[2-(2-methoxymethylethoxy)methylethoxy]propanol

Repeated dose toxicity: dermal

Administrative data

Endpoint:

sub-chronic toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1952

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: This study was conducted prior to GLP and guidelines but sufficient data is available for the interpretation of study results.

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1952

Report date:

1952

Reference 2

Reference Type:

publication

Title:

Toxicology of mono-, di-, and tri-propylene glycol methyl ethers

Author:

Rowe, V.K., McCollister, D.D., Spencer, H.C., Oyen, F., Hollingsworth, R.L., Drill, V.A., (1954).

Year:

1954

Bibliographic source:

Published in AMA Arch. Ind. Hyg. Occ. Med. 9(1):509-525.

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

[2-(2-methoxymethylethoxy)methylethoxy]propanol

EC Number:

247-045-4

EC Name:

[2-(2-methoxymethylethoxy)methylethoxy]propanol

Cas Number:

25498-49-1

Molecular formula:

C10H22O4

IUPAC Name:

[2-(2-Methoxymethylethoxy)methylethoxy]propanol

Details on test material:

- Name of test material (as cited in study report): Tripropylene glycol methyl ether
- Physical state: Clear liquid
- Analytical purity: Essentially 100
- Stability under test conditions: Stable

Test animals

Species:

rabbit

Strain:

not specified

Sex:

male

Administration / exposure

Type of coverage:

occlusive

Vehicle:

other: Distilled water

Details on exposure:

Route of Administration: dermal
TEST SITE
- Area of exposure: Shaved abdomen of rabbit
- Type of wrap if used: Impervious saran wap
- Time intervals for shavings or clipplings:

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

Not specified in the report

Duration of treatment / exposure:

90 days

Frequency of treatment:

5 times a week

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
1.0 ml/kg
Basis:
nominal per unit body weight

Doses / concentrations 2

Remarks:

Doses / Concentrations:
3.0 ml/kg
Basis:
nominal per unit body weight

Doses / concentrations 3

Remarks:

Doses / Concentrations:
5.0 ml/kg
Basis:
nominal per unit body weight

Doses / concentrations 4

Remarks:

Doses / Concentrations:
10 ml/kg
Basis:
nominal per unit body weight

No. of animals per sex per dose:

Control- 5 animals
1 ml/kg-6 animals
3 ml/kg-7 animals
5 ml/kg-8 animals
10 ml/kg-8 animals

Control animals:

yes

Details on study design:

Post-exposure period: none

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily


BODY WEIGHT: Yes
- Time schedule for examinations: Weekly


HAEMATOLOGY: Yes
- Time schedule for collection of blood: Prior to study begun, 30th day, 90th day

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes At necropsy, samples from liver, kidneys, spleen, adrenals, heart, lungs, and G.I. tract collected for processing into slides for histological evaluation.

Other examinations:

organ weights were also monitored.

Statistics:

Not specified.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Dermal irritation:

not examined

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

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: The highest dose, 10 ml/kg-d, produced narcosis and death in 7 of 8 of the subjects. All but one non-survivor died within 3 weeks of initiation of treatment. The remaining non-survivor died during the 10th week of exposure. Other observations in the high dose group included weight loss .

BODY WEIGHT AND WEIGHT GAIN: At 3.0 ml/kg and 5.0 ml/kg-d dose levels body weight loss was evident on days 84 and 90 but not at earlier exposure times.

HAEMATOLOGY: Hematology was normal at all dose levels

ORGAN WEIGHTS: At 3 ml/kg and 5.0 ml/kg-d dose levels kidney weights were increased.

GROSS PATHOLOGY: Gross examination of the skins of the rabbits at the site of TPM application indicated occasional erythema "scalding" but did not reveal significant severity or incidence differences from water treated controls. Autopsy of the high dose group showed that organs appeared normal when examined grossly.

HISTOPATHOLOGY: NON-NEOPLASTIC: Histopathology was largely normal in all organs in the high dose group with the exception that kidneys occasionally showed granular degeneration and hydropic changes. Oddly, at 1.0 ml/kg and 3.0ml/kg, but not at 5.0 ml/kg-d, tubular necrosis was observed in some rabbits.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

965 other: mg/kg

Sex:

male

Basis for effect level:

other: Overall effects

2

Dose descriptor:

LOAEL

Effect level:

2 895 other: mg/kg

Sex:

male

Basis for effect level:

other: Overall effects

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Based on the results of this study NOAEL is 1.0 ml/kg (965 mg/kg) and the LOAEL is 3.0 ml/kg (2895 mg/kg) based on increased kidney weights and decreased body weights later in the study.

Executive summary:

Groups of 5 to 8 adult rabbits per dose level received topical applications of tripropylene glycol methyl ether at doses of 0, 1.0 ml/kg, 3 ml/kg, 5 ml/kg, 10 ml/kg five days per week over a period of 3 months (for a total of 65 applications).Tripropylene glycol methyl ether was applied to a gauze pad (7.5 ×7.5 cm sq) at the appropriate dose level. This pad was applied to clipped or shaved abdomen of the rabbit, covered with impervious saran wrap covered with heavy cloth and secured to the rabbit with adhesive tape. This application procedure was repeated 5 times per week.

Monitored for effects included general observations, body weights, clinical hematology, necropsy, organ weights and histopathology. At 3.0 ml/kg and 5.0 ml/kg-d dose levels body weight loss was evident on days 84 and 90 but not at earlier exposure times.

The highest dose level 10 ml/kg-d, produced narcosis and death in 7 of 8 of the subjects. All but one non-survivor died within 3 weeks of initiation of treatment. The remaining non-survivor died during the 10th week of exposure. Other observations in the high dose group included weight loss.

The hematology analyses for the rabbits were unremarkable, revealing no differences between control and exposure group of animals At 3 ml/kg and 5.0 ml/kg-d dose levels kidney weights were increased.

Gross examination of the skins of the rabbits at the site of TPM application indicated occasional erythema "scalding" but did not reveal significant severity or incidence differences from water treated controls. Autopsy of the high dose group showed that organs appeared normal when examined grossly.

Histopathology was largely normal in all organs in the high dose group with the exception that kidneys occasionally showed granular degeneration and hydropic changes. Oddly, at 1.0 ml/kg and 3.0ml/kg, but not at 5.0 ml/kg-d, tubular necrosis was observed in some rabbits.

Based on the results of this study NOAEL is 1.0 ml/kg (965 mg/kg) and the LOAEL is 3.0 ml/kg (2895 mg/kg) based on increased kidney weights and decreased body weights later in the study.