Nonanoic acid

Repeated dose toxicity: dermal

Administrative data

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

experimental study

Adequacy of study:

other information

Study period:

1 Dec 1980 to 29 Dec 1980

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Does not meet important criteria of today standard methods: Low animal numbers, only one dose tested, treatment period only 14 days, limited parameters examined (no organ weights, no hematology, clinical biochemistry, or urinalysis)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1981

Report date:

1981

Materials and methods

Principles of method if other than guideline:

14-day repeated dose dermal toxicity study using 5 male and 5 female rabbits at one dose level. A satellite group of 3 animals was allowed to recover for 14 days

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Nonanoic acid

EC Number:

203-931-2

EC Name:

Nonanoic acid

Cas Number:

112-05-0

Molecular formula:

C9H18O2

IUPAC Name:

nonanoic acid

Details on test material:

- Name of test material (as cited in study report): C-182 (nonanoic acid),
- purity: > 96% (see attached document)
- Substance type: colourless liquid
- Physical state: liquid
- Lot/batch No.: C-182
- Storage condition of test material: at room temperature

Test animals

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Dutchland Laboratory Animals, Denver, PA, USA
- Age at study initiation: young adult
- Weight at study initiation: 2.1-3.2 kg (males); 2.3-3.2 kg (females)
- Housing: individually
- Diet (ad libitum): Purina rabbit chow
- Water (ad libitum): tap water
- Acclimation period: 21 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 15.5-21.1
- Humidity (%): monitored daily
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Type of coverage:

other: open, animals with collar

Vehicle:

other: mineral oil

Details on exposure:

TEST SITE
- Area of exposure: dorsal and lateral, about 10% of the total body surface
- % coverage: about 10%
- Type of wrap if used: application sites not covered
- Time intervals for shavings or clipplings: prior to first dose, reclipping as nessesary during the dosing period
REMOVAL OF TEST SUBSTANCE
- Washing (if done): no

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 500 mg/kg/day (about 2 mL of test substance solution); test solution and vehicle (for controls) were applied directly onto skin and spread evenly over the entire area with a glass rod.
- Concentration (if solution): 25% w/w in mineral oil; to 100 g of test substance, vehicle was added to acchieve a total weight of 400 g. The mixture was stirred slowly to achieve a homogeneous mixture. Fresh mixtures were prepared weekly.
- Constant volume or concentration used: yes

VEHICLE
- Justification for use and choice of vehicle (if other than water): suitable solvent
- Amount(s) applied (volume or weight with unit): 2 mL
- Concentration (if solution): 25% w/w test substance in vehicle

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes; Elisabethan collars

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

14 d

Frequency of treatment:

1x/d, 5d/wk, 10x

Doses / concentrations

Remarks:

Doses / Concentrations:
500 mg/(kg bw day) as 25 % solution in mineral oil
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: no data
- Rationale for animal assignment (if not random): random by random numbers table
- Rationale for selecting satellite groups: 3 animals (from 10 of the dosed group) were selected as satellite animals for the recovery group
- Post-exposure recovery period in satellite groups: 2 weeks
- Section schedule rationale (if not random): no data
-Skin treatment: The skin of half of the animals (3 males, 2 females) was abraded prior to the first, sixth and eighth substance application. If the integrity of the skin was interrupted because of response to test material application, additional abrasions were not made.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: mortality twice daily, cage side observations daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: prior to first dosing and daily thereafter

BODY WEIGHT: Yes
- Time schedule for examinations: prior to first application, weekly thereafter

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
- Time schedule: 6 animals after 2 weeks (3 each with abraded and intact skin regardless of sex, end of treatment period), remaining 3 animals after 4 weeks (end of post exposure recovery period).
- Preserved tissues: adrenals (2), brain, eyes, gonads, heart, intestine (colon, duodenum, ileum), kidneys (2), liver (2), lungs (2) lymph nodes (mesenteric), mammary gland, pancreas, pituitary, salivary gland, skeletal muscle, skin (treated, untreated), spinal cord (cervical), spleen, stomach, thyroid, urinary bladder, uterus/prostate, gross lesions tissue masses. Tissues were preserved in 10% neutral buffered formalin.

HISTOPATHOLOGY: Yes
- Tissues: brain, heart, kidneys, liver, lungs, skin treated and untreated. Tissue slides were prepared, stained with hematoxylin and eosin, and examined microscopically

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:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

no effects observed

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:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
No mortality and no overt clinical signs occured.

DERMAL IRRITATION
Most animals showed slight to severe erythema and edema without necrosis or eschar formation during the first week of the study. Necrosis and eschar occured subsequently in all animals during the second week of treatment. Further effects were atonia, desquamation, fissuring and exfoliation. These effects subsided during the recovery period. One animal exhibited hair loss during the recovery period.

BODY WEIGHT AND WEIGHT GAIN
Most animals treated with the test substance exhibited slicht body weight losses (0.1-0.4 kg) after one week and/or two weeks of study. Animals held for the two weeks recovery period gained weight during this interval.

FOOD CONSUMPTION
Several aminals exhibited a decreased food consumption during the second and third week of the study.

GROSS PATHOLOGY
Mostly, morphological abnormalities of the treated skin were observed (see Dermal Irritation). Other gross morphological and microscopic alterations occured sporadically in treated and control animals and do not appear to be related to the exposure. Other changes were too inconclusively to demonstrate the presence or absence of systemic effect of the test substance.

HISTOPATHOLOGY: NON-NEOPLASTIC
Microscopic examination showed epidermal necrosis, epidermal hyperplasia, hyperkeratosis as well as diffuse and perifollicular dermal inflammation at the test sites. The application sites appeared to be healed at the end of the recovery period (re-epitheliazed and continuous, mild to moderate epidermal hyperplasia and hyperkeratosis, normal follicular structure and population). Treatment-related tissue reactions occured in abraded as well as non-abraded sites.

Effect levels

Dose descriptor:

LOAEL

Effect level:

500 mg/kg bw/day

Sex:

male/female

Basis for effect level:

other: reduced food consumption and slight weight losses during exposure, no clearly treatment-related systemic effects, local effects: skin irritation and necrosis

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Under the conditions of this repeated dermal toxicity study on rabbits the most prominent effect was irritation and necrosis of the skin. The effects subsided in a recovery group of 3 animals within 14 days. Systemic toxic responses were restricted to unspecific effects (reduced food consumption, body weight loss).

Executive summary:

5 male and female New Zealand rabbits each were exposed dermally to 0 or 500 mg/kg bw of the test item (purity not stated) 5 d/w for 2 weeks. The skin of 50% of the animals (3 males, 2 females) has been abraded. Six animals (three with abraded and three with intact skin) were examined at the end of exposure. 3 of 10 animals were selected as satellite group for a 2 weeks recovery period.

Several aminals exhibited a decreased food consumption during the second and third week of the study.

Most animals exhibited weight loss (0.1 - 0.4 kg) after 1 or/and 2 weeks of  the study. Animals regained weight during the recovery period.

Most animals showed slight to severe erythema and edema during the first week of the study. Necrosis and eschar occured subsequently in all animals during the second week of treatment. Further effects were atonia, desquamation, fissuring and exfoliation. Microscopic examination showed epidermal necrosis, epidermal hyperplasia, hyperkeratosis as well as diffuse and perifollicular dermal inflammation at the test sites. The skin application sites appeared to be healed at the end of recovery period. No clearly treatment-related macroscopic or microscopic lesions were observed in other organs.

The LOAEL in this study is 500 mg/kg bw/day, based on body weight reduction and skin damage, a NOAEL was not derived (Bio/dynamics, 1981).