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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
sub-chronic toxicity: dermal
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 well conducted study where key information is reported.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Toxicology of diethylene glycol butyl ether 4. Dermal subchronic/reproduction study
Author:
Auletta CS, Schroeder RE, Krasavage WJ, Stack CR
Year:
1993
Bibliographic source:
J Am coll. Toxicol. 12, 2, 161-168.

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
other: TSCA: 40CFR 798.2250 as amended by 40CFR 799.1560
Deviations:
no
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
Deviations:
not specified
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): diethylene glycol monobutyl ether (DGBE)
- Physical state: liquid
- Analytical purity: 99%
- Stability under test conditions: confirmed a homogeneous and stable for 1 week
- Storage condition of test material: under nitrogen in refridgerator
- Other: supplied by Dow Chemical Co.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories (reported as 'CD' rats)
- Age at study initiation: 6 wks
- Housing: individual in suspended stainless steel cages, except during mating and lactation period. During latter, solid steel pan fitted and hardwood shaving bedding added.
- Use of restrainers for preventing ingestion (if dermal): no
- Diet (ad libitum): Certified Purina lab chow #5002 mash diet
- Water (ad libitum): tap
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-24
- Humidity (%): 8 - 77
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Type of coverage:
occlusive
Vehicle:
water
Details on exposure:
TEST SITE
- Area of exposure: back
- % coverage: 3x3cm
- Type of wrap if used: polyethylene (PE) patch held in place by adhesive bandage wrapped around trunk of animal. Gauze pad added beneath PE patch after start of study
- Time intervals for shavings or clipplings:


REMOVAL OF TEST SUBSTANCE
- Washing (if done): wiped only.
- Time after start of exposure: 6hrs


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2ml/kg
- Concentration (if solution): neat
- Constant volume or concentration used: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Periodic analysis of diluted dosing solutions showed that 10% dose within 99.5(+/-3.1)% and 30% dose within 99.8(+/-2.6)%.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 hours/day, 5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 200, 600 or 2000 mg/kg bw/day, applied as 10, 30 and 100% solution in water to give constant application volume per unit body weight.
Basis:
nominal per unit area
No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
- Rationale for animal assignment (if not random): randomised but to keep mean body weights of control and treatment groups equal.
- other: Post-exposure period: none
Positive control:
no

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily checks for morbidity/mortality and overt toxic effects

DETAILED CLINICAL OBSERVATIONS: No data

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: twice daily qualitative analysis at treatment (dosing) time and after wrapping removed.

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, weekly

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pre-study and near end study

HAEMATOLOGY:
- Time schedule for collection of blood: Pre-study and at 4 and 13 weeks. Collected by venipuncture of orbital sinus.
- Anaesthetic used for blood collection: Yes
- Animals fasted: Yes, overnight and not dosed until after blood collection.
- Parameters examined: Hb, Hct, RBC, MCV, MCH, MCHC, total and differential WBC
- How many animals: no data

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Pre-study and at 4 and 13 weeks. Collected by venipuncture of orbital sinus.
- Animals fasted: Yes, overnight
- How many animals: No data
- Parameters examined: ALP, AST, ALT, BUN, glucose, total protein, albumin, globulin, creatinine, bilirubin, Na, K, Cl, Ca, inorganic P.

URINALYSIS: Yes / No / No data
- Time schedule for collection of urine: Pre-study and at 4 and 13 weeks
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters examined: appearance, colour, pH, protein, glucose, ketones, bilirubin, occult blood, urobilinogen, 16hr volume, microscopic analysis.

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: During a 14 day period near the end of the study, daily vaginal smears were collected to dermine if normal oestrus cycle was occuring.
Sacrifice and pathology:
Sacrifice by ether anesthesia.
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes, including adrenals, brain, kidneys, pituitary, prostate, testes, epididymides, seminal vesicles, liver, ovaries and spleen. All weighed and fixed. Other tissues preserved. High dose and control animal tissues sectioned for histology.
Other examinations:
none
Statistics:
Body weights, feed consumption, organ weights using Bartlett's test to determine if variances equal. If variances equal, parametric procedures used (ANOVA followed by Dunnett's test if appropriate). Alternative non-parametric procedures were Kruskal-Wallis test follwed by Dunn's summed rank test if appropriate. Tests for trend using regression analysis and Jonckheere's test. Walsh's test used to determine equality of means. Comparisons made at 1 and 5% signficance levels (two sided.)

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
No observations related to treatment.

URINALYSIS: Occult blood was noted in females treated at 600 or 2000  mg/kg but there was no evidence of urinary casts or significant numbers of erthyrocytes.

OTHER FINDINGS: IRRITATION: Concentration dependent increase in irritation worse in females. In females it was evident (erythema) from week 1 at the high dose and week 8 at the mid and high dose, with increasing numbers of animals affected with time. In males, it was only seen at the end of the study and and never effected more than 50% of animals. In males the severity was slight or very slight whilst in females there was necrosis and eschar in some animals at high doses.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
< 200 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: skin irritation
Dose descriptor:
NOAEL
Effect level:
> 2 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: all other effects

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Females appeared to be more susceptible than males to concentration-dependent irritation at the application site. Effects at the highest dosage were desquamation,  atonia, eschar and necrosis.

Applicant's summary and conclusion

Conclusions:
The only effect of note was dermal irritation at the site of repeated application which occured at all doses, albeit very slight at the low dose and only in males at towards the end of the study. Irritancy was more marked in females than males and produced some necrosis at the highest dose. There were no other adverse findings noted.
Executive summary:

In a well conducted study designed to assess the sub-chronic and reproductive toxicity of 2 -(2 -butoxyethoxy)ethanol to rats, the test substance was administered by the dermal route for 13 weeks to the maximum practical concentration attainable of 2ml/kg. The only effect of note was dermal irritation at the site of repeated application which occured at all doses, albeit very slight at the low dose and only in males at towards the end of the study. Irritancy was more marked in females than males and produced some necrosis at the highest dose. There were no other adverse findings noted.