Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1983
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Fully documented GLP guideline study report available. Read-across based on supporting substance (analogue approach). The data in this record is for the metabolite 2-butoxyethanol (CAS; 111-76-2, EC no 203-905-0) for which the systemic toxicity will be the same. Full details of the justification for the use of an analogue for this end point are included in the document appended to chapter 13 of this dossier.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1983

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
Deviations:
no
Remarks:
, no significant deviations noted
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
-Source: Union Carbide Corporation
- Name of test material (as cited in study report): butyl cellosolve, ethylene glycol monobutyl ether
- Substance type:
- Physical state: clear, colourless liquid
- Analytical purity: described as 'high purity'
- Stability under test conditions: established as stable at dosage concentrations for at least 32 days with little or no deterioration. Test solutions prepared monthly.
- Storage condition of test material: abient

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Langshaw Farms, Augusta, MI
- Age at study initiation: 3-4 months
- Weight at study initiation: 2.2-3.1kg
- Fasting period before study: none specified
- Housing:stainless steel, wire bottomed cages
- Diet (ad libitum except prior to blood sampling): Purina certified rabbit chow 5322
- Water (ad libitum): tap
- Acclimation period: 14 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 69-75
- Humidity (%): 40
- Air changes (per hr): 10-15
- 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:
- Type of wrap if used: Treated skin covered with gauze which was secured in place with hypoallergenic tape. Trunk then wrapped with 3 layers of Handiwrap (polyvinylidene chloride wrap) secured with adhesive tape. Occlusive wrap removed 6 hours after dosing
- Time intervals for shavings or clipplings: Area clipped around entire trunk from shoulder to rump

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.35ml/kg
- Concentration (if solution): adjusted weekly to adapt to changing animal body weight whilst keeping dosing volume the same.
- Constant volume used: yes

USE OF RESTRAINERS FOR PREVENTING INGESTION: yeno
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dosage solutions checked on days 1, 4, 11, 21, 32 using gas chromatography (Varian 3700) and an FID. Glass column contained 10% Carbowax 20M on CHromosorb WHP/100 mesh, 200cmx6.35mmx2mm. Carrier gas N2 (30cc/min) with detector air at 300cc/min and H2 at 30cc/min. Detector 280C, injector 250C, column 140C. Injection vol: 5ul. Retention time ~1.9min
Duration of treatment / exposure:
90 days
Frequency of treatment:
daily, 5 days per week for 13 weeks.
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 2.8, 14.3, 42.8%
Basis:
other: solution concentration
Remarks:
Doses / Concentrations:
0, 10, 50, 150mg/kg
Basis:
nominal per unit body weight
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Not specified but highest dose likely to be based on tolerance to irritation.
Positive control:
no

Examinations

Observations and examinations performed and frequency:
CAGE SIDE AND CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations: general health, signs of toxicity, behavioural changes

DERMAL IRRITATION (if dermal study): Yes, using Draize scoring system
- Time schedule: Daily for first 3 weeks, then weekly.

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


OPHTHALMOSCOPIC EXAMINATION: Yes / No / No data
- Time schedule for examinations:
- Dose groups that were examined:

HAEMATOLOGY: Yes
- Time schedule for collection of blood: week 4 and end of study
- Anaesthetic used for blood collection: No
- Animals fasted: Yes, overnight
- How many animals:all
- Parameters checked: WBC/RBC count, Hg, Hc, MCV, MCHC, MCH, differential WBC count, RBC fragility (at termination time point only).

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: week 4 and end of study
- Animals fasted: Yes, overnight
- How many animals:all
- Parameters checked: glucose, urea, protein, direct and total bilirubin, albumin, ALP

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
Animals sacrificed on days 92-98 (T-61 Euthenasia solution) followed by exsanguination.
GROSS PATHOLOGY: Yes, from all 6 animals per dose level: heart, spleen, kidneys, thymus, liver, testes, ovaries
HISTOPATHOLOGY: Yes fixed in 10% buffered formalin then processed for histopathogy using standard procedures and staining using H&E. Tissues examined included: adrenals, aorta, bone (sternebrae), brain (3 transverse sections), epididymis (both, tail), esophagus, eyes, gall bladder, heart, intestines, (cecum, duodenum, jejunum, ileum, colon), kidneys, liver (left and median lateral lobes), lung, lymph node (mesenteric, thoracic), mammary gland, ovaries, pancreas, parathyroids, pituitary, prostate, sciatic nerve, seminal vesicles, skeletal muscle, skin (test stie and adjacent normal skin), spleen, stomach (pylorus and fundus), submandibular salivary gland, testes, thyroid, thymus, tongue, trachea, urinary bladder, uterus (both horns), vagina, all gross lesions.
Other examinations:
none
Statistics:
Dunnett's test for haematology and clinical chemistry data.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
no effects observed
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 specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY: no observations were noted that were attributed to treatment. Most animals in all groups, including controls were reported to show some signs of nasal discharge, matted and/or moistened forepaws and anorexia.

BODY WEIGHT AND WEIGHT GAIN: No alteration is body weights noted and isolated changes observed were not attributed to treatment.

DERMAL IRRITATION: Slight to moderate erythema and some odema were observed either on the test area (some or all of area) or perimeter of test area throughout the study. Scaling and flaking was also seen. These effects were noted across all dose groups, including controls, with no obviously consistent pattern or dose response relationship. The irritative reponse could not therefore be related primarily to treatment.

HAEMATOLOGY: Sporadic changes in haematology parameters and RBC fragility values were noted but values were within normal ranges for the laboratory. Sporadic change in WBC parameters were also similarly noted. No changes that could be attributed to treatment were observed.

CLINICAL CHEMISTRY: The mean values for changes noted were within the normal control ranges for the laboratory. No changes that could be attributed to treatment were observed.

ORGAN WEIGHTS: No test material related changes observed.

HISTOPATHOLOGY: NON-NEOPLASTIC: Changes that were noted were either sporadic or changes associated with parasitic or bacterial origins and not related to the test material.

Effect levels

Dose descriptor:
NOAEL
Effect level:
> 150 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: No changes seen at maximum dose tested.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

On a molar basis, these results would need to be increased by a factor of 1.36 to covert to a NOAEL/LOAEL for butoxyethyl acetate.

Applicant's summary and conclusion

Conclusions:
Sub-chronic dermal exposure of rabbits to 2-butoxyethanol at doses of up to 150mg/kg does not produce any adverse changes of note.
Executive summary:

2 -butoxyethanol was administered dermally to male and female rabbits at doses up to 150mg/kg/day for 90 days. The maximum dose tested was the maximum that could be tolerated without irritation from prolonged exposure. No clinical, haematological, clinical chemistry or pathological changes were observed that could be attributed to treatment.

Synopsis:

NOAEL (rabbit, dermal, 90 day) > 150mg/kg/day (maximum dose tested.). On a molar basis, these results would need to be increased by a factor of 1.36 to covert to a NOAEL/LOAEL for butoxyethyl acetate.