for blood.
Executive summary:

Blood and brain concentrations of o-, m- and p-xylene were determined in young adult male Sprague-Dawley rats following oral gavage administration of 8.47 mmol/kg of each isomer. Levels of p-xylene in blood and brain (Cmax, AUC) were approx. double, and tissue half-lives slightly shorter, compared to those found for o- and m-xylene. Levels of p-xylene in brain (Cmax, AUC) were around 2 to 3-fold greater than those for blood. The results indicate slight toxicokinetic differences for the three xylene isomers in the rat following acute oral exposure.