2-piperazin-1-ylethylamine

Repeated dose toxicity: dermal

Administrative data

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Not applicable

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: 1a: GLP guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1998

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

2-piperazin-1-ylethylamine

EC Number:

205-411-0

EC Name:

2-piperazin-1-ylethylamine

Cas Number:

140-31-8

Molecular formula:

C6H15N3

IUPAC Name:

2-piperazin-1-ylethanamine

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Administration / exposure

Type of coverage:

occlusive

Vehicle:

other: distilled water

Details on exposure:

TEST SITE
- Area of exposure: no data
- % coverage: The test material was applied to an area which was approximately 10% of the total body surface area.
- Type of wrap if used: The exposure site was occluded with an absorbent gauze pad and non-absorbent cotten and the animal was wrapped in an elastic wrap and tape to hold the test material, gause pad and cotton in place.
- Time intervals for shavings or clipplings: no data


REMOVAL OF TEST SUBSTANCE
- Washing (if done): The application site was wiped with a water-dampened towel to remove any residual test material.
- Time after start of exposure: Wraps were removed approximately 6 hours after application and the application site was wiped with a water-dampened towel to remove any residual test material.


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): Dose volume of 4 ml/kg yielded the appropriate dose.
- Concentration (if solution): AEP was administered as a solution in distilled water such that a dose volume of 4 ml/kg yielded the appropriate dose.
- Constant volume or concentration used: yes



VEHICLE
- Amount(s) applied (volume or weight with unit): no data
- Concentration (if solution): no data
- Purity: no data


USE OF RESTRAINERS FOR PREVENTING INGESTION: no data

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

6 hours/application

Frequency of treatment:

5 days/week for 29 days

Doses / concentrations

Remarks:

Doses / Concentrations:
100, 500 or 1000 mg/kg/application
Basis:
nominal per unit body weight

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: no data

DETAILED CLINICAL OBSERVATIONS: Yes

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: no data

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

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

WATER CONSUMPTION: No

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

HAEMATOLOGY: Yes
- Time schedule for collection of blood: No data
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals: all

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: No data
- Animals fasted: Yes
- How many animals: all

URINALYSIS: Yes
- Time schedule for collection of urine: Urinalysis was conducted during the week prior to termination of the study.
- Metabolism cages used for collection of urine: No data
- Animals fasted: Yes / No / No data ******

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:

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Statistics:

All parameters examined statistically were first tested for equality of variance using Bartlett’s test. If the results from Bartlett’s test were significant, then the data for the parameter were subjected to a transformation to obtain equality of the variances. Transformations examined included common log, inverse and square root, in that order with a Bartlett’s test following each transformation. When Bartlett’s test was satisfied no further transformations were applied. In-life body weights were evaluated using a three wayrepeated measures analysis of variance for time, sex and dose. Terminal body weight, organ weight (absolute and relative, excluding ovaries and testes), hematologic parameters (excluding differential WBC and RBC indices), clinical chemistry parameters, and urine specific gravity were evaluated using a two-way ANOVA with the factors of sex and dose. Results for ovaries and testes weight (absolute and relative) were analyzed using a one-way ANOVA. Final interpretation of numerical data considers statistical analyses along with other factors, such as dose-response relationships and whether the results were plausible in light of other biological and pathological findings. Descriptive statistics only were reported for feed consumption, feed efficiency, WBC differential counts and RBC indices.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Dermal irritation:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

no effects observed

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

not examined

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

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:

There was no evidence of dermal irritation in male and female rats administered 100 mg/kg/application AEP during the course of the study.

Three male rats administered 500 mg/kg/application AEP were observed to have very slight erythema (barely perceptible) at the test site on the last day of study. Two of five male rats administered the highest dose of 1000 mg/kg/application AEP had very slight erythema (barely perceptible) following two applications of test material. All high dose male rats were observed to have very slight erythema at the test site on test day 10 that continued throughout the duration of the study. Scabbing, scaling and fissuring were observed at the test site of 4/5 on test day 24. All high dose male rats had scabbing, scaling and fissuring observed at the test site at study end.

Female rats administered 500 and 1000 mg/kg/application AEP had very slight erythema (barely perceptible) observed on test day 24 that remained evident throughout the duration of the study. Additionally, scabbing was observed on 1/5 and 3/4 female rats administered 500 and 1000 mg/kg/application AEP, respectively, on test day 24. Scaling and fissuring were observed on all female rats given 500 or 1000 mg/kg/application AEP on test day 24. At the end of the study (test day 29), 4/5 and 3/4 female rats given 500 and 1000 mg/kg/application AEP, respectively, had scabbing at the test site. On test day 29, scaling and fissuring were observed at the test site on 2/5 and 2/4 female rats given 500 and 1000 mg/kg/application AEP, respectively.

In life body weights, feed consumption, clinical pathology including hematology, clinical chemistry and urinalysis, and organ weights exhibited no treatment-related effects.

Gross and histopathological findings considered to be treatment-related were confined to the application site. Treatment-related gross necropsy observations at the dermal test site were present in rats from the 500 and 1000 mg/kg/application groups. All males and females from the 500 and 1000 mg/kg/application groups had erythema at the dermal test site. Multifocal scabs at the dermal test site were present in 2/5 and 4/5 females from the 500 mg/kg/application group, and in 5/5 males and 5/6 females in the 1000 mg/kg/application group. Male and female rats from the 100 mg/kg/application group had no gross observations at the dermal test site.

Treatment-related histopathologic skin lesions at the dermal test site were present in males exposed to 100, 500 or 1000 mg/kg/application, and females exposed to 500 or 1000 mg/kg/application. Females exposed to 100 mg/kg/application had no significant histopathologic lesions at the dermal test site. In general, there was a dose-related increase in the incidence and/or severity of skin lesions from all dose groups. More extensive lesions at the dermal test site, consisting of sebaceous gland hyperplasia, dermal chronic-active inflammation, parakeratosis, ulcers and epidermal pustules, were present in some male and female rats from the 500 and/or 1000 mg/kg/application groups.

Given that testicular and ovarian weights of high dose animals were comparable to control values and there were no grossly visible effects considered to be treatment related, histopathologic examination of testes and ovaries were not performed on all animals.

Testes of a limited number of animals were examined from the 100 (1 rat) and 500 (3 rats) mg/kg groups. One rat from the 500 mg/kg/application group was observed upon gross examination to have flaccid testis unilateral. This animal along with 3 others were examined histopathologically. Moderate tubule atrophy along with tubule mineralization, multifocal, was observed in one testis. The other testes examined were within normal limits. Testes from the highest dose, 1000 mg/kg/application, were not examined.

Under conditions of this study, the repeated dermal administration of AEP resulted in dose-related irritative effects at the dermal test site in male rats administered 100, 500 or 1000 mg/kg/application, and in female rats administered 500 or 1000 mg/kg/application. There was no evidence of systemic toxicity in rats administered AEP at dosages of 100, 500 or 1000 mg/kg/application. Therefore, the no-observed-effect-level (NOEL) for systemic toxicity was considered 1000 mg/kg/application AEP for male and female Fischer 344 rats following dermal administration

Effect levels

Dose descriptor:

NOEL

Effect level:

>= 1 000 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: No systemic effects were seen at the highest dose level of 1000 mg/kg/application

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Under conditions of this study, the repeated dermal administration of AEP resulted in dose-related irritative effects at the dermal test site in male rats administered 100, 500 or 1000 mg/kg/application, and in female rats administered 500 or 1000 mg/kg/application. There was no evidence of systemic toxicity in rats administered AEP at dosages of 100, 500 or 1000 mg/kg/application. Therefore, the no-observed-effect-level (NOEL) for systemic toxicity was considered 1000 mg/kg/application AEP for male and female Fischer 344 rats following dermal administration.