Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Comparable to guideline study with acceptable restrictions (In order to determine MTD or maximum non irritation dose on the skin, study focused only on point-of-contact changes caused by the test substance. No clinical chemistry, no haematology, limited histopathology, limited gross pathology, no post exposure group)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report Date:
1991

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
Deviations:
yes
Remarks:
(No clinical chemistry, no haematology, limited histopathology, limited gross pathology, no post exposure group, no food consumption determined)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Propionsaeure
- Analytical purity: greater than or equal to 99.7%
- Test substance number: 85/473-1
- Physical state/colour: liquid/colourless
- Storage: RT

Test animals

Species:
mouse
Strain:
other: Crl:CD1(ICR)BR
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Firma Charles River Wiga GmbH, Sulzfeld
- Age at study initiation: 49 days old
- Weight at study initiation: 25.2 - 30.2
- Fasting period before study: no data
- Housing: singly in Type I macrolon cages from BECKER GmbH and Co
- Diet: ad libitum; Kliba Haltungsdiaet Ratte/Maus/Hamster GLP 343 (Klingentak Muehle AG, Switzerland)
- Water: ad libitum (drinking water)
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Type of coverage:
open
Vehicle:
water
Details on exposure:
TEST SITE
- Area of exposure: no exact data; interscalpular region ~1 cm²
- Time intervals for shavings: test site shaved as required

REMOVAL OF TEST SUBSTANCE: No, after application of the test substamnce, the test substance was spread on the skin using a stab.
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 50 µl
- Concentration (if solution): 6, 8, 10 % in aqua bidest. After 3 weeks, the 6% propionic in water was replaced by 14% propionic acid in water
- Constant volume used: yes

USE OF RESTRAINERS FOR PREVENTING INGESTION: no data
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
TEST SUBSTANCE
- Rate of preparation of substance preparations (frequency): every 14 days
- Stability: characterized before and at the end of the study
- Stability in vehicle: stable for 20 days in water
- Method of analysis: potentiographic titration
Duration of treatment / exposure:
90 days
Frequency of treatment:
1x/day, 5 days/week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
136.9, 169.0, 237.4 mg/kg bw (calculated from concentrations and mean bodyweights over the entire study period)
Basis:
nominal per unit body weight
Remarks:
Doses / Concentrations:
8%, 10% and 14% aqueous solution
Basis:
other: concentration
Remarks:
Doses / Concentrations:
At the beginning of the study the applied concentrations were 6%, 8% and 10%. When after 3 weeks of treatment no dermal effects occurred the 6% and 8%, the 6% was increased to 14%.
Basis:

No. of animals per sex per dose:
10 female animals
Control animals:
yes
Details on study design:
- Controls: from a study which was being performed parallel to this study
- Dose selection rationale: based on the results of a preliminary dose range finding study (BASF AG 18C0473/85124) whereby 6% of propionic acid in water caused no effects on skin, 8% exhibited minimal skin irritations and 16% caused skin marked skin changes
- Rationale for animal assignment: random
- Post-exposure recovery satellite groups: No


Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once weekly

MORTALITY: Yes
- Time schedule: twice daily on work days and once daily over the weekends and on public holidays

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: once weekly

BODY WEIGHT: Yes
- Time schedule for examinations: once weekly

FOOD CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
SACRIFICE:
- Time schedule: moribund animals and at termination
- CO2 asphyxiation

GROSS PATHOLOGY AND HISTOPATHOLOGY: Yes
- Only skin was examined

Results and discussion

Results of examinations

Details on results:
MORTALITY
No mortality occurred over the entire study period.

BODY WEIGHT AND WEIGHT GAIN
Body weights were comparable throughout the study between all test groups and the control groups:

Mean body weights after 98 days
- control 29.79 g
- 8%: 29.2 g
- 10%: 29.58 g
- 14%: 29.49 g

CLINICAL SIGNS/GROSS PATHOLOGY
- 8% propionic acid: no skin changes were observed over the entire dosing period of 90 days

- 10% propionic acid: totally, the skin of 6/10 animals was affected whereby following was observed: skin crusts in 2 animals, scad in one animal, scales in 2 animals.

- 14% propionic acid: the skin of all 10 animals were affected: formation of crustaceous skin tissue (1/10 animals), skin defects (3/10 animals), scab formation (5/10 animals), erythema (1/10 animals)

HISTOPATHOLOGY
- 8% propionic acid: 3/10 animals displayed acanthosis and fibrous condensation with inflammation of corium connective tissue usually accompanied by the skin loosing its ability to fold normally and 2/10 animals displayed crustaceous tissue and ulceration of the skin. The maximum non-irritant dose lies below 8 %.

10% propionic acid: 6/10 animals showed skin lesions from erythema and crust formation to ulceration which were in general less pronounced than in the high concentration. This was affirmed pathologically and histology revealed acanthosis and fibrous condensation with inflammation of corium connective tissue usually accompanied by the by the skin loosing its ability to fold normally.

14%: all animals showed skin lesions ranging from erythema and crust formation to ulceration in 5/10 animals. This was affirmed pathologically and histology revealed acanthosis and fibrous condensation with corium inflammation of connective tissue usually accompanied by the skin loosing its ability to fold normally.

Effect levels

Dose descriptor:
LOAEL
Effect level:
136.9 mg/kg bw/day (nominal)
Sex:
female
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion