Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1993
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: A published study which contains sufficient experimental detail to be able to judge it reliable for risk assessment purposes

Data source

Reference
Reference Type:
publication
Title:
Toxicology of diethylene glycol butyl ether 2. Disposition studies with 14C-diethylene glycol butyl ether and 14C-diethylene glycol butyl ether acetate after dermal application to rats
Author:
Boatman RJ, Schum DB, Guest D, Stack CR
Year:
1993
Bibliographic source:
J. Am. Coll. Toxicol. 12(2), 145-54.

Materials and methods

Objective of study:
absorption
excretion
metabolism
Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
not specified
Principles of method if other than guideline:
Purpose of study to look at washing efficiency and disposition/excretion/metabolic fate
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): diethylene glycol butyl ether
UNLABELLED MATERIAL
- Analytical purity: >99%
- Source: Dow Chemical Company, Midland, MI
LABELLED MATERIAL
- Chemical purity: >96%
- Radiochemical purity (if radiolabelling): >98%
- Specific activity (if radiolabelling): no data
- Locations of the label (if radiolabelling): no data
- Supplier: Wizard Laboratories (Davis, CA)
- Other: supplied in acetone which was stripped off and replaced with unlabelled test material to produce required radioactivity level
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Kingston, NY
- Age at study initiation: 7-9 weeks
- Individual metabolism cages: yes
- Weight at study initiation: 194-236g (females); 244-326g (males)

ENVIRONMENTAL CONDITIONS
- no data

Administration / exposure

Route of administration:
dermal
Vehicle:
other: water for washing study. Disposition study no vehicle
Details on exposure:
TEST SITE
- Area of exposure: dorsal thoracic region
- % coverage: 2x2inch area
- Type of wrap if used: 1.25in diameter borosilicate glass tubing, shaped for snug fit to animal and sealed on open end with polyethylene cover slips. Cells attached to animals with Permabond 910 adhesive. Test material injected via small hole in cover slip. For disposition study, animals/cells wrapped with surgical tape.
- Time intervals for clipping: 24hrs prior to exposure


REMOVAL OF TEST SUBSTANCE (WASHING EFFICIENCY STUDY)
- Washing (if done): Yes, repeatedly with Phisoderm solution (40%) then 5 aliquots of water on cotton wool. All washings and swabs retained for radioactivity analysis
- Time after start of exposure: 5mins. Animals then placed in metabolism cages.

REMOVAL OF TEST SUBSTANCE (ABSORPTION/DISTRIBUTION/METABOLISM STUDY)
- Washing (if done): Yes, as above
- Time after start of exposure: 24hrs
- Other: Unabsorbed liquid then collected at end of exposure period and exposure area washed as for washing study. Animals then returned to metabolism cages.


TEST MATERIAL
- Amount(s) applied (volume or weight with unit):0.2g/kg
- concentration (if solution): 10% (washing study only)
Duration and frequency of treatment / exposure:
Washing study: 5 minutes under light anasthetic (metofane).
Metabolism/disposition study: 24 hours. No data on overall length of study.
Doses / concentrations
Remarks:
Doses / Concentrations:
Washing study: 0.2g/kg (in neat and 10% aqueous forms)
Disposition/metabolite study: 0.2 and 2.0/kg.
Nominal applied radioactivity 100uCi/kg
No. of animals per sex per dose:
Washing study: 4 females only
Disposition study: 4 males and 4 females.
Control animals:
no
Positive control:
no
Details on study design:
no further data
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled : urine, faeces, cage washes
- Time and frequency of sampling: 8, 24hours then daily


METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine
- Time and frequency of sampling: 8, 24hours then daily
- From how many animals: (samples pooled or not): not specified
- Method type(s) for identification:GC-MS. Quantitation by HPLC
- Limits of detection and quantification: no data
- Other: Urine from 1 rat at 24hr time point was subject to semi-preparative HPLC to collect samples of major peaks for analysis. Reference materials used for comparison. urine from 1 rat at 24hr time point was treated with beta glucoronidase and then analysed by HPLC


TREATMENT FOR CLEAVAGE OF CONJUGATES (if applicable): Metabolites acidified then methylated before GC-MS analysis.
Statistics:
Mean and standard deviation calculated

Results and discussion

Preliminary studies:
The substance was efficiently removed from skin by washing. ~92% of dose recovered from neat exposure and ~95% from aqueous exposure. Only traces of applied dose (<2%) accounted for in urine, faeces and cage washes.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Substance was not completely absorbed with significant amounts left in cage washes. Females seemed to absorb and excrete more than males
Details on distribution in tissues:
not examined
Details on excretion:
Excretion primarily in urine. 97% complete after 24 hours and effectively 100% after 48hrs.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
2-(2-butoxyethoxy)acetic acid was main metabolite accounting for 61-80% of total excreted radioactivity. Females seemed to excrete a higher percentage than males. Glucoronidase treatment resulted in the appearance of a single HPLC component with identical retention time to that of 2-(2-butoxyethoxy)ethanol.. Acid treatment of samples produced no change in metabolite profile suggesting that a glycine conjugate was not present. Based on the results, the glucoronide conjugate was estimated to be at levels of 5-8%.

Any other information on results incl. tables

Total recovered radioactivity: 81 -89%. Unaccounted for radioactivity could have been lost as expired CO2, which was not captured in this experiment.. Calculated absorption rates based on applied dose and area exposed were 0.73 and 1.46mg/cm2/hr for males and females respectively. Results from the study using undiluted low dose are shown below. This is the only study where all the liquid was absorbed and the skin at the site of exposure analysed for radioactive content. The table shows the site and percentage of applied dose recovered, rounded to 2 significant figures. :

   Male  Female
Washing recovery, residual dose andcage washes*  56 (+/-14)   28 (+/-25)
 Faeces  0.9 (+/-0.3)  1.5 (+/-0.9)
 Urine  27 (+/-0.5)  51 (+/-16)
 Dermal exposure site (skin)  0.7 (+/-0.5)  0.4 (+/-0.1)
 Carcass 1.4 (+/-0.3)   1.8 (+/-0.6)

* includes material washed from skin, contaminating surgical tape and metabolism cages washes.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Skin absorption is slow but detectable. Absorbed material is eliminated >95% within 24 hours, primarily in the urine in the form of the acid metabolite 2-(2-butoxyethoxy)acetic acid.
Executive summary:

In a study to examine the absorption and elimination of radio-labelled 2 -(2 -butoxyethoxy)ethanol in rats following 24hr dermal occluded exposure, it was established that the main route of elimination is overwhelmingly via the urine and the metabolite 2 -(2 -butoxyethoxy)acetic acid. The glucoronidate conjugate was also found at significant levels (5 -8%). Females appeared to absorb and therefore excrete larger quantities than males and the dermal absorption rate was estimated to be 0.73 and 1.46mg/cm2/hr for males and females respectively. Washing studies showed that 90%+ of externally applied substance could be removed after 5 minutes exposure by skin washing.