Oxydipropanol

Endpoint summary

Description of key information

Dipropylene glycol has a low acute toxicity by oral, dermal and inhalation routes. In rats, LD50 value by oral route is > 5000 mg/kg bw. In the acute dermal toxicity study with rabbits, LD50 was > 5010 mg/kg bw.  The classification for acute toxicity is not warranted based on these values. In the acute inhalation toxicity study with rats, LC50 value was > 2.34 mg/l/4h. The latter value is below the cut-off value of 5 mg/l/4 h, established for classification of aerosols in accordance to Directive 67/548/EEC. However, as higher concentration levels were not attainable and based on the absence of mortality and of any clinical signs of toxicity in the study, the classification of dipropylene glycol for acute inhalation toxicity is not warranted.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP compliant, guideline study, available as unpublished report, no restrictions, fully adequate for assessment.

Qualifier:

according to guideline

Guideline:

EPA OPP 81-1 (Acute Oral Toxicity)

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: bred in the laboratory colony (Branchville)
- Age at study initiation: males, 8 weeks of age; females, 10 weeks of age
- Weight at study initiation: males, 254 to 259 grams; females, 201 to 216 grams
- Fasting period before study: 18 hours, water was available at all times
- Housing: individually housed in wire cages under laboratory conditions.
- Diet (e.g. ad libitum): Agway NIH-31M Rodent Diet or equivalent
- Water (e.g. ad libitum): potable municipal water ad libitum
- Acclimation period: 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 68-74ºF
- Humidity (%): 35-65%
- Photoperiod (hrs dark / hrs light): 12 hours /12 hours

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Doses:

5.01 g/kg body weight

No. of animals per sex per dose:

group of 5 male and 5 female rats.

Control animals:

no

Details on study design:

- Duration of observation period following administration: Animals were observed for mortality and pharmacotoxic signs frequently during the first 5 hours and then at approximately 24 hours following dosing and twice daily for the remainder of the 14 day observation period, (once daily Saturday and Sunday)
- Frequency of weighing: each animal were determined pre-fasted, on the day of dosing, weekly thereafter and at sacrifice.
- Necropsy of survivors performed: yes. Animals that survived through the 14 day observation period were sacrified and a gross necropsy was performed. Any animal found dead during the study would have undergone necropsy immediately. The gross necropsy included by was not limited to the following organs: heart, lungs, spleen, liver, adrenals, kidneys, urinary bladder, stomach, small intestine, large intestine and reproductive organs.

Statistics:

None used

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 other: g/kg bw

Mortality:

There were no deaths

Clinical signs:

other: At one hour after dosing two males showed decreased locomotor activity and the remaninder of the group (3 male, 5 female) were ataxic. Similar signs persisted at three hours. At five hours following dosing several rats (4 male, 1 female) also showed yello

Gross pathology:

At necropsy all organs and tissues examined grossly appeared normal and there were no pathognomonic signes.

There were no deaths among rats dosed at 5.01 g/kg body weight, therefore the LD50 is greater than 5.0 g/kg. The EPA oral toxicity indicator for test substance dipropylene glycol is best described ar Category IV.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP compliant, guideline study, available as unpublished report, no restrictions, fully adequate for assessment.

Qualifier:

according to guideline

Guideline:

EPA OPP 81-3 (Acute inhalation toxicity)

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: bred in the laboratory colony (Branchville)
- Age at study initiation: approximately 8 weeks of age
- Weight at study initiation: males 242 to 269 grams; females 189 to 209 grams.
- Fasting period before study: no data
- Housing: individually housed in wire cages under laboratory conditions in the study room
- Diet (e.g. ad libitum): Agway NIH-31M Rodent Diet or equivalent.
- Water (e.g. ad libitum): potable municipal water ad libitum
- Acclimation period: 5 days


ENVIRONMENTAL CONDITIONS
- Temperature: 68-74ºF
- Humidity (%): 35-65%
- Photoperiod (hrs dark / hrs light): 12 hours on/12 hours off cycle

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

other:

Details on inhalation exposure:

Each chamber used was made of plexiglass, and measured approximately 50.5 cm long x 29.5 cm high (semi-cylindrical), having a volume of 47.4 liters. A wire mesh floor was raised 5.0 cm from the floor of the chamber and on this the rats were individually caged in all wire-mesh cages. The total "volume" of the test animals was not more than 5% of the volume of the test chamber based on a 1:1 equivalence between body volume (ml) and body weight (g). On one side near the top of the exposure chamber was a portal through which the test substance and air flow were introduced, and at the opposite side near the bottom there was a portal for exhaust to which a vacuum pump was attached. Test substance generation was established and maintained from the DeVilbiss Glass Nebulizer by using a Gast Air Pump supplying air at a measured pressure. The test substance was delivered from the nebulizer which was maintained at the portal of the exposure chamber. The vapor or inlet tube was set to deliver the aerosol directly through the portal into the exposure chamber. In addition to the four hour exposure period, a period of time (t99) was allowed to compensate for the time required for delivery system stabilization to a nominal chamber concentration greater than 5 mg of test substance per liter of air or to the maximum concentration of aerodynamic particles at the "limit dose".
The time for stabilization of the system was determined by the formula t99 = 4.605 x a/b, where t99 = time required to reach 99% of desired concentration; a = volume of chamber (liters), b= flow rate through the chamber (l/min).

Analytical verification of test atmosphere concentrations:

yes

Remarks:

thrice by gravimetric measurement

Duration of exposure:

4 h

Concentrations:

Mean 2.34 mg/ in the breathing zone

No. of animals per sex per dose:

5/sex/dose

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Observations: animals were observed from outside the chamber for mortality and pharmacotoxic signs hourly during the exposure period. Rats were observed immediately following the t99 period after they had been returned to standard cages and then at approximately 1, 3 and 5 hour following the exposure, and once daily thereafter. In addition, mortality was checked each afternoon (except weekends and holidays) for the remainder of the 14 day observation period.
- Weighing: was obtained on day 0 (before dosing) and on days 2, 3, 4, 7 and 14.
- Necropsy of survivors performed: yes. A postmorten examination of each animal was carried out with detailed examination of the nasal air passages, trachea, bronchii and lungs. Additionally, the gross necropsy included but was not limited to the following organs: heart, spleen, liver, adrenals, kidneys, urinary bladder, stomach, small intestine, large intestine and reproductive organs. Sections from the lungs and other parts of the respiratory tract exhibiting evidence of specific pathology related to test substance administration were retained in 10% buffered formalin until all rats had undergone necropsy. Unless histopathology of these tissus was considered essential to interpretation of the results, the preserved tissues were discarded.

Statistics:

None used

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 2.34 mg/L air

Exp. duration:

4 h

Mortality:

There were no deaths

Clinical signs:

other: Control rats remained normal in appearance and behavior during exposure and during the subsequent 14-day observation period. Rats exposed to the test substance remained normal during the exposure period except for "wetting' of the fur due to deposition of

Body weight:

All exposed rats had a similar body weight gain compared to controls during the study.

Gross pathology:

Neither in the control group nor in the group exposed to the test substance were there any pathognomonic findings. All organs and tissues examined grossly, including the respiratory tract, appeared normal.

In rats exposed to the maximum attainable concentration of 2.34 mg/l of the test substance during a 4 -hour period there was no mortality. At this exposure level, rats appeared normal throughout the study.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

2 340 mg/m³ air

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP compliant guideline study, available as unpublished report, no restrictions, fully adequate for assessment.

Qualifier:

according to guideline

Guideline:

EPA OPP 81-2 (Acute Dermal Toxicity)

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:

TEST ANIMALS
- Source: bred in the laboratory colony (Branchville)
- Age at study initiation: males approximately 17 weeks of age, females approximately 16 weeks of age.
- Weight at study initiation: males 2.70 to 2.95 kilograms, females 2.50 to 2.60 kg.
- Housing: the animals were housed singly in wire cages in the study room
- Diet (e.g. ad libitum): Blue Seal Rabbit Feed, ID #1679 JJA, supplemented with oats if necessary
- Water (e.g. ad libitum): potable municpal water (ad libitum)
- Acclimation period: acclimated to the study room for 5 days.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 68-74ºF
- Humidity (%): 35-65
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 hours on/12 hours off cycle

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

The test substance was applied uniformly at the required dose to the shaved intact skin in an area forming a band on the dorsal and lateral trunk that approximated 10% of the body surface of the rabbit as nearly as the dose allowed. The test substance was held in contact with the skin by a gauze pad held in place with hypo-allergenic tape. The entire trunk of the rabbit was then wrapped with no-irritating perforated plastic sheeting secured at each end with masking tape in order to prevent displacement or ingestion of the test substance.

Duration of exposure:

24 hours

Doses:

5.01 g/kg body weight

No. of animals per sex per dose:

5/sex/dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Observation and scoring: 30 to 60 minutes after cleaning the skin at approximately 24 hours, the local reaction was recorded; erythema and edema were scored using the variation of the method of Draize. Readings were also made on days 3, 7, 14 and at other times if major changes were observed. The animals were observed for mortality and pharmacotoxic signs frequently on the day of dosing and once daily for the remainder of the 14 day observation period. This included time of death, or nature, onset, severity and duration of all gross visible toxic or pharmacologic effects, e.g. changes in skin and fur, eye and mucous membranes, respiratory, circulatory, autonomic and central nervous systems, somato-motor activity and behavioral pattern. In addition, animals were checked for mortality each afternoon (except weekends and holidays).
- Body weights: were detemined on the day of dosing, weekly thereafter and at sacrifice.
- Necropsy of survivors performed: yes. Animals that survived the 14 day observation period were sacrificed and a gross necropsy was performed. Any animals found dead during the study would have undergon necropsy immediately. Gross necropsy consisted of examination of the carcass (including the test site), the visceral organs in the thorax and abdomen, and examination of the reproductive organs.

Statistics:

None used

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 010 mg/kg bw

Mortality:

The were no deaths

Clinical signs:

other: Cageside observation of the rabbits during the study did not reveal any overt signs of systemic pharmacologic or toxic effects. Approximately three quarters of an hour after removal of the wraps and cleaning the skin there was very slight irritation char

Gross pathology:

At necropsy all organs and tissues examend grossly appeared normal and there were no pathognomonic signes. The shaved skin in the area of application of the test substance appeared normal.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 010 mg/kg bw

Additional information

Two acute oral toxicity studies with rats are available for assessment, both leading to the same conclusion. Out of these studies, the more recent one, a GLP-compliant study performed in accordance with EPA OPP 81-1 (Acute Oral Toxicity) guideline, was chosen as a key study (Cosmopolitan Safety Evaluation, Inc., 1995a). In this study, 5 male and 5 female rats were exposed by gavage to 5.01 g/kg bw dipropylene glycol. No deaths occurred. At one hour after dosing two males showed decreased locomotor activity and the remainder of the group (3 male, 5 female) were ataxic. Similar signs persisted at three hours. At five hours following dosing several rats (4 male, 1 female) also showed yellow perineal staining, By Day 1 all rats appeared normal and remained so through the duration of the study. The LD50 value in rats was concluded to be > 5000 mg/kg bw. The supporting study (CIVO-TNO, 1980) confirmed this result, with LD50 = 16.1 g/kg bw (calculated based on the LD 50 of 15.8 ml/kg bw and density of dipropylene glycol of 1.02 g/cm³).

 

One inhalation toxicity study with rats has been located, performed in accordance with EPA OPP 81-3 (Acute inhalation toxicity) guideline study and under GLP (Cosmopolitan Safety Evaluation, Inc., 1995b). Five female and five male Sprague-Dawley rats were exposed to dipropylene glycol aerosol concentration of 2.34 mg/l (mean in the breathing zone) for 4 hours, which was the maximum attainable concentration of aerodynamic particles in the study. There were no deaths. Control rats remained normal in appearance and behavior during exposure and during the subsequent 14-day observation period. Rats exposed to the test substance remained normal during the exposure period except for "wetting' of the fur due to deposition of test substance, and remained normal during the subsequent 14-day observation. An LC50 value of > 2.34 mg/l/4h was concluded based on the results of this study.

 

One acute dermal toxicity study with rabbits, performed under GLP and in accordance with EPA OPP 81-2 (Acute Dermal Toxicity) was available for assessment (Cosmopolitan Safety Evaluation, Inc., 1995c). Animals were exposed via the dermal route to 5.01 g/kg bw under occlusion. No animals died. Cageside observation of the rabbits during the study did not reveal any overt signs of systemic pharmacologic or toxic effects. Approximately three quarters of an hour after removal of the wraps and cleaning the skin there was very slight irritation characterized by erythema at five sites. By day 2 the application sites were free of erythema and all sites appeared normal. On day 14 all sites appeared normal. There was no corrosive effect or evidence of injury in depth at any time. Based on the results of the test, the LD50 value in rats was determined to be > 5010 mg/kg bw.

Justification for classification or non-classification

Based on the oral and dermal LD50 values of > 5000 mg/kg bw, classifcation for acute oral and dermal toxicity is not warranted in accordance to Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008. For acute inhalation toxicity, the LC50 value of >2.34 mg/l/4 h was obtained, which is below the cut-off value of 5 mg/l/4 h, established for classification of aerosols.

However, as higher concentration levels were not attainable and based on the absence of mortality and of any clinical signs of toxicity in the study, the classification of dipropylene glycol for acute inhalation toxicity is not warranted in accordance to Directive 67/548/EEC and EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.