Propane-1,2-diyl dibenzoate

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

25 February 1997 - 25 March 1997

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted according to OECD, EC EPA and Japanese test guidelines and in compliance with GLP.

Justification for type of information:

A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.

Cross-reference

Reason / purpose for cross-reference:

read-across: supporting information

Reference

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

25 February 1997 - 25 March 1997

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted according to OECD, EC EPA and Japanese test guidelines and in compliance with GLP.

Justification for type of information:

A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

EPA OTS 798.1175 (Acute Oral Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: Japan Ministry of International Trade and Industry MITI Directive concerning the conduct of acