α-chlorotoluene

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The authors tested the basic toxicokinetics of benzyl chloride with a methodology similar to the OECD Guideline 417. Deviations to this guideline were limited (i.e. number of dose-levels tested, caging and duration period of excretion test). GLP standards were not specified, but sufficient data was given concerning materials and methods. Hence the study should be considered reliable with restrictions, a Klimisch 2c study, comparable to a guideline study with acceptable restrictions.

Data source

Reference

Reference Type:

publication

Title:

Pharmacodynamics of benzyl chloride in rats

Author:

Saxena S. and Abdel-Rahman M. S.

Year:

1989

Bibliographic source:

Archives of Environmental Contamination and Toxicology, 18(5): 669-677

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

other: elimination

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

yes

Remarks:

only one dose while at least two dose levels should be used; not individually caged but per two; duration excretion was 3d and 95% excretion level was not reached

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

α-chlorotoluene

EC Number:

202-853-6

EC Name:

α-chlorotoluene

Cas Number:

100-44-7

Molecular formula:

C7H7Cl

IUPAC Name:

(chloromethyl)benzene

Constituent 2

Reference substance name:

chloromethylbenzene

IUPAC Name:

chloromethylbenzene

Details on test material:

- Name of test material: methylene-14C-benzyl chloride diluted with benzyl chloride
- Supplier of methylene-14C-benzyl chloride: Amersham Co
- Supplier of benzyl chloride: Fisher Scientific Co
- Radiochemical purity (if radiolabelling): 95%
- Specific activity (if radiolabelling): 15.9 mCi/mmol
- Final activity (if radiolabelling): 155.5 µCi/mL

No more data available

Radiolabelling:

yes

Remarks:

mixture of radiolabelled test material with unlabelled test material

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Duration and frequency of treatment / exposure:

Treatment frequency: single application

Exposure duration:
- absorption, distribution and elimination studies: 48h
- excretion and metabolism studies: 72h

Doses / concentrations

Remarks:

Doses / Concentrations:
50 mg/kg

No. of animals per sex per dose / concentration:

- absorption, distribution and elimination studies: 7 animals were used for the adsorption and elimination study of which 4 were sacrificed to study distribution
- excretion and metabolism studies: 6 animals

Control animals:

no

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The peak level was reached at 30 min and then began to decline.

The elimination pattern follows a 2-compartment model:
(1) distribution half-life (alpha phase) was 1.3 h
(2) elimination half-life (beta phase) was 58.5h

Details on distribution in tissues:

After 48h the activity of radioisotopes was highest in stomach, gastric content, gastric wash, ileum and duodenum, followed by liver, adrenal, bone marrow, whole blood, pancreas, lung, esophagus, skin, kidney, heart, thymus, fat, testes, spleen, brain and carcass

Details on excretion:

The total fraction of the initial dose eliminated after 72h was highest in urine, followed by expired air and feces. Majority of the activity by renal pathway was detected during the first 12h collection period (53.5% initial dose). After 72h the total activity by renal route was 76.1 %.The expired air collection revealed that 6.7 % was CO2 and 1.3 % was present as the parent compound 14C-benzyl chloride or its metabolites. The fecal route was the lowest route of the excretion with 0.9% detected during the time studied (i.e. 72h)

Toxicokinetic parameters

Toxicokinetic parameters 1

Toxicokinetic parameters:

half-life 1st: 58.5h (elimination, beta-phase)

Toxicokinetic parameters 2

Toxicokinetic parameters:

Tmax: 30 min

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

In urine the following metabolites were detected as a result of benzyl chloride administration: mercapturic acid, benzyl alcohol and benzaldehyde.
After 12h of administration the major metabolite was mercapturic acid, followed by benzyl alcohol and benzaldehyde, with total radioactivity of 44.2%, 6.5% and 1.5% respectively of the initial dose. After 72h of administration there was no change in this pattern and the total radioactivity was 59.9%, 9.8% and 3.8% for mercapturic acid, benzyl alcohol and benzaldehyde respectively.
Presence of benzyl alcohol and benzaldehyde were confirmed by GC/MS

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results
The authors tested the basic toxicokinetics of benzyl chloride with a methodology similar to the OECD Guideline 417. Under the test conditions, adsorption reached a peak level at 30 min and then began to decline. Concerning the distribution of the test substance, the study noted that after 48h the activity of radioisotopes was highest in stomach, gastric content, gastric wash, ileum and duodenum. Furthermore the elimination pattern followed a 2-compartment model: (1) distribution half-life (alpha phase) of 1.3 h and (2) elimination half-life (beta phase) of 58.5h. The total fraction of the initial dose eliminated after 72h was highest in urine (76.1 %), followed by expired air (6.7 % as CO2 and 1.3 % as 14C-benzyl chloride or its metabolites) and feces (0.9%).

Executive summary:

The authors tested the basic toxicokinetics of benzyl chloride (CAS ° 100-44-7) with a methodology similar to the OECD Guideline 417. Deviations to this guideline were limited (i.e. number of dose-levels tested, caging and duration period of excretion test). Male Sprague Dawley rats were administered 50 mg/kg of a mixture of methylene-¹⁴C-benzylchloride (specific activity 15.9 mCi/mmol) and benzyl chloride (final activity 155.5 µCi/mL) and this mixture was only given once in corn oil by gavage. During 48h after application adsorption, distribution and elimination was followed. For adsorption and elimination 7 animals were used and of these 4 were sacrificed to study the distribution after 48h. Excretion and metabolism was studied in 6 animals during 72h. Under the test conditions, adsorption reached a peak level at 30 min and then began to decline. Concerning the distribution of the test substance the authors noted that after 48h the activity of radioisotopes was highest in stomach, gastric content, gastric wash, ileum and duodenum, followed by liver, adrenal, bone marrow, whole blood, pancreas, lung, esophagus, skin, kidney, heart, thymus, fat, testes, spleen, brain and carcass. Furthermore the elimination pattern followed a 2-compartment model: (1) distribution half-life (alpha phase) of 1.3 h and (2) elimination half-life (beta phase) of 58.5h. The total fraction of the initial dose eliminated after 72h was highest in urine (76.1 %), followed by expired air (6.7 % as CO2 and 1.3 % as ¹⁴C-benzyl chloride or its metabolites) and feces (0.9%). The following metabolites were detected in urine as a result of benzyl chloride administration: mercapturic acid, benzyl alcohol and benzaldehyde. After 12h and 72h of administration the major metabolite was always mercapturic acid, followed by benzyl alcohol and benzaldehyde, with total radioactivity of 44.2%, 6.5% and 1.5% respectively after 12h and 59.9%, 9.8% and 3.8% respectively after 72h. Presence of benzyl alcohol and benzaldehyde were confirmed by GC/MS.

GLP standards were not specified, but sufficient data was given concerning the materials and methods and results. Hence the study should be considered reliable with restrictions, a Klimisch 2c study, comparable to a guideline study with acceptable restrictions.