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

Endpoint summary

Description of key information

Acute oral studies in Rats (Fisher 344 and Wistar), Acute dermal study in New Zealand White Rabbits. Acute inhalation study in Sprague-Dawley albino rats.  A review of the three studies available by the acute route concluded that the LD50 is above 2000 mg/kgbw.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

other: Modeling and QSAR of existing exeperimental studies

Adequacy of study:

key study

Study period:

2009

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: QSAR

Reason / purpose for cross-reference:

other: source study used in overall assessment

Reason / purpose for cross-reference:

other: source study used in overall assessment

Reason / purpose for cross-reference:

other: source study used in overall assessment

Qualifier:

no guideline required

Principles of method if other than guideline:

Modeling: EPA Log Probit method, Hill Plot, QSAR (EPA Toxicity Estimation Software Tool (T.E.S.T.). Assessment of three existing studies and a conclusion of overall indication of toxicity

GLP compliance:

no

Remarks:

not applicable

Test type:

other: Modeling and assessment of existing studies

Limit test:

no

Species:

rat

Strain:

other: Wistar, Sprague Dawley and Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

Not applicable

Route of administration:

other: oral gavage and stomach intubation

Details on oral exposure:

Not applicable

Doses:

Not applicable

No. of animals per sex per dose:

Not applicable

Details on study design:

Modeling: EPA Log Probit method, Hill Plot, QSAR (EPA Toxicity Estimation Software Tool (T.E.S.T.).

Statistics:

See study design

Preliminary study:

Not Applicable

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

other: Modeling data

Mortality:

Not Applicable

Clinical signs:

other: Not Applicable

Gross pathology:

Not Applicable

Other findings:

Not Applicable

1.     Re-evaluation of the Gilbert et al., 1995’s arrival at the LD₅₀value estimate.

 

The Gilbert et al. (1995)(see reference 1)study was conducted by the Dow Chemical Company where male and female rats were given a single dose of 500, 2500 or 5000 mg/kg. The study reported no deaths at 500 mg/kg, 4/5 females and 3/5 males deaths at 2500 mg/kg and all animals dying at 5000 mg/kg. The animals exhibited “lateral recumbancy” within 30 minutes of dosing indicating an acute CNS depressant effect that more than likely induced CNS-depression induced cardiopulmonary collapse and death. The study reported an LD₅₀value of 1500 mg/kg in female rats claiming the use of linear interpolation. The studycited a method by Stephan 1977 although no mathematical modeling or information was provided in the actual report to verify that this was done. However, instead of applying some type of modeling approach in deriving the 1500 mg/kg estimates, it appears that the authors simply added 500 mg/kg and 2500 mg/kg (3000 mg/kg) and divided by “2” to obtain the LD₅₀estimate of 1500 mg/kg. 

 

Because of the dosing interval (doses not closely spaced around the monotonic increase in lethality), it is difficult to simply approximate the 50% response as shown in the following log-transformation of the data (Figure 1). Almost one order of magnitude exists between the 500 and 2500 mg/kg dose selection data and it cannot be determined by using a simple approximation where the monotonic increase occurs. The dose selection did not follow the current guidelines of progression factor of the half-log units (or 3.2 dose progression factor, for example 550, 2000 mg/kg doses) specified in the Acute Oral Toxicity: Up and Down Procedure. 

Hill coefficient estimates for the combined LD50 data, the monotonic relationship between narcosis-induced lethality and the dose for DPnP, appears rather steep (e.g., Hill coefficients > 1.0). It appears that the CNS-depressant basis for lethality is a very steep dose-response curve wherein the monotonic portion of the response is likely to begin at the in the range of LD₅₀criterion of >2000 mg/kg. 

When the data are subjected to simple linear regression an LD₅₀estimate of 2204.7 mg/kg is obtained for female rats. Attempts to fit the data with more standard, non-linear dose-response models were unsuccessful due to limited Gilbert et al. data. With linear regression, a fit of the line provides for an LD₅₀estimate that would exceed the 2000 mg/kg criteria.

