1-(1-methyl-2-propoxyethoxy)propan-2-ol

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

February 23, 2000 - August 29, 2000

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted according to OECD TG 408 and in accordance with the principles of GLP.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2000

Report date:

2000

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Version / remarks:

also EEC Part B.26, 87/302/EEC, Japanese MITI (Subchronic Oral Study) and USEPA-OPPTS 870.3100

Deviations:

no

Principles of method if other than guideline:

not applicable

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

1-(1-methyl-2-propoxyethoxy)propan-2-ol

EC Number:

249-949-4

EC Name:

1-(1-methyl-2-propoxyethoxy)propan-2-ol

Cas Number:

29911-27-1

Molecular formula:

C9H20O3

IUPAC Name:

1-(1-methyl-2-propoxyethoxy)propan-2-ol

Details on test material:

Purity of the test material determined by gas chromatography(GC) using flame ionization detector (FID) was 99.3%. The structure was confirmed by nuclear magnetic resonance (NMR). Water content was 0.01% by the Karl Fisher method.

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

Animals were obtained from Charles River Laboratories Inc. (Raleigh, NC) and were 7 weeks old at the start of the study. The animals were uniquely identified and housed two to three per cage (acclimation period) or one per cage (study) in stainless steel wire cages in a room maintained at 21.5 -22.2 degrees C, 48.5 -51.9% relative humidity and a 12 hour light/12 hour dark cycle. Room air was exchanged 12-15 times per hour. Animals were provided Purina Certified Rodent Lab Diet #5002 (Purina Mills, Inc., St. Louis, MO) and tap water ad libitum. There were no contaminants that could adversely affect the study. Rats were acclimated for 15 days prior to the start of the study, stratified according to body weight and randomly assigned to groups. Animals chosen for use were considered by a veterinarian to have adequate health.

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

Four groups of Fischer 344 rats (10/sex/dose level) received test material in their drinking water at concentrations equivalent to target doses of 0, 50, 150 or 500 mg/kg-day for 13 weeks. Drinking water solutions were prepared weekly. The amount of test material administered was adjusted weekly based on the most recent body weights and water consumption data.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

According to the MSDS, the test material is totally miscible in water at concentrations up to 17.5% (25 degrees C), approximately twice the concentration of the high dose for the study. Therefore, a homogeneity analysis was not performed. Samples of water from the first female in the low dose group and the first male in the high dose group were taken during week one for stability analysis. The material was shown to be stable in water for at least 8 days. Analysis of all dose levels (HPLC with UV detection and external standards) was conducted during Weeks 1, 8 and 13 (concentrations were 90 - 108% of target).

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

continuous

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

50 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

150 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

500 mg/kg bw/day (nominal)

No. of animals per sex per dose:

10

Control animals:

yes, concurrent no treatment

Details on study design:

The high-dose level of 500 mg/kg/day was chosen based on results of the 2-week drinking water study and was expected to produce increased liver weights. The remaining dose levels were expected to provide dose-response data for any treatmentrelated effect(s) observed in the high-dose group. The low-dose was also expected to be a no-observed-effect level (NOEL).

Positive control:

None

Examinations

Observations and examinations performed and frequency:

Rats were observed for clinical signs of toxicity prior to the start of the study and twice daily thereafter. A detailed clinical observation was conducted pre-exposure and weekly during the study. Functional testing (sensory evaluation, rectal temperature, grip performance and motor activity) was conducted predosing and during the last week of the study. Body weights and feed and water consumption were measured during the pre-exposure period and once per week during the study. Ophthalmological examinations were conducted by a veterinarian prior to treatment and at termination. Urinalyses were conducted on urine collected (16 hours in metabolism cages) one week prior to termination.

Sacrifice and pathology:

Standard hematology and clinical chemistries and a prothrombin time analysis were performed on blood collected form the orbital sinuses of anesthetized animals at termination (after an overnight fast). At termination, all animals were euthanized and subjected to complete necropsy. The eyes were examined in situ by application of a moistened glass slide to each cornea. The brain, liver, kidneys, heart, adrenals, testes, epididymides, uterus, ovaries, thymus and spleen were weighed. The adrenals, aorta, auditory sebaceous glands, bone, bone marrow, brain, cecum, cervix, coagulating glands, colon, duodenum, epididymides, esophagus, eyes, gross lesions, heart, ileum, jejunum, kidneys, lacrimal/Harderian glands, larynx, liver, lungs, mammary gland, mediastinal lymph node and tissues, mesenteric lymph node and tissues, nasal and oral tissues, ovaries, oviducts, pancreas, parathyroid gland, peripheral nerve, pituitary, prostate, rectum, salivary glands, seminal vesicles, skeletal muscle, skin and subcutis, spinal cord, spleen, stomach, testes, thymus, thyroid gland, tongue, trachea, urinary bladder, uterus and vagina were collected from all animals and preserved. All tissues collected from control and high dose animals were examined histologically. The lungs, liver, kidneys and relevant gross lesions (with the exception of a fractured tail) from the other groups also were examined histologically.

Other examinations:

None

Statistics:

All data were first tested for equality of variance using Bartlett's test (alpha (a) = 0.01). If the results from the test were significant, then data were transformed (common log, inverse or square root) to obtain equality of variances. Motor activity counts were reported as square roots. Body weights were evaluated using a repeated measures analysis of variance (ANOVA) for time, sex and dose. If the test was significant (a = 0.02) the analysis was repeated separately for each sex. The time-dose interaction was examined next. If significant (a = 0.05), linear contrasts tested this interaction for each dose group (compared to control). A Bonferroni correction was applied to control the experiment-wise error rate. Final body weight, organ weight (excluding sex organs), hematology (excluding RBC indices and differential WBC), clinical chemistry and urine specific gravity data were evaluated using a two-way ANOVA with the factors of sex and dose. If the sex-dose interaction was significant (a = 0.05), a one-way ANOVA was performed for each sex. Weights of sex organs were analyzed using a one-way ANOVA. Comparisons of data (to control) were made with Dunnett's test when a significant dose effect (a = 0.05) was identified. Water and feed consumption data were evaluated by a Bartlett's test for equality of variances (a = 0.01), followed by a parametric ANOVA and a Dunnett's test (if significant at a = 0.05). Descriptive statistics were reported for body weight gains, RBC indices and WBC differential counts. Outliers were identified by a sequential test (a = 0.02), and excluded from feed consumption evaluations. Rectal temperature and grip performance data were analyzed by a factorial analysis of covariance (ANCOVA) with the factors of sex and dose and the covariate of the pre-exposure value. Motor activity data were analyzed by a factorial repeated-measures design with factors of sex, treatment and time. DCO incidence scores were analyzed by a Z-test.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

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

effects observed, treatment-related

Description (incidence and severity):

500 mg/kg bw decreased water consumption in females (10% reduction)

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

500 mg/kg bw increased cholesterol in males (by 17%). Slightly lower alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in males and females were not considered to be treatment-related or toxicologically relevant. Lower ALT in males and females seen at 150 mg/kgbw/day was not considered to be biologically significant.

Endocrine findings:

not examined

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

500 mg/kg bw decreased urine volume in males (3.9 +/-0.6 ml vs. 4.6 +/- 0.7 ml in control) and females (3.8 +/- 3.7 ml vs. 5.3 +/- 3.5 ml in control) and increased urine specific gravity for females (1.079 +/- 0.022 vs. 1.059 +/- 0.018).

Behaviour (functional findings):

no effects observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

500 mg/kg bw: Increased absolute and relative liver weight in males (16%). Three males had livers which appeared increased in size. Higher relative kidney and adrenal weights of males and females and higher absolute and relative kidney weights of males and females were not considered to be treatment-related or toxicologically relevant. Higher absolute and relative thymus weights of males seen at 150 mg/kgbw/day was not considered to be biologically significant.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

One male and one female had hemolyzed blood in the lumen of the stomach in the high dose group. One male had hemolyzed blood in the lumen of the stomach at 150 mg/kgbw/day.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No histopathological changes were noted that could be attributed to the test material.

Histopathological findings: neoplastic:

not examined

Details on results:

500mg/kgbw/day was considered to be the NOAEL for males by the study investigator. It was not considered to be the NOAEL for females based on the decreased water consumption and urine volume and increased urine specific gravity. 150mg/kgbw/day This was considered to be the NOEL for males and females by the study investigator.

Effect levels

Dose descriptor:

NOAEL

Effect level:

> 500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Remarks on result:

other: no effects seen at maximum tested concentration potentially limited by palatability

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

The authors concluded that the differences in liver weight and cholesterol were likely due to induction of organelles required for metabolism of the test material and altered lipid metabolism (respectively) and were not toxicologically significant, particularly in the absence of any histopathological changes. Alterations in urinary parameters for females were attributed to decreased water consumption. None of the changes seen at the maximum tested dose of 500mg/kgbw/day were therefore considered adverse.

Applicant's summary and conclusion

Conclusions:

Based on the subchronic study results for dipropylene glycoln-propyl ether, the no-observed-adverse-effect level (NOAEL) for male/female Fischer 344 rats was the targeted concentration of 500 mg/kg/day while the no-observed-effect level (NOEL) for males and females was 150 mg/kg/day.

Executive summary:

Four groups of 10 male and 10 female Fischer 344 rats were given drinking water solutions supplying 0, 50, 150, or 500 mg Dipropylene glycol n-propyl ether (DPnP)/kilogram body weight/day (mg/kg/day) for 13 weeks to evaluate the potential for systemic toxicity. Standard toxicologic parameters were evaluated.

 

Treatment-related effects consisted of 1) an increased absolute and relative liver weight for males given 500 mg/kg/day, 2) decreased water consumption for females given 500 mg/kg/day, 3) decreased urine volume in males and females given 500 mg/kg/day, 4) increased urine specific gravity for females given 500 mg/kg/day, and 5) an increase in cholesterol of males given 500 mg/kg/day.

 

The differences in liver weight and cholesterol were likely due to the induction of organelles required for the metabolism of DPnP and altered lipid metabolism, respectively, and were not toxicologically significant. Alterations in urinary parameters for females were directly attributed to decreased water consumption.

 

The no-observed-adverse-effect level (NOAEL) for male and female Fischer 344 rats was the targeted concentration of 500 mg/kg/day. The no-observed-effect level (NOEL) for males and females was 150 mg/kg/day.