Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
April-May 1986
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Purity of a.i. has been indicated; complete composition of the test substance is not available (available in departmental study file).

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1986
Report Date:
1986

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
Test material form:
other: liquid
Details on test material:
Lot no.: TA860220D
Purity: 48.2% linear tetraethylenepentamine

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Ray Nichols Rabbitry, Lumberton, TX, USA
- Age at study initiation: ca. 5 months
- Weight at study initiation: ca. 3.1 - 4.0 kg
- Fasting period before study: not applicable
- Housing: individually in stainless steel cages
- Diet (e.g. ad libitum): restricted to 4 oz per animal per day
- Water (e.g. ad libitum): ad lib
- Acclimation period: at least 14 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 72 ± 5 degr F (22 ± 1.5 degr C)
- Humidity (%): 50
- Air changes (per hr): no info
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 9 April 1986 To: no info (most probably 31 days later)

Administration / exposure

Type of coverage:
occlusive
Vehicle:
water
Details on exposure:
TEST SITE
- Area of exposure: 10 x 15 cm
- % coverage: 100
- Type of wrap if used: an occlusive bandage of absorbent gauze and non-absorbent cotton; the bandage was held in place using a lycra/spandex jacket
- Time intervals for shavings or clipplings: periodically as required

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no info
- Time after start of exposure: ca. 6 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): a 10% solution was applied with the volume adjusted to provide the required dose
- Concentration (if solution): 10%
- Constant volume or concentration used: yes, constant concentration

VEHICLE
- Justification for use and choice of vehicle (if other than water): water
- Amount(s) applied (volume or weight with unit): 1 ml/kg BW

USE OF RESTRAINERS FOR PREVENTING INGESTION: no (but animals wore jackets)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Test material concentration (100 mg/g) was measured 3 times during the study in triplo. % of target concentrations were 87.0, 95.3 and 90.9%, respectively. Stability was measured 2, 4 and 7 days after preparation. % of Day 0 was, 92.1, 59.4 and 59.9%, respectively.
Duration of treatment / exposure:
31 days
Frequency of treatment:
20 exposures, 5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50, 100 and 200 mg/kg bw/day
Basis:
nominal per unit body weight
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on a probe study using 2 female rabbits per group, at levels of 0, 50, 100 or 200 mg/kg bw/day for 4 days
- Rationale for animal assignment (if not random): computer-generated tables of random numbers
- Rationale for selecting satellite groups: not used
- Post-exposure recovery period in satellite groups: not used
- Section schedule rationale (if not random): no info
Positive control:
not used

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily on working days (one additional routine monitoring on these days and on weekend and holidays for dead animals and check for water and food availability)

DETAILED CLINICAL OBSERVATIONS: No

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: daily upon removal when bandage and jacket were removed.

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: Since the animals were maintained on a restricted diet and normally ate all their ration, measurement of food consumption was not doen. Qualitative changes in consumption were monitored by a periodic visual check.

FOOD EFFICIENCY: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: not applicable

HAEMATOLOGY: Yes
- Time schedule for collection of blood: immediately prior to necropsy
- Anaesthetic used for blood collection: Yes (no info which was used)
- Animals fasted: No
- How many animals: all
- Parameters examined: RBC, WPC, platelet count, haemoglobin, packed cell volume

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: immediately prior to necropsy
- Animals fasted: No
- How many animals: all
- Parameters examined: blood urea nitrogen, ALP, ALAT, glucose, total protein, albumin, Cl, Na, K, globulin (calculated)

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (including eyes)
HISTOPATHOLOGY: Yes (complete set) of control and high dose animals; skin (application site and a non-treated section), liver kidneys and gross pathologic lesions were aslo examined from low and mid dose animals
Organ weights: brain, liver, kidneys, adrenals, ovaries, testes
Other examinations:
None
Statistics:
Yes, for body weights, organ weights, clinical chemistry, haematology.

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:
CLINICAL SIGNS AND MORTALITY: one control female was removed from the study on day 14 because of a broken back.
There were no signs other than local dermal effects. These were dose-related and consisted of red dermal test sites on days 1-2. By study Day 6, animals tretaed with 200 mg/kg bw showed very red and slightly swollen test sites; on Day 16 the skin of some of these females was severely irritated with some crusting and bleeding. Other animals of the 200 mg/kg bw group and those of the 100 mg/kg group had irritated skin that did not progress further.

BODY WEIGHT AND WEIGHT GAIN: no effects

FOOD CONSUMPTION: no effects

FOOD EFFICIENCY: not measured

WATER CONSUMPTION: not measured

OPHTHALMOSCOPIC EXAMINATION: not applicable

HAEMATOLOGY: no effects

CLINICAL CHEMISTRY: no effects

URINALYSIS: not measured

NEUROBEHAVIOUR: not measured

ORGAN WEIGHTS: no effects

GROSS PATHOLOGY: confined to the skin of the 100 and 200 mg/kg groups, characterised by multifocal areas of epidermal and dermal necrosis often covered with crusts comprised of dry serum and necrotic debris.

HISTOPATHOLOGY: NON-NEOPLASTIC
Only dose-related changes in the skin consisting of: multifocal necrosis of the epidermis with extension into the dermis, acanthotic and hyperkeratotic areas, underlying dermis had a subacute inflammatory response consisting of lymphocytes, macrophages and heterophils. Dermal arterioles contained marginated leukocytes, hair folicles showed keratinization. Grading of the skin lesions reflected the extent if the lesion and the degree of functional damage.

HISTOPATHOLOGY: NEOPLASTIC (not applicable)

HISTORICAL CONTROL DATA (not applicable)

OTHER FINDINGS: none

Effect levels

Dose descriptor:
NOEL
Effect level:
50 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: skin effects; no systemic toxicity

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
At 100 and 200 mg/kg bw/day, the only lesions noted were skin lesions; the NOEL was 50 mg/kg bw/day.
Executive summary:

Groups of 5 male and 5 female rabbits were treated on their skin with 50, 100 or 200 mg TEPA per kg/bw ca. 6 h/day day, 5 days/week for a period of 31 days (under occlusive conditions). These levels were based on a 4 -day RF study using the same levels using 2 females per group. Controls were treated with the vehicle, distilled water. No changes were observed in body weights, food intake, haematology, clinical chemistry, and organ weights. The only lesions observed were local skin lesions; the degree of irritation was dose-related; effects in the 200 mg/kg group were generally more severe than in the 100 mg/kg group. There were no indications of systemic toxicity. Because no changes were seen in the 50 mg/kg group, the NOEL was 50 mg/kg bw/day.