 

2.     Modeling of Gilbert et al., 1995 data with the log probit model.

 

Log probit analysis, one of the EPA-recommended models for determining acute toxicity estimates, was also run on the Gilbert et al. (1995) data. The log probit model produced the following estimates: 2420 mg/kg for males and 2015 mg/kg for females (see analysis included in Appendix A).

 

3.     Modeling of all acute toxicity studies for DPnP.

 

A sole reliance on the study of Gilbert et al., 1995 does not provide for a robust assessment of the LD₅₀relationship for DPnP. It would be preferable to evaluate the LD₅₀response across all of the rat data available, especially since different rat strains would provide a basis for examining variability that could account for differences in population sensitivity. The entire data set of LD₅₀information in rats is provided in the following summary table(see references 1, 2, and 3).

The combined LD₅₀data were plotted and analyzed in GraphPad Prism 5 (Hill plots, Figure 3) and in EPA’s Benchmark Dose (BMD) program. The following are Hill equation fits of the data fit in GraphPad Prism 5. The figure on the left shows all of the data and an estimated female rat composite LD₅₀of 2351 mg/kg. This estimate is close to the log probit analysis of the Gilbert et al. (1995) results in female rats. The graph on the right shows a higher LD₅₀estimate of 3171 mg/kg when the one UCC result at 1840 mg/kg is removed.

An important estimate from these graphs is the Hill coefficient. For the male and female rats (all data included), Hill coefficients of 8.6 and 2.8, respectively, were obtained. These Hill coefficients indicate a steep monotonic relationship between the dose of DPnP and narcosis-induced cardiopulmonary collapse contributing to the lethality of DPnP. This information is important for evaluating the Gilbert et al., 1995 data because it supports the opinion that the dose spacing between 500 and 2500 mg/kg is too widely spaced to truly reflect the steep slope of the line. 

 

The entire LD₅₀data set was then analyzed with EPA’s Benchmark (BMD) software. The analysis was run in the log probit model. The results are summarized in the following table and the BMD work sheets follow in Appendix A. Overall, the log probit model with or without the UCC LD₅₀result of 1840 mg/kg, yielded female LD₅₀estimates that exceeded 2000 mg/kg. 

4.     QSAR estimate of LD₅₀value for DPnP.

To further utilize all the tools available for estimation of LD₅₀values, an acute oral toxicity value for rat was estimated using the EPAToxicity Estimation Software Tool(T.E.S.T.), the EPA-developed modeling software. The T.E.S.T. QSAR program recognized the reported LD₅₀value for DPnP of 1490.14 mg/kg, but also predicted 2551.05 mg/kg value for rat acute oral toxicity endpoint. This method also arrived at a predicted acute oral toxicity value for DPnP in excess of 2000 mg/kg as presented throughout this discussion. The –Log10(mol/kg) estimate of 1.8 is equal to 2,789 mg/kg as an LD50 estimate.

To summarize, the EPA T.E.S.T. model used an extensive set of glycol ether compounds to estimate the LD₅₀value for DPnP. This analog identification lends further support to the argument presented earlier by Dow to include a “read-across’ approach to the composite of acute toxicity data for the P-series glycol ethers for any trends that would indicate excessive toxicity in the category. In general, glycol ether toxicity depends on both the size of the alkyl chain and the number of glycol groups; toxicity potential decreases as the alkyl chain length increases as well as with the increasing number of glycol units.

 

5.     P-series glycol ether summary of acute studies.

 

