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

Endpoint summary

Description of key information

13-week drinking water toxicity study in Fischer 344 rats including a 2 week range finding study, Reproduction/Developmental Toxicity Screening Test in CRL:CD(SD) Rats

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

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.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

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

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.

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

Dose / conc.:

50 mg/kg bw/day (nominal)

Dose / conc.:

150 mg/kg bw/day (nominal)

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

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.

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.

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

Critical effects observed:

not specified

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.

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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

500 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

good

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose oral toxicity:

In a 13 week drinking water toxicity study (as per OECD TG 408 and in accordance with the principles of GLP) conducted in Fischer 344 rats, four groups of 10 male and 10 female were given drinking water solutions at levels of 50, 150 and 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 an increased absolute and relative liver weight for males given 500 mg/kg/day, decreased water consumption for females given 500 mg/kg/day, decreased urine volume in males and females given 500 mg/kg/day, increased urine specific gravity for females given 500 mg/kg/day and 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. Effects on the liver in repeated dose toxicity studies with the propylene glycol ethers are common and are considered to be adaptive changes due to the metabolism of the glycol ethers rather than evidence of toxicity. This is justified by the absence of histological and clinical chemical findings typically associated with liver toxicity (such as necrosis, hyperplasia, increased liver enzymes activity in the blood, etc.).

Alterations in urinary parameters for females were directly attributed to decreased water consumption. This decrease in water consumption was most likely a consequence of a palatability issue rather than an adverse toxicoloigcal effect. This is consistent with the range finding study where the dose level of 1000 mg/kg bw was associated with a significant decrease in water intake due to palatability issues.

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

In addition to the 90 -day repeated dose drinking water study, a reprodcutive developmental screening study (OECD 421) is also available. In this study groups of 12 male and 12 female CRL:CD(SD) rats were administered Dipropylene Glycol n-Propyl Ether (DPnP) daily, by gavage at dose levels of 0 (control), 100, 300, or 1000 mg/kg/day. Females were dosed once daily for two weeks prior to breeding, through breeding (up to two weeks), gestation (three weeks), and lactation up to postpartum day 4. Females were necropsied on postpartum day 5. Males were dosed two weeks prior to breeding and continuing through breeding (two weeks) until necropsy (test day 29). Effects on reproductive function as well as general toxicity were evaluated. In addition, postmortem examinations included a gross necropsy of the adults with collection of organ weights and histopathologic examination of tissues. Litter size, pup survival, sex, body weight, and the presence of gross external abnormalities were also assessed. Only the general toxicity findings in this study are discussed here. The reproductive endpoints are discussed in section 7.8.

Administration of 1000 mg/kg/day of DPnP resulted in treatment-related parental toxicity in males and females consisting of increases in the incidence of hepatocellular hypertrophy and corresponding increases in absolute and relative liver weights. In addition, absolute and relative kidney weights were increased in males and females at this dose level. Microscopic examination of the kidneys revealed hyaline droplet formation in the proximal renal tubules of males given 1000 mg/kg/day, but there were no treatment-related histopathologic findings in the kidneys of high-dose females. Transient, excess salivation was noted in the majority of high-dose males and females immediately after dosing, but was considered to be a local response and of no toxicological significance. Based on these results, the no-observed-effect level (NOEL) for parental toxicity was 300 mg/kg/day. This NOEL is lower than that from the 90 -day study, however this is due to the dose level selection rather than inconsistency in the toxicological profile. Therefore, based on the findings from these two studies, the NOAEL of 500 mg/kg bw/day from the 90 -day study is selected as the starting point for the DNEL derivation.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Key, reliable 90-day study

Justification for classification or non-classification

Based on the results of the study and Guidance to Regulation (EC) No. 1272/2008 on Classification, Labelling and Packaging of substances and mixtures, dipropylene glycol n-propyl ether will not be classified for repeated dose toxicity, i.e. STOT (RE).