Valeric acid

Repeated dose toxicity: dermal

Administrative data

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1980-12-01 through 1980-12-29

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

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 hematoilogy, clinical biochemistry, or urinalysis). No organ weights. Dermal route of administration not appropriate for a corrosive substance.

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1981

Report date:

1981

Reference 2

Reference Type:

other company data

Title:

Unnamed

Year:

1982

Report date:

1982

Reference 3

Reference Type:

other company data

Title:

Unnamed

Year:

1986

Report date:

1986

Materials and methods

Test guideline

Qualifier:

no guideline followed

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:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Valeric acid

EC Number:

203-677-2

EC Name:

Valeric acid

Cas Number:

109-52-4

Molecular formula:

C5H10O2

IUPAC Name:

pentanoic acid

Details on test material:

- Name of test material (as cited in study report): C-180
- Physical state: clear liquid
- Analytical purity: > 99% (see reference 2)
- Expiration date of the lot/batch: 1981-06-01
- Stability under test conditions: stable material
- Storage condition of test material: room temperature
- Other: test material received from sponsor (Celanese Corp., New York) on December 01, 1980

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 adults
- Weight at study initiation: males: 2.1 to 3.2 kg, females: 2.3 to 3.2 kg
- Fasting period before study: no data
- Housing: individually, in suspended stainles steel cages
- Diet (e.g. ad libitum): Purina Rabbit Chow, ad libitum
- Water (e.g. ad libitum): municipal water supply, ad libitum, automatic watering system
- Acclimation period: 21 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 15.6 - 21.1° C
- Humidity (%): daily controlled, no specified data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: November 10, 1980 To: December 29, 1980

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 removal of test substance referred

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:

2 weeks

Frequency of treatment:

5 days / week

Doses / concentrations

Remarks:

Doses / Concentrations:
ca. 500 mg/kg
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:

effects observed, treatment-related

Dermal irritation:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

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:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
1 out of 10 animals died (female, day 7). It exhibited hypopnea, hypoactivity, food consumption decrease, and red anal discharge prior to death.
Several animals exhibited atonia, nasal discharge and vocalization when handled. Individual animals showed hair loss and evidence of ocular irritation.
Recovery animals were free of signs of significant toxicity at termination of the study.

DERMAL IRRITATION
All animals exhibited severe erythema, moderate to severe edema, necrosis and eschar formation, desquamation and fissuring of the skin and exfoliation of eschar tissue by the second week of treatment. Dermal response subsided in animals held for recovery.

BODY WEIGHT AND WEIGHT GAIN
Most animals showed no change in weight or exhibited slight (0.1 to 0.3 kg) weight losses during the first week. All animals lost weight during the second week (0.1 to 0.3 kg). Animals held for a recovery period exhibited weight gains after one and/or two weeks of recovery.

FOOD CONSUMPTION
Several animals showed food consumption decrease.

GROSS PATHOLOGY
Mostly, morphological abnomalities of the treated skin were observed (see Dermal Irritation). Treatment-related tissue reactions occured in abraded as well as non-abraded sites.
For other organs no significant gross pathological findings were noticed.
In several treated animals, discolorations of the gastric mucosa could be seen. Other morphologic findings observed gross pathologically occured sporadically in the treated and/or control animals. They do not appear to be related to the administration of the test substance.

HISTOPATHOLOGY: NON-NEOPLASTIC
Epidermal necrosis was present in the application sites of treated animals. It was accompanied by epidermal hyperplasia and hyperkeratosis. Skin application sites in all surviving animals appeared healed by two-weeks post treatment (scheduled recovery period). In all cases the sites were re-epithelialized and continuous and showed normal follicular structure and population.
A variety of inflammatory changes were observed in kidneys, lungs, and brain. These were, however, random and were not regraded as being treatment related. Other changes were too inconclusively to demonstrate the presence or absence of systemic effect of the test substance.

Effect levels

Dose descriptor:

dose level:

Effect level:

500 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: local skin effect ( corrosion in intact and abraded skin, regardless of sex)

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Valeric acid at 500 mg/kg bw and day (10 treatments within 14 days) caused severe local effects (severe dermal irritation/corrosion/necrosis) in all animals. Mortality and body weight decreases were both low. Clear systemic effects could not be demonstrated. Recovery from the local effects was apparent in in a small 14-day recovery group.

Executive summary:

In a repeated-dose subacute dermal toxicity study, valeric acid was applied to the shaved skin of New Zealand White rabbits (5 animals/sex/dose) at dose levels of 0 and 500 mg/kg bw and day, for 5 days/week during a 14-day period. The skin of 50 % of the animals (3 males and 2 females) was abraded. 3 of the 10 animals were selected as satellite group for a 2 weeks post exposure recovery period.

 

1 out of 10 animals died (female, day 7). Prior to death, this animal as well as other surviving animals showed clinical signs. Body weight decrease was observed primarily during the second week of treatment. Recovery animals were free of signs of significant toxicity at termination of the study.

 

All animals exhibited local skin effects (severe erythema, moderate to severe edema, necrosis, eschar formation and other skin reactions) by the second week of treatment. Dermal response subsided in animals held for recovery.

 

With the exception of discolored gastric mucosa in some animals, no significant gross pathological findings were observed. Histological findings were related to the skin irritation of the test substance. Hematological, clinical, and urinary parameters were not examined as well as organ weights.

 

A NOAEL was not derived (Celanese/Hazleton, 1981).

 

This dermal toxicity study in the rabbit is regarded to be not of acceptable reliability due to important deviations from the OECD TG 410 (low animal number, short treatment period, only one dose level tested, examinations limited).