Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic data given; similar to guideline study

Data source

Reference
Reference Type:
publication
Title:
Toxicology of mono-, di- and tripropylene glycol methyl ethers.
Author:
Rowe VK, McCollister DD, Spencer HC, Oyen F, Hollingsworth RL, Drill VA.
Year:
1954
Bibliographic source:
AMA Arch Ind Hyg Occup Med 9:509-525.

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
Principles of method if other than guideline:
Study pre-dated OECD test guidelines but study followed basic principles of current OECD guidelines
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
1-methoxypropan-2-ol is a close structural analogue of 1-ethoxypropan-2-ol, which is the major hydrolysis product of the submission substance (1-ethoxypropan-2-yl acetate).

- Name of test material (as cited in study report): Propylene glycol methyl ether
- Molecular formula (if other than submission substance):
- Molecular weight (if other than submission substance):
- Smiles notation (if other than submission substance):
- InChl (if other than submission substance):
- Structural formula attached as image file (if other than submission substance): see Fig.
- Substance type:
- Physical state:
- Analytical purity: essentially 100%
- Impurities (identity and concentrations):
- Composition of test material, percentage of components:
- Isomers composition:
- Purity test date:
- Lot/batch No.:
- Expiration date of the lot/batch:
- Radiochemical purity (if radiolabelling):
- Specific activity (if radiolabelling):
- Locations of the label (if radiolabelling):
- Expiration date of radiochemical substance (if radiolabelling):
- Stability under test conditions:
- Storage condition of test material:
- Other:

Test animals

Species:
rabbit
Strain:
not specified
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source:
- Age at study initiation:
- Weight at study initiation:
- Fasting period before study:
- Housing:
- Diet (e.g. ad libitum): Commercial rabbit chow (Rockland)
- Water (e.g. ad libitum):
- Acclimation period:


ENVIRONMENTAL CONDITIONS
- Temperature (°C):
- Humidity (%):
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light):


IN-LIFE DATES: From: To:

Administration / exposure

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: abdomen
- % coverage:
- Type of wrap if used: A pad of absorbent cotten, about 3 x 3 inches in size and sufficiently thick to just absorb the volume of test material, was applied to the clipped or shaved abdomen and covered with an impervious saran film about 5 x 5 inches. The saran film was covered with a heavy cloth, and the whole application was then strapped onto the animal with adhesive tape.
- Time intervals for shavings or clipplings:


REMOVAL OF TEST SUBSTANCE
- Washing (if done):
- Time after start of exposure:


TEST MATERIAL
- Amount(s) applied (volume or weight with unit):
- Concentration (if solution):
- Constant volume or concentration used: yes/no
- For solids, paste formed: yes/no


VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Amount(s) applied (volume or weight with unit):
- Concentration (if solution):
- Lot/batch no. (if required):
- Purity:


USE OF RESTRAINERS FOR PREVENTING INGESTION: yes/no
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Three months.
Frequency of treatment:
Five times per week
Doses / concentrations
Remarks:
Doses / Concentrations:
0.0, 2.0, 4.0, 7.0 or 10.0 ml/kg
Basis:
nominal per unit body weight
No. of animals per sex per dose:
5 to 11
Control animals:
other: Yes, control animals were similarly exposed to water

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes / No / No data
- Time schedule:
- Cage side observations checked in table [No.?] were included.


DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule:


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


BODY WEIGHT: Yes
- Time schedule for examinations: Animals were weighed before the application of each daily dose of test material.


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


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 / No / No data


WATER CONSUMPTION: Yes / No / No data
- Time schedule for examinations:


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


HAEMATOLOGY: Yes
- Time schedule for collection of blood: Before start of the study and on the 30th and 90th days of treatment.
- Anaesthetic used for blood collection: Yes (identity) / No / No data
- Animals fasted: Yes / No / No data
- How many animals:
- Parameters examined: Hemoglobin, red blood cell count, white blood cell count (total and differential)


CLINICAL CHEMISTRY: Yes / No / No data
- Time schedule for collection of blood:
- Animals fasted: Yes / No / No data
- How many animals:
- Parameters checked in table [No.?] were examined.


URINALYSIS: Yes / No / No data
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked in table [No.?] were examined.


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:


OTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes: liver, kidneys, spleen, adrenals, heart, lungs and occasionally stomach.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Dermal irritation:
no effects observed
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
Haematological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Details on results:
Doses of 7 and 10 ml/kg produced narcosis which generally led to the death of the animal. These animals showed a terminal loss in body weight, probably related to decreased food consumption. Deaths seen in the groups receiving 2 or 4 ml/kg were associated with respiratory infections and were not correlated with narcotic effects or histological changes in any of the organs examined except the lungs. These doses did not effect body weight gain.

Haematological parameters were normal, and organ weights were normal except in animals that died. No gross or histological pathology was seen in the lungs, heart, adrenals, testes, stomach or intestines of animals that survived the study. Animals that exhibited narcosis and died often showed pneumonia and empyema. Pyelonephritis or early interstitial nephritis was observed in occasional animals, and moderate to marked renal tubular necrosis was observed in three rabbits that died from the 7 or 10 ml/kg groups.

Careful gross and histological examinations of the skin revealed occasional scaling and erythema, but there was no significant difference between the skin of the treated animals and the control animals similarly treated with water only.

The study authors concluded that the dosage level of 2 ml/kg was well tolerated by the animals.

Effect levels

Dose descriptor:
NOAEL
Effect level:
2 other: ml/kg
Based on:
test mat.
Sex:
male
Basis for effect level:
other: overall effects clinical signs; mortality; body weight; food consumption

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

 Dose (ml/kg)  No. Deaths / No. Treated
 0.0  0/5
 2.0  1/6*
 4.0  2/7*
 7.0  8/9
 10.0  11/11

* Deaths were associated with respiratory infections and were not attributed to the test material.

Applicant's summary and conclusion

Executive summary:

In a 90-day dermal toxicity study, occluded application of methoxypropanol (a close structural analogue of the hydrolysis product of ethoxypropyl acetate) to the clipped abdominal skin of rabbits at doses of 7.0 ml/kg or higher 5 days per week resulted in narcosis and death. No effects were noted on body weight, organ weight or haematological parameters in animals that survived the study. Slight liver and kidney changes were noted at the higher doses. No effects seen on the skin by gross or histological examination. The study authors concluded that doses of 2 ml methoxypropanol/kg (1800 mg/kg) were well tolerated by the animals.

On a molar basis this would be equivalent to a dose of 2,920 mg/kg of ethoxypropyl acetate.