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

Acute Toxicity: oral

Administrative data

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

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

other: source study used in overall assessment

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1989

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Qualifier:

no guideline available

Principles of method if other than guideline:

Not specified

GLP compliance:

yes

Test type:

other: Peroral Intubation

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Fasting period before study: The rats were fasted overnight before dosing.
- Diet (e.g. ad libitum): ad libium except for fasting period
- Water (e.g. ad libitum): ad libitum
- Weight: Between 200 and 300 g

ENVIRONMENTAL CONDITIONS
No information available

Route of administration:

other: Stomach intubation with a ball-end stainless steel needle

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

DOSAGE PREPARATION: Sprague-Dawley albino rata, weighing between 200 and 300 g, receive the teat material by stomach intubation with a ball-end stainless steel needle. The sample is injected through the needle by means of a syringe and doses are varied by adjusting the volume of the test material or its dilution. The rats are fasted overnight before dosing. Five males and 5 females are included on each level used for the LD5O calculations.

Doses:

1.0 ml/kg; 2.00 ml/kg; 2.83 ml/kg; 4.00 ml/kg; 8.00 ml/kg

No. of animals per sex per dose:

5

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days

Statistics:

Dosages are reduced until significant signs of toxicity are not observed. LD5O's and the estimated LD50 elopes are calculated by the moving average method (Thompson, 1947; Weil, 1983) and are based on a 14-day observation period. Animal weights are recorded at 0 days (before dose), 7 daye and 14 days (just prior to sacrifice).

Sex:

female

Dose descriptor:

LD50

Effect level:

1.62 mL/kg bw

Based on:

test mat.

Sex:

male

Dose descriptor:

LD50

Effect level:

2.73 mL/kg bw

Based on:

test mat.

Mortality:

Yes, deaths occurred at one hour to one day.

Clinical signs:

other: 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).

Gross pathology:

At necropsy, there were mottled red lungs and livers, opaque stomachs (glandular portion), stomachs filled with clear liquid, red intestines and mottled dark red kidneys. These findings were evident only in victims, while survivors had no remarkable gross lesions at necropsy.

Other findings:

N/A

Peroral intubation, Single dose to Rats

Dosage, ml/kg	Dead/Dosed	Days to Death	Mean Weight g±S.D (0 Day)	Mean Weight g±S.D (7 Days)	Mean Weight g±S.D (14 Days)	Signs of Toxicity	Gross Pathology
8.00	2/2	0,0	248±14.8	-	-	Marked sluggishness, Kyphosis at 10 min; piloerection at 45 min; prostration at 50 min. Death of 2 at 1.0 hr	Stomachs opaque; Stomachs filled with clear liquid; livers dark red
4.00	5/5	0,0,0,1,1	222± 8.8	-	-	Marked sluggishness, unsteady gait, kyphosis at 10 min; prostration at 1.0hr. Death of 3 at 4.0hr	Lungs mottled, dark red; stomachs opaque; stomachs filled with clear liquid; livers dark red; intestines red; kidneys of 2 mottled and/or dark red.
2.83	3/5	0,1,1	227±5.41	271±1.41	296± 4.95	Marked sluggishness, unsteady gait at 1.0 hr; prostration at 1.0 to 3.0 hr; red crust on perinasal and periocular fun of 1 at 1 day. Death of 1 at 2.5 hr. Survivors recovered at 1 and 2 days	In victims, lungs mottled dark red; stomachs opaque; stomachs filled with clear liquid; livers dark red; intestines red. In survivors othing remarkable
2.00	0/5	-	238±8.56	286±8.01	313±8.02	Sluggishness, unsteady gait at 30 min; marked sluggishness in 2 at 2.5 to 4.0 hr. Recovery at 1 day.	Nothing remarkable.
1.00	0/5	-	229±8.1	274± 12.4	293±14.6	Slight sluggishness, unsteady gait in 2 at 2.5 hr. Recovery at 1 day.	Nothing remarkable

Interpretation of results:

Category 5 based on GHS criteria

Remarks:

Migrated information

Conclusions:

Peroral, Rat (Fasted):
Males: LD50 = 2.73 ml/kg; sample dosed as received.
Females: LD50 = 1.62 ml/kg; sample dosed as received.

Executive summary:

The LD50 for male 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. Survivors recovered at one to 2 days. At necropsy, there were mottled red lungs and livers, opaque stomachs (glandular portion), stomachs filled with clear liquid, red intestines and mottled dark red kidneys. These findings were evident only in victims, while survivors had no remarkable gross lesions at necropsy.

Cross-reference 2

Reason / purpose for cross-reference:

other: source study used in overall assessment

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1995

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

The study was conducted according to OECD TG 401 and EU Method B.1 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 401 (Acute Oral Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Deviations:

no

Principles of method if other than guideline:

not applicable

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Animals were obtained from Charles River, Germany. They were approximately 7 weeks old at start of treatment. Body weights of animals used in the study were within +/- 20% of the sex mean.

Animals were housed in a room maintained at 21 degrees C and a relative humidity of 50%. Fluctuations from these conditions occurred, but did not affect study integrity. The lighting cycle was 12 hours light/12 hour dark, and there were 15 air changes/hour.

Animals were housed 5/sex/cage in polycarbonate cages containing purified sawdust bedding material, and were allowed free access to standard pelleted laboratory animal diet (Carfil Quality BVBA, Oud-Turnhout, Belgium) and tap water (with the exception that food was withheld overnight prior to dosing until 3-4 hours after dosing). Animals were acclimated at least 5 days before treatment.

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

Five animals/sex dosed once, on Day 1

Doses:

2000 mg/kg body weight (2.247 ml/kg)

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

Animals were observed twice daily for mortality and at periodic intervals on Day 1 and once daily thereafter for clinical signs. All animals surviving to the end of the 15 day observation period were euthanized and subjected to a gross necropsy.

Statistics:

No statistical analyses was perrformed

Preliminary study:

not applicable

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

One male died within 1 hour of treatment.

Clinical signs:

other: Lethargy, uncoordinated movements and/or hunched posture in all animals until Day 2. These symptoms had disappeared in all surviving by day 2. Chromodacryorrhea was observed in one male from Day 1 to Day 6.

Gross pathology:

No abnormalities

Other findings:

None

None

Interpretation of results:

GHS criteria not met

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The oral LD50 value of Dowanol ® DPnP (Dipropylene glycol n-propylether) in rats (both sexes) was established as greater than 2000 mg/kg bw. and hence based on the Guidance to Regulation (EC) No. 1272/2008 on Classification, Labelling and Packaging of substances and mixtures, Dowanol ® DPnP (Dipropylene glycol n-propylether) will not be classified.

Executive summary:

This study was carried out in accordance with OECD Guideline No. 401, "Acute Oral Toxicity" and EEC Directive 92/69/EEC, Part B.1, "Acute Toxicity-Oral” to evaluate the acute oral toxicity potential of Dowanol ® DPnP (Dipropylene glycol n-propylether).

Dowanol ® DPnP (Dipropylene glycol n-propylether) was administered by oral gavage to five rats of each sex per group, at 2000 mg/kg body weight. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed on the day of death or at the end o f the experimental period (day 15). One male died on day 1. Lethargy, uncoordinated movements and/or hunched posture were observed in the animals on day 1.Chromodacryorrhoea was observed in one male from day 1 until day 6. Body weight gain shown by the animals over the study period was considered to be normal. No abnormalities were found in the animals at macroscopic post mortem examination.

The oral LD50 value of Dowanol ® DPnP (Dipropylene glycol n-propylether) in rats was established as exceeding 2000 mg/kg body weight and hence based on the Guidance to Regulation (EC) No. 1272/2008 on Classification, Labelling and Packaging of substances and mixtures, Dowanol ® DPnP (Dipropylene glycol n-propylether) will not be classified.

Cross-reference 3

Reason / purpose for cross-reference:

other: source study used in overall assessment

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

September 27, 1994 - March 3, 1995

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

The study was conducted according to OECD TG 401 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 401 (Acute Oral Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPP 81-1 (Acute Oral Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: MAFF Acute Oral Toxicity Study

Deviations:

no

Principles of method if other than guideline:

not applicable

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

Rats were obtained from Charles River Breeding Laboratories, Inc. (Kingston, NY) and were approximately 9 weeks of age on arrival. They were housed 2-3 per cage in a room maintained at 40-70% relative humidity, 22 +/- 3 degrees C, and a 12 hour light/12 hour dark cycle. Room air exchanged 15 times/hour. Purina Certified Rodent Chow #5002 (Purina Mills Inc., St. Louis, MO) and tap water were provided ad libitum (with the exception that rats were fasted overnight prior to treatment). Animals were acclimated for at least one week before use.

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

Single-dose gavage

Doses:

500, 2500, 5000 mg/kg body weight

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

Five male and five female rats received 5000, 2500 or 500 mg of DPnP per kg body weight by single-dose gavage. The test material was administered neat. Rats were fasted the night prior to treatment. Feed was provided to all rats immediately following administration of the test material. Careful in-life observations were made frequently the day of treatment and at least once each working day throughout the two-week observation period. All in-life observations were recorded. Each animal was weighed, prestudy, the day of treatment, and on test days 2,s and 15. A necropsy was performed on all animals.

Statistics:

Mean and standard deviations of body weights were calculated and the data were evaluated for statistical outliers by a sequential test. The LD50 value was calculated using nonlinear interpolation. Outliers were not "routinely excluded" from statistical analysis.

Preliminary study:

not applicable

Sex:

male

Dose descriptor:

LD50

Effect level:

2 032 mg/kg bw

Based on:

test mat.

Remarks on result:

other: no information on 95% CL

Sex:

female

Dose descriptor:

LD50

Effect level:

1 500 mg/kg bw

Based on:

test mat.

Remarks on result:

other: no information on 95% CL

Mortality:

5000 mg/kg body weight: 5/5 males and 5/5 females died on Day 1
2500 mg/kg body weight: 3/5 males and 4/5 females died on Day 1
500 mg/kg body weight: no deaths

Clinical signs:

other: 5000 mg/kg body weight: lateral recumbancy (day of treatment only) 2500 mg/kg body weight: lateral recumbancy, decreased activity, lacrimation (day of treatment only) 500 mg/kg body weight: decreased activity, salivation (day of treatment only)

Gross pathology:

5000 mg/kg body weight: watery contents of digestive tract and general visceral congestion
2500 mg/kg body weight: watery contents of digestive tract and general visceral congestion (in decedents). Two males that died also had hemolyzed blood in the lumen of the stomach and/or dark contents of the digestive tract. No changes in survivors.
500 mg/kg body weight: no effect of treatment

Other findings:

None

None

Interpretation of results:

Category 5 based on GHS criteria

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of this study, the acute oral LD50 of dipropylene glycol n-propyl ether for male Fischer 344 rats was 2032 mg/kg and 1500 mg/kg for female Fischer 344 rats and based on this result, dipropylene glycol n-propyl ether will be classified as Toxicity Catergory IV - Harmful if swallowed.

Executive summary:

Dipropylene glycol n-propyl ether (DPnP), which has a purity of 99.32%(by weight), was evaluated for oral toxicity. Five male and five female Fischer 344 rats received 5000, 2500 or 500 mg/kg of DPnP, by single-dose oral gavage. Parameters evaluated during the two-week observation period included body weights and in-life observations. All animals were examined for gross pathological changes.

 

All rats died at the 5000 mg/kg dose level. Two male rats and one female rat survived at the 2500 mg/kg dose level, and all rats survived the 500 mg/kg dose level. Inlife observations noted were lacrimation, salivation, decreased activity and lateral recumbency. These clinical signs began within a half hour of dosing and continued through test day one. All surviving animals were observed as normal by test day two. All surviving rats gained body weight during the two week observation period.

 

All rats administered 5000 mg/kg, and7of 10 rats administered 2500 mg/kg died on day 1 of the study. Rats that died all had watery contents of the digestive tract and general visceral congestion. In addition, two males from the 2500 mg/kg dose level had hemolyzed blood in the lumen of the stomach, and/or dark contents of the digestive tract. The hemolyzed blood in the stomach, and dark contents of the digestive tract, were consistent with stressinduced alterations. The remaining observations were non-specific signs of toxicity. Three of ten rats administered 2500 mg/kg, and all rats administered 500 mg/kg, survived to the end of the two week observation period. There were no treatment-related gross pathologic observations in any of the surviving rats.

Under the conditions of this study, the acute oral LD50 of dipropylene glycol n-propyl ether for male Fischer344rats was 2032 mg/kg and 1500 mg/kg for female Fischer 344 rats, as determined by linear interpolation.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2009

Report date:

2009

Materials and methods

Test guideline

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

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

Test material form:

other: Not applicable

Details on test material:

Not applicable

Test animals

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

Administration / exposure

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

Results and discussion

Preliminary study:

Not Applicable

Effect levels

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

Any other information on results incl. tables

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. 

 

Applicant's summary and conclusion

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.