2-(2-butoxyethoxy)ethyl methacrylate

Repeated dose toxicity: dermal

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:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

minor deviations to OECD guideline

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Toxicology of diethylene glycol butyl ether 4. Dermal subchronic/reproduction study in rats.

Author:

Auletta CS, Schroeder RE, Krasavage WJ, Stack, CR

Year:

1993

Bibliographic source:

J. Am. Coll. Toxicol. 12(2), 161-168

Reference 2

Reference Type:

review article or handbook

Title:

Unnamed

Year:

2008

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)

Deviations:

yes

Remarks:

minor deviations to OECD guideline

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-(2-butoxyethoxy)ethanol

EC Number:

203-961-6

EC Name:

2-(2-butoxyethoxy)ethanol

Cas Number:

112-34-5

Molecular formula:

C8H18O3

IUPAC Name:

2-(2-butoxyethoxy)ethanol

Test material form:

liquid

Specific details on test material used for the study:

- Name of test material (as cited in study report): diethylene glycol butyl ether (DGBE)
- Supplier: Dow Chemical Company
- Physical state: liquid
- Stability under test conditions: yes

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at room temperature under nitrogen

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

CD rats

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: CharlesRiver Lab., Raleigh,NC (USA)
- Age at study initiation: 8 weeks

- Housing: individually in suspended stainless steel cages
- Diet: Certified Purina Rodent Chow mash diet ad libitum
- Water: from Elizabethtown Water Company, ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24 (67 - 76 °F)
- Humidity (%): 30 - 70 %

- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Type of coverage:

occlusive

Vehicle:

water

Remarks:

distilled

Details on exposure:

TEST SITE
- Area of exposure: back (clipped skin)
- % coverage: 3 x 3 cm area
- Type of wrap if used: polyethylene patch, covered by an adhesive banage wrapped around the trunk


REMOVAL OF TEST SUBSTANCE
- Washing (if done): residual test material was gently wiped from the application site
- Time after start of exposure: 6 hrs

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 200, 600 and 2000 mg/kg/d
- Concentration (if solution): undiluted, 10 % solution and 30 % solution
- Constant volume or concentration used: yes

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

5 days / week , 6 hrs daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day

Remarks:

untreated control

Doses / concentrations 2

Dose / conc.:

200 mg/kg bw/day (nominal)

Remarks:

equals 10% solution

Doses / concentrations 3

Dose / conc.:

600 mg/kg bw/day (nominal)

Remarks:

equals 30% solution

Doses / concentrations 4

Dose / conc.:

2 000 mg/kg bw/day (nominal)

Remarks:

undiluted equals 100% of the test sustance

No. of animals per sex per dose:

10

Control animals:

yes

Details on study design:

- Post-exposure recovery period in satellite groups: no

Positive control:

no

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes (observation twice daily for morbidity/rnortality and overt signs of toxic effects)
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule for examinations: each treatment day (5 days/week) prior to the application of the test article and after the wrappings were removed

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: each treatment day (5 days/week) prior to the application of the test article and after the wrappings were removed

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly


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

HAEMATOLOGY: Yes
- Time schedule for collection of blood: pre-study, after 1 month, and at the end of the study
- Anaesthetic used for blood collection: Yes (light)
- Animals fasted: Yes
- How many animals: all toxicity study animals


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: pre-study, after 1 month, and at the end of the study
- Animals fasted: Yes
- How many animals: all toxicity study animals


URINALYSIS: Yes
- Time schedule for collection of urine: pre-study, after 1 month, and at the end of the study
- How many animals: all toxicity study animals
- Metabolism cages used for collection of urine: No data
- Animals fasted: Yes / No / No data
- Parameters checked in table [No.?] were examined.

NEUROBEHAVIOURAL EXAMINATION: Yes / No / No data
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:

OTHER:

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes, incl. adrenal glands, kidneys, pituitary gland, prostate gland, testes, epididymides, seminal vesicles, liver, ovaries, spleen;
multiple sections of testes, epididymides and ovaries were prepared for examination

Other examinations:

During a 14-day period near the end of the study, daily vaginal smears were performed to determine whether normal estrous cycling was occurring.

Statistics:

Bartlett's test / ANOVA (parametric procedures)
Kruskal-Wallis test (non-parametric procedures)
Furtherly used: Dunn's summed-rank test; Jonckheere's test for monotonic trends for nonparametric comparisons; Fisher exact test.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Clinical observations during the toxicity study revealed one mid-dose and one high-dose female with hematuria or red urinary staining on the haircoat, first seen at week 7 of the study. Urinalyses at the end of the study revealed
a slightly increased incidence of occult blood in the urine of females treated with 30 or 100% DGBE(Table I). However, microscopic examination of the urine revealed no urinary casts and no significant numbers of erythrocytes.
see Urinalysis

Dermal irritation:

effects observed, treatment-related

Description (incidence and severity):

Evaluation of the application sites revealed dermal irritation, which was concentration-dependent in incidence, severity, and time of onset and was slightly more severe in females than in males.
Weekly evaluations and dermal scoring performed immediately after removal of the wrappings generally indicated more irritation than when the evaluations were made daily just prior to dosing, which indicated that some recovery occurred overnight
from any acute irritation produced during the daily dosing. Application of undiluted DGBE produced dermal irritation in all animals; some were affected after as few as two doses.
Males generally exhibited very slight or slight erythema with some desquanation or atonia, while most of the females exhibited more severe dermal effects such as areas of necrosis, generally with eschar formation
and subsequent sloughing of the scab at one or more intervals during the study. The necrosis and scab formation were located in most cases at the margin of the wrappings, suggesting that there may have been some mechanical
abrasion due to the wrapping procedure.
Microscopic examination of skin sections from the application site revealed no DGBE-related histological changes, slight thickening of the epidermis being seen for both control and treated animals.

Mortality:

no mortality observed

Description (incidence):

There was no mortality in any of the groups throughout the toxicity or the reproductive phases of the study.

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Endocrine findings:

not examined

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

slighlty increased incidence of occult urinary blood in mid-and high dose females

Behaviour (functional findings):

not specified

Immunological 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:

Female animals were significantly more sensitive to skin irritation

Effect levels

1

Key result

Dose descriptor:

LOAEL

Effect level:

200 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

dermal irritation

2

Key result

Dose descriptor:

NOAEL

Effect level:

2 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Systemic toxicity

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

No evidence for systemic toxicity in male and female rats; Skin irritation dependent on time, concentration and sex (pronounced effects in females).

Executive summary:

The alcohol Butyldigylycol (CAS 112-34-5) was tested for subchronic toxicity in a well conducted 90 d study in male and female rats (10 animals per sex and dose group). The substance was applied dermally at doses of 200, 600 and 2000 mg/kg/day (6 -hour exposure interval, 5 days/week for 13 weeks). Dermal irritation occurred which was dependent on time and concentration. Female animals were significantly more sensitive. There was a slightly increased incidence of occult blood in the urine of 2 femals (mid-and high dose) which showed no clear time or dose dependency and was not confirmed by microscopic examination of the urine. There was no evidence for systemic toxicity by clinical and histopathological evaluations for all dose groups. Therefore, the NOAEL of the study can be determined to 2000 mg/kg/d.