C12-18-(even numbered, C18 unsaturated)-alkylamines acetates

Repeated dose toxicity: dermal

Administrative data

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

1985

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: No OECD guideline study but according to GLP and following scientific principles of this type of study. The study was well conducted, well referenced and is of reliable quality.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1985

Report date:

1985

Materials and methods

Test guideline

Test guideline 1

Qualifier:

equivalent or similar to guideline

Guideline:

other: EPA TSC Health Effects Guideline (OTS 1983)

Deviations:

no

Test guideline 2

Qualifier:

equivalent or similar to guideline

Guideline:

other: EPA Pesticide Assessment Guidelines - Subdivision F - Hazard Evaluation 1982

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

(Z)-octadec-9-enylamine

EC Number:

204-015-5

EC Name:

(Z)-octadec-9-enylamine

Cas Number:

112-90-3

IUPAC Name:

octadec-9-en-1-amine

Constituent 2

Reference substance name:

(Z)-Octadec-9-enylamines

IUPAC Name:

(Z)-Octadec-9-enylamines

Test material form:

other: pasty wax

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: in-house breeding station at Intox
- Age at study initiation: young adults
- Weight at study initiation: 206 - 321 g
- Fasting period before study: no
- Housing: stainless-steel cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: approx 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 22 °C
- Humidity (%): 40 - 56
- Air changes (per hr): not stated
- Photoperiod (hrs dark / hrs light): 12 hours periodically

Administration / exposure

Type of coverage:

semiocclusive

Vehicle:

other: mineral oil

Details on exposure:

TEST SITE
- Area of exposure: 10 %
- % coverage: 100
- Type of wrap if used: porous gauze covered with Vetwrap elastic bandage
- Time intervals for shavings or clipplings: 7 days

REMOVAL OF TEST SUBSTANCE
- Washing (if done): daily
- Time after start of exposure: 6 hours after test article apllication

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 5 mL/kg
- Concentration (if solution): 0, 0.3, 1.5 and 3%
- Constant volume or concentration used: yes

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Two 5-day periods with an intermediate 2-day non-dosing period

Frequency of treatment:

daily, 5 days per week, 2 weeks

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 0.3, 1.5 and 3 % (w/v)
Basis:
nominal per unit area

No. of animals per sex per dose:

4 male and 4 female animals per dose group

Control animals:

yes

Details on study design:

- Dose selection rationale: based on pilot study
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: no satellite groups
- Post-exposure recovery period in satellite groups: n.a.
- Section schedule rationale (if not random): n.a.

Positive control:

no

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: days 2, 4, 6, 8, 10, 12 and 14 (first dosing day = day 1)

BODY WEIGHT: Yes
- Time schedule for examinations: prior to study initiation, weekly thereafter

FOOD CONSUMPTION:
- Food consumption: determined weekly

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: No data

CLINICAL CHEMISTRY: No data

URINALYSIS: No data

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Dermal irritation:

effects observed, treatment-related

Description (incidence and severity):

erythema at lowest test concentration; necrosis at mid- and high dose

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

weight loss in females of highest dose, but only during first week

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:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Effect levels

Dose descriptor:

LOAEL

Remarks:

local dermal effects (irritation)

Effect level:

0.3 other: % (w/v)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no systemic toxic effects noted but dermal irritative responses

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Based on mild to moderate dermal irritation observed in all dose groups, a NOAEL for local effects could not be established. Based on the grading of dermal effects, the lowest dosage of 0.3% (v/v) is regarded to be a LOAEL.

Executive summary:

Octadecenylamine (oleylamine) was dermally applied on two 5-days periods with intermediate 2-day non dosing-period to male and female Sprague-Dawley rats. Animals of the control groups received the vehicle only (mineral oil). Based on the results of a pilot study, groups of young adult rats (4 males and 4 females) were treated dermally with the test substance at concentrations of 0, 0.3, 1.5 and 3.0% (v/v) in mineral oil (corresponding to doses of 0, 12.5, 62.5 and 125 mg/kg bw/d). Rats were treated for two five-day dosing periods with an intermediate two-day non-dosing period in order to more closely reproduce conditions of human exposure to the test substance. The first day of dosing was designated as Day 1. Due to excessive tissue destruction indicated by sloughing, scores of moderate to severe erythema, scabbing, hardening of the skin, and sensitivity to touch, the dosing at the intermediate and high dose levels (1.5 and 3.0%) was discontinued on Day 9. These animals were subsequently sacrificed on Day 10. At initiation of dosing the rats’ body weights ranged from 205.7 to 321.3 g. Rats were acclimated to the laboratory for seven days prior to test substance application. Water and food were provided ad libitum. Approximately 24 hours prior to test substance application, the fur was clipped from the dorsal area of each animal. Shaving was repeated one week later. The test substance was applied at a volume dosage of 5 ml/kg. The application site was covered by a porous gauze dressing that was held in place with tape, and covered with a taped elastic bandage. Each day, wrappings were removed approximately six hours after test substance application and the test sites were washed with warm water to remove excess test substance. Observations of signs of toxicity were made once each day. Body weights were recorded during acclimation, weekly during the study and at sacrifice. Food consumption was recorded weekly during the study. Morbidity/mortality checks were examined prior to test substance administration on days 2, 4, 6, 8, 10, 12 and 14 for signs of erythema and necropsies were performed. Animals were killed and discarded three days following the completion of dosing.

All rats survived until scheduled sacrifice. Concentrations of 1.5 and 3.0% produced moderate to severe irritation (erythema scores 2-4), which in some instances progressed to hardening and sloughing of the skin. A number of rats were sensitive to touch. In the 0.3 % group, erythema scores of 1 to 2 were observed, indicating mild to moderate irritation, and flaking of the outer layers of the epidermis was observed. An increased sensitivity in females to the irritant effects of the test substance as compared to males was observed. In the control group, one male showed an erythema score of 1 at one observation. All rats in the 1.5 and 3% groups were sacrificed on day 9 of the study due to the irritant/corrosive effects of the test substance. No other treatment-related irritant effects or clinical signs were observed. A significant treatment-related effect on body weight was observed for males at day 7. Individual group comparisons revealed that body weights in both the 1.5 and 3% groups were significantly lower than controls. Females in the 3.0% group showed a mean weight loss during the first week of the study, although this finding was not significant. Food consumption during the first week of study was reduced significantly in the 1.5% group males when expressed as total food consumed. No significant difference was noted when expressed on a per weight basis. The study provides additional data on the toxicity of repeated dermal dosing, including severe irritation, of this test substance at concentrations of 0.3, 1.5 and 3.0%. A NOAEL for local dermal effects could not be derived, the LOAEL was 0.3% (v/v). No NOAEL for systemic toxicity was derivable because of lack of histomorphology data from other organs and tissues. However, no macroscopic indication of systemic toxicity was observed.