Reliable sets of data exist for acute mammalian toxicity endpoints within the P-series category. A summary of acute oral toxicity data for the propylene-series (P-series) glycol ethers is presented in Table 3 and indicates that acute oral toxicity for all of the members in the category is >2000 mg/kg/day. It also demonstrates that the estimated LD₅₀of DPnP of 1500 mg/kg/day would be an outlier. The closest analogs to DPnP for read-across comparison are:Dipropylene Glycol n-Butyl Ether (DPnB, one carbon unit longer within the alcohol chain than DPnP),Dipropylene Glycol Methyl Ether (DPM, CAS #34590-94-8,2 carbon units shorter within the alcohol chain)and Propylene Glycol n-Propyl Ether (PnP, with single propylene unit and thus differing by three carbon units from DPnP). These three DPnP analogs have accepted LD₅₀values well in excess of 2000 mg/kg. For DPM, three acute oral studies in rat strains and one in dog are available(see references 4, 5, 6 and 7). All studies arrived at LD₅₀values greater than 5000 mg/kg/day for DPM. For acute dermal toxicity endpoint, all four glycol ethers including DPnP, have reported LD50 values > 2000 mg/kg/day. This conclusion is also confirmed with the other lines of evidence presented in this document for DPnP. 

 

Interpretation of results:

GHS criteria not met

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

Multiple lines of evidence, including re-evaluation of the original Gilbert et al., 1995 report and methods, suggest an oral acute toxicity value for DPnP in excess of 2000 mg/kg for male and female rats.

Executive summary:

There are three acute oral LD50 studies for DPnP available (see references 1, 2, and 3). Rincken (1995) andGilbert (1995) are test guideline-compliant studies that were conducted under Good Laboratory Practices (GLP). The third study,Myers (1989), does not cite any testing guidelines nor GLP’s and thus does not appear to be conducted under these conditions. Thus, we would assign a Klimisch score of 1, reliable without restriction to the Rincken (1995) andGilbert (1995) studies, and a Klimisch score of 2, reliable with restrictions to the Myers (1989) study.

The following five conclusions were reached based on a thorough review of the three available acute oral LD50 studies for DPnP:

1.     Re-evaluation of the Gilbert et al., 1995 study questions the validity of the 1500 mg/kg LD50 approximation. The estimate of 1500 mg/kg was a rough approximation that is not supported by the data. A simple linear modeling of the data is preferred in view of the uncertainty with where the point of departure begins in view of the apparent steepness of the lethality response.

2.     Modeling of Gilbert et al., 1995 data with EPA log-probit methodology establishes LD₅₀values exceeding 2000 mg/kg for both males and females.

3.     Modeling of all the DPnP acute toxicity studies available to Dow with standard Hill Plot approaches finds LD₅₀estimates exceeding 2000 mg/kg for both males and females.

4.     QSAR estimate of LD₅₀value for DPnP supports the > 2000 mg/kg estimate for DPnP.

5. P-series glycol ether summary of acute studies shows LD₅₀values for the class in of excess of 2000 mg/kg.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

Good

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1989

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Follow GLP guidelines

Qualifier:

equivalent or similar to guideline

Guideline:

EU Method B.52 (Acute Inhalation Toxicity - Acute Toxic Class Method)

Version / remarks:

Not specified

Principles of method if other than guideline:

Not Specified

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Diet (e.g. ad libitum): ad libium
- Water (e.g. ad libitum): ad libitum
- Weight: Between 200 and 300 g

ENVIRONMENTAL CONDITIONS
No information available

Route of administration:

inhalation: vapour

Type of inhalation exposure:

not specified

Vehicle:

not specified

Details on inhalation exposure:

Sprague-Dawley albino rats, weighing between 200 and 300 g, are exposed to substantially saturated vapor for 6 hours. The vapor is produced by enclosing approximately 100 g of the test material in a sealed 100 to 151-liter animal chamber for approximately 18 hours (static conditions). A mixing fan periodically agitates the chamber atmosphere to aid in distribution of the vapor. Oxygen is added, as needed, for static exposures to maintain a chamber oxygen content of approximately 20%. If deaths occur, exposure times are varied to determine an LT50. Five males and 5 females are included for each exposure period.

Analytical verification of test atmosphere concentrations:

not specified

Duration of exposure:

6 h

Concentrations:

saturated vapor

No. of animals per sex per dose:

5 males and 5 females

Control animals:

not specified

Details on study design:

Sprague-Dawley albino rats, weighing between 200 and 300 g, are exposed to substantially saturated vapor for 6 hours. The vapor is produced by enclosing approximately 100 g of the test material in a sealed 100 to 151-liter animal chamber for approximately 18 hours (static conditions). A mixing fan periodically agitates the chamber atmosphere to aid in distribution of the vapor. Oxygen is added, as needed, for static exposures to maintain a chamber oxygen content of approximately 20%. If deaths occur, exposure times are varied to determine an LT50. Five males and 5 females are included for each exposure period.

Statistics:

Not applicable

Sex:

male/female

Dose descriptor:

other: LC50 > Substantially Saturated Vapor (Static)

Remarks on result:

other: LC50 > Substantially Saturated Vapor (Static)

Mortality:

No Mortality

Clinical signs:

other: No signs of toxicity

Body weight:

No data

Gross pathology:

No remarkable gross lesions were evident

Other findings:

No additional data

Interpretation of results:

GHS criteria not met

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

Inhalation, Rat; Substantially Saturated Vapor (Static):
Males: 6.0 hours killed 0 of 5.
Females: 6.0 hours killed 0 of 5.

Executive summary:

Exposure to a statically-generated, substantially saturated vapor produced no deaths of male and female rats during or following the 6-hour test. There were no signs of toxicity evident and no remarkable gross lesions were evident at necropsy.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

Good

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

November 30, 1994 - March 3, 1995

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted according to OECD TG 402 and in accordance with the principles of GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPP 81-2 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: MAFF Acute Dermal Toxicity

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: EEC Methods Number B.2 Acute Toxicity (Dermal

Deviations:

no

Principles of method if other than guideline:

not applicable

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

Rabbits were obtained from Hazleton Research Products, Inc. (Kalamazoo, MI) and weighed 2.37 - 2.69 kg upon arrival. They were housed in a room maintained at 40-60% relative humidity, 19 +/- 3 degrees C, and a 12 hour light/12 hour dark cycle. Room air exchanged 15 times/hour. Four ounces of Purina Certified Rabbit Chow #5322 (Purina Mills Inc., St. Louis, MO) were provided daily and tap water was provided ad libitum. Animals were acclimated for at least two weeks before use.

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

The test material was applied to trunk skin that had been clipped free of fur the day the previous day. The site was then covered with a piece of gauze, non-absorbent cotton (10 x 14 cm), and an elastic rabbit jacket. Twenty four hours later, the dressings were removed and the site was wiped with water and dried with a soft, disposable towel.

Duration of exposure:

24 hours

Doses:

2000 mg/kg

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

Animals were observed for signs of toxicity frequently on the day of dosing and at least once each work day throughout the two-week observation period. The skin was evaluated for irritation after removal of the dressing. Animals were weighed prestudy, the day of treatment and on Days 2, 8, and 15.

At study termination all animals were euthanized and subjected to a gross necropsy. The eyes were examined in situ using a moistened glass microscope slide applied to the corneal surface.

Statistics:

Means and standard deviations were calculated for body weights and the data were evaluated for statistical outliers by a sequential test. Outliers were not "routinely excluded" from statistical analysis.

Preliminary study:

not applicable

Sex:

male/female

Dose descriptor:

LD50

Effect level:

>= 2 000 mg/kg bw

Mortality:

No deaths

Clinical signs:

other: No signs indicative of systemic toxicity. Erythema was noted on all animals (one or two days after exposure; resolved by Day 9 in all except one rabbit) and edema was noted on four animals immediately after test material removal (resolved by Day 3). The

Gross pathology:

No treatment-related findings

Other findings:

None

None

Interpretation of results:

GHS criteria not met

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

As per LD50 dose > 2000 mg/kg bw, dipropylene glycol n-propyl ether will not be classified toxic via the dermal route.

Executive summary:

Dipropylene glycol n-propyl ether (DPnP), which has a purity of 99.32%(by weight), was evaluated for dermal toxicity. Five New Zealand White rabbits per sex received a single, 24-hour, dermal exposure of 2000 mg/kg of DPnP. Parameters evaluated included body weights, in-life observations and gross pathologic evaluation.

 

All rabbits survived the 2000 mg/kg limit test established by the guidelines, therefore, no other dose levels were tested. All rabbits gained or maintained body weight during the two week observation period.

 

No clinical signs indicative of systemic toxicity were noted. Erythema was observed on all animals, one or two days after exposure. Edema was noted on four of the animals immediately after test material removal, and was resolved by test day three on all animals. The erythema was resolved by test day nine in all but one rabbit. This rabbit had erythema for the entire two week observation period, and developed scales on test day eight. No treatment-related observations were made at necropsy.

 

Under the conditions of this study, the acute dermal LD50 of dipropylene glycol n-propyl ether was greater than 2000 mg/kg, the limit dose, for male and female New Zealand White rabbits.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

Good

Additional information

Acute oral toxicity:

Three studies are available for this substance. Different strains of rats and different dose ranges were used. In the first study, Fisher 344 rats (male and female) were dosed with DPnP (no vehicle) at 500, 2500 and 5000 mg/kg bw. At 500 mg/kg there were no mortalities, at 2500 mg/kg there were 3/5 male deaths and 4/5 female deaths. At 5000 mg/kg bw, all rats died.

In the second study using Wistar rats, a single dose level of 2000 mg/kg bw was dosed to 5 male and 5 female rats. One male died on day 1 after dosing, but there were no other mortalities.

In the third study the LD50 for male Sprague-Dawley rats receiving peroral doses of Propyl DIPROPASOLB Solvent was 2.73 rnl/kg; that for females was 1.62 ml/kg. Signs of toxicity included sluggishness, kyphosis, marked lacrimation (in one), piloerection, prostration, unsteady gait, a moribund appearance and red crust on the perinasal and/or periocular fur (of 2). Deaths occurred at one hour to one day.

The following five conclusions were reached based on a thorough review of the three available acute oral LD50 studies for DPnP:

1.     Re-evaluation of the Gilbert et al., 1995 study questions the validity of the 1500 mg/kg LD50 approximation. The estimate of 1500 mg/kg was a rough approximation that is not supported by the data. A simple linear modeling of the data is preferred in view of the uncertainty with where the point of departure begins in view of the apparent steepness of the lethality response.

2.     Modeling of Gilbert et al., 1995 data with EPA log-probit methodology establishes LD₅₀values exceeding 2000 mg/kg for both males and females.

3.     Modeling of all the DPnP acute toxicity studies available to Dow with standard Hill Plot approaches finds LD₅₀estimates exceeding 2000 mg/kg for both males and females.

4.     QSAR estimate of LD₅₀value for DPnP supports the > 2000 mg/kg estimate for DPnP.

5.     P-series glycol ether summary of acute studies shows LD₅₀values for the class in of excess of 2000 mg/kg.

Acute Dermal toxicity:

5 New Zealand white rabbits per sex were dosed dermally (occlusive conditions) with 2000 mg/kg bw. No mortality was observed therefore the LD50 is >2000 mg/kg bw.

Acute Inhalation toxicity:

Exposure to a statically-generated, substantially saturated vapor produced no deaths of male and female rats during or following the 6-hour test. There were no signs of toxicity evident and no remarkable gross lesions were evident at necropsy.

Justification for selection of acute toxicity – oral endpoint
Recent reliable standard guideline study

Justification for selection of acute toxicity – dermal endpoint
Recent reliable standard guideline study

Justification for classification or non-classification

The weight of evidence from the available acute oral toxicity studies indicates that the LD50 value for this substance is likely to be greater than 2000 mg/kg bw but less than 2500 mg/kg bw. As such no classification for acute oral toxicity is required according to CLP. Classification as Category 5 for acute oral toxicity according to GHS is appropriate in those regions employing this additional acute toxicity category.

No mortality was observed at 2000 mg/kg bw dosed dermally to rabbits. As such the LD50 is considered to be >2000 mg/kg bw.

Exposure to a statically-generated, substantially saturated vapor produced no deaths of male and female rats during or following the 6-hour test. There were no signs of toxicity evident and no remarkable gross lesions were evident at necropsy.