Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 12 Mar 1984 to 21 June 1985
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well conducted and reported study.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1985
Report Date:
1985

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
Test substance: Tributoxy ethyl Phosphate
Analytical purity: 98-99.5% active ingredient
Lot QD-1

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazleton Dutchland Inc., Denver, PA
- Age at study initiation: no data
- Weight at study initiation: approximately 1.8 - 2.2 kg
- Fasting period before study: no data
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 28 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 64-71 F
- Humidity (%): 22-70
- Air changes (per hr): no data
- Photoperiod: 12 hrs dark / 12 hrs light


IN-LIFE DATES: From: 9 April 1984 To: 30 April 1984

Administration / exposure

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: 10 cm wide from suprascapular to hindquarters
- % coverage: 25
- Type of wrap if used: 8-ply gauze covered with impervious plastic sleeve
- Time intervals for shavings or clipplings: "as required"

REMOVAL OF TEST SUBSTANCE
- Washing (if done): not done
- Time after start of exposure:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): applied as received
- Concentration (if solution): 100%
- Constant volume or concentration used: yes

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes
Duration of treatment / exposure:
21 days
Frequency of treatment:
Once per day, 5-days per week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 10, 100 or 1000 mg/kg
Basis:
nominal per unit body weight
No. of animals per sex per dose:
6
Control animals:
yes, concurrent no treatment

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations included: mortality, gross toxicology, behaviour, appearance

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: pretest and 5 times per week (pre dosing)

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- pretest and days 1, 3, 5, 8, 10, 12, 15, 17 and 19

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes / No / No data
- Time schedule for collection of blood: at termination
- Anaesthetic used for blood collection: No
- Animals fasted: Yes (16 h)
- How many animals: all
- All standard parameters were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at termination
- Animals fasted: Yes (16 h)
- How many animals: all
- All standard parameters were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, all animals
HISTOPATHOLOGY: Yes, controls and high dose

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:
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:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
Other: Local Dermal Effects:
Local irritation (slight to moderate erythema, oedema, atonia and desquamation) occurred in a dose-related manner and severity and increased with time.
Microscopic observations of treated skin from high dose animals included squamous cell hyperplasia, hyperkeratosis, hair follicles distended with keratin and surface accumulation of keratin and erosions/ulcers. No such observations were seen in control males and only infrequently in control females.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: NOAEL for systemic toxicity
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: Minimal local irritation only at low dose

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Repeated sub-acute dermal exposure to TBEP caused local effects on the skin only. There was no evidence of any adverse systemic toxicity seen as a consequence of this exposure route following 1000mg/kg/day dosing with TBEP for 21-days.
Executive summary:

In a study to investigate the dermal toxicity of TBEP to rabbits on repeated exposure, groups consisted of 6 male and 6 female rabbits (mean weight at initiation 2546g (male) 2714g (female). Twenty-four hours prior to application of TBEP an area on the trunk equivalent to ca. 25% was carefully clipped free of hair; approximately 10 cm wide and extending from the subscapular area to the hind quarters. Test sites were occluded for 6-h after each application to prevent oral ingestion by wrapping a layer of 8-ply gauze around the trunk and securing this with an impervious plastic sleeve attached with tape. Elizabethan collars were worn by all animals throughout the study. Observations for mortality and gross signs of toxicity were carried out twice daily. Bodyweights were recorded pre-test and weekly thereafter and at study termination. Food consumption was checked pretest and on days 1, 3, 5, 8, 10, 12, 15, 17 and 19. Evaluations of dermal irritation were performed pretest and 5-times/week just prior to dosing. Clinical pathology studies were carried out on blood collected via the medial ear vein in animals fasted overnight prior to the terminal kill. At the end of the study period all surviving animals were killed and subject to a standard post-mortem examination; histopathologic evaluations were performed on a selection of tissues from control and high dose animals.

There were no deaths and no adverse clinical signs of toxicity were observed in treated rabbits. No adverse systemic toxicity was observed following dosing at 1000 mg/kg/day. Local irritation (minimal to moderate erythema, oedema, atonia and desquamation) occurred in a dose-related manner and severity and increased with time. Microscopic observations of treated skin from high dose animals included squamous cell hyperplasia, hyperkeratosis, hair follicles distended with keratin and surface accumulation of keratin and erosions/ulcers. No such observations were seen in control males and only infrequently in control females.

A no effect level for skin irritation was therefore not established in this study, but irritation at the low dose was minimal. The NOAEL for systemic toxicity was 1000 mg/kg bw/day.