Chlorine

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1999

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Publicly avaialble literature, non GLP

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1999

Materials and methods

Objective of study:

distribution

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Guideline or Method not indicated.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Chlorine

EC Number:

231-959-5

EC Name:

Chlorine

Cas Number:

7782-50-5

Molecular formula:

Cl2

IUPAC Name:

dichlorine

Details on test material:

chlorine

Radiolabelling:

no

Test animals

Species:

human

Sex:

male/female

Details on test animals or test system and environmental conditions:

Five males, five females, non-smokersAge: 18-36 years (mean: 24.7±5.4 years)Weight: 55.1-94.8 kg (mean: 71.4±13.8 kg)

Administration / exposure

Route of administration:

inhalation

Vehicle:

other: air

Details on exposure:

The bolus inhalation session comprised three experiments:oral breathing with a peak concentration of 3.0 ppmnasal breathing with a peak concentration of 3.0 ppmnasal breathing with a peak concentration of 0.5 ppm

Duration and frequency of treatment / exposure:

2-4h

Doses / concentrations

Remarks:

Doses / Concentrations:10 mL Cl2 bolus was injected into the airflow

No. of animals per sex per dose / concentration:

5

Control animals:

not specified

Positive control reference chemical:

no positive control

Details on study design:

To observe the longitudinal distribution of Cl2 absorption in intact human airways during quiet breathing the non-invasive bolus inhalation method previously developed for ozone was employed. The apparatus could deliver Cl2 boluses and continuously monitor the Cl2 concentration. By using the apparatus, bolus measurements were compared during nasal and oral breathing to determine whether the site of air access influenced the penetration of Cl2 beyond the upper airways. Bolus inhalation measurements: All 10 volunteers participated in a 2- to 4-h session in which bolus measurements were made during nasal and oral quiet breathing. The person was seated comfortably on a stool, wore noseclips during oral breathing, and maintained a closed mouth during nasal breathing. The subject controlled his or her breathing so that the respired volume signal followed a pre-drawn pattern corresponding to equal inspiratory and expiratory flows of 250 mL/s and a tidal volume of 500 mL. At a pre-determined time during inhalation, the data-acquisition system automatically injected a 10 mL Cl2 bolus into the inspired airflow. Three experiments were conducted during the bolus inhalation session: oral breathing with a peak inhaled Cl2 concentration (cmax) of 3.0 ppm; nasal breathing with a cmaxof 3.0 ppm ; and nasal breathing with a cmax of 0.5 ppm. Anatomic measurements: The anatomy of the respiratory system of each subject was characterised by measurements of FVC (forced vital capacity) by using a forced spirometer, and dead space (VD) by using a nitrogen-washout apparatus. In addition, the nasal volume (VNS), oral volume (VOR), and pharyngeal volume (VPH) of each person were determined by an acoustic reflection apparatus.

Details on dosing and sampling:

see detail on study design

Statistics:

not indicated.

Results and discussion

Preliminary studies:

not indicated.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

In general, the inhaled Cl2 boluses were completely absorbed at a Vp of ~ 80 mL , which was immediately distal to the upper airways. Decreasing Cmax. from 30.0 to 0.5 ppm appears to increase the absorbed fraction of Cl2 at Vp below 60 mL, which is within the hypopharynx. The relationship between VB and Vp is similar for both modes of breathing, with oral values of VB being somewhat larger than nasal values at Vp > 10 mL. Values of σ2 appear relatively insensitive to Vp, with oral values being somewhat larger than nasal values at Vp < 70 mL. The calculated Ka(nasal) averaged for all subjects was significantly larger (P = 0.04) than Ka(oral) (please refer to table A6.2/01 1). On the other hand, there was a significant difference (P = 0.97) between the average Ka(nasal) obtained when cmax. was 0.5 ppm and that when cmax. was 3.0 ppm. The values of Ka(pharyngeal) were 1.5 s-1 during oral breathing of 3.0 ppm Cl2 boluses; 1.1 s-1 during nasal breathing of 3.0 ppm Cl2 boluses; and 1.6 s-1 during nasal breathing of 0.5 ppm Cl2 boluses. This suggests that mass transfer in the hypopharynx was not markedly affected by the mode of breathing or inhaled Cl2 concentration.

Details on distribution in tissues:

not indicated.

Details on excretion:

not indicated.

Metabolite characterisation studies

Metabolites identified:

not specified

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no dataNearly all of the inspired Cl2 was absorbed in the upper airways, and ~ 90 % of the inspired Cl2 was absorbed in the nose or mouth of all the subjects. This result was independent of the mode of breathing and of cmax.

Executive summary:

To summarise, measurements of the single breath-bolus penetration distribution of Cl₂ during nasal as well as oral quiet breathing in five men and five women indicated that > 95 % of inspired Cl₂ was absorbed in the upper airways of all subjects, whereas the dose delivered to the respiratory air spaces was negligible. Although there were no statistically significant gender differences in the results, individual values of Ka(oral) were inversely correlated with individual values of V_OR. Representative overall mass transfer coefficients estimated in the nose were in good agreement with gas-phase mass transfer coefficients calculated from established correlations. This suggested that diffusional resistance in the nasal mucosa was negligible relative to diffusional resistance in the respired gas. Both the high absorptivity of Cl₂ in the upper airways and the domination of the gas-phase diffusion resistance were attributable to the rapid hydrolysis of Cl₂in the mucosa.