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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:
key study
Study period:
2003
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
publication
Title:
OECD SIDS 1,2-DICHLOROPROPANE
Author:
OECD SIDS
Year:
2003
Bibliographic source:
UNEP PUBLICATIONS
Report Date:
2003

Materials and methods

Objective of study:
distribution
Test guideline
Qualifier:
according to
Guideline:
other: EPA test rule study
Principles of method if other than guideline:
EPA test rule study.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Sex:
male/female

Administration / exposure

Route of administration:
inhalation
Vehicle:
other: air
Duration and frequency of treatment / exposure:
6 hours
Doses / concentrations
Remarks:
Doses / Concentrations:
Doses, males: 5, 50 or 100 ppm
Doses, females: 5, 50 or 100 ppm
No. of animals per sex per dose:
4 males and 4 females
Control animals:
not specified

Results and discussion

Metabolite characterisation studies

Details on metabolites:
Approx. 60-90% of the radioactivity present in the exhaled volatile fraction was unchanged PDC. HPLC analysis of urine (pooled from the 3 inhalation experiments) revealed the presence of three n-acetylcysteine conjugates of PDC (N-acetyl-S-(2-hydroxypropyl)-L-cysteine, N-acetyl-S-(2-oxopropyl)-L-cysteine and N-acetyl-S-(2-carboxyethyl)-L-cysteine) but no detectable parent compound. Attempts to identify four other HPLC peaks were unsuccessful.

Any other information on results incl. tables

The measured concentration of PDC in the chambers was 4.6/4.7 ppm, 52.4/56.8 ppm and 141.8/125.2 ppm for males/females, respectively, in the low, mid and high exposure groups, respectively. Mean end exposure body burdens were 0.4/0.3, 2.8/2.8 and 6.3/7.1 mg equivalents of PDC for males/females in the low, mid and high exposure groups, respectively. The distribution of recovered radioactivity is summarized in Attachment 5.0b. In summary, urine (54-66% of recovered dose) and expired air (15-23% as carbon dioxide) were the principle routes of excretion with smaller amounts present in tissues and carcass (6-10%) and faeces (6-10%). Less than 4% of the recovered radioactivity was present in cage washings. Exhaled volatiles accounted for 2-3% of the dose in animals exposed to 5 ppm and 50 ppm, and 6-7% in the 100 ppm group (high dose group significantly different from mid and low dose groups). The pattern of excretion did not differ between males and females.

Analysis of tissues

Radioactivity was distributed among all the tissues examined and generally represented less than 0.18% of the recovered dose/g wet weight. The liver and kidneys contained the highest amount of radioactivity, accounting for 0.1-0.3% and 0.1-0.2% of the dose/g wet weight, respectively. There were no obvious differences in tissue distribution between the sexes or in distribution or concentration for the different exposure concentrations.

Timecourse for elimination

Urinary elimination of radiolabel was greatest over the first 24 hr post-dosing (47-62% of dose) relative to the following 24 hr (2-9%). Comparative figures for exhaled carbon dioxide were 13-20% and <3%, and 5-8% and 0.7-3.0% for faeces (at 0-24 and 24-48 hr, respectively). The majority of exhaled volatiles were also eliminated during the 24 hr following exposure, with <0.03% detected during the 24-48 hr time period.

Blood concentrations in both sexes were generally at a maximum 4 hr into the exposure (exception: 5 ppm females which peaked at 1 hr). In both sexes the peak blood PDC level was not proportional to dose indicating a dose-dependent non-linearlity in clearance. The concentration in blood was below the limit of detection (0.03 ug/g) 2 hr after exposure ended. Modelling (one-compartment open model with linear fit) indicated a post-exposure blood clearance half life for PDC of 30 min in males and 24 min in females.

In plasma, the highest concentration of 14C in both sexes was found at 4 hr in the exposure, and ranged from 2, 12-15 and 27-29 ug eq/g plasma present in the 5, 50 and 100 ppm groups respectively. Corresponding AUCs were 21-23, 130-134 and 288-320 ug g^-1, respectively. Comparison of the 5 ppm peak plasma 14C level and AUC with the mid- and high dose groups indicated that plasma 14C was less than proportional to dose.

Applicant's summary and conclusion

Conclusions:
Urine and exhaled carbon dioxide were the principle routes for elimination of PDC in male and female rats after 6 hr inhalation exposure to 5, 50 or 100 ppm. The majority of radioactivity was excreted within 24 hr, with little unchanged PDC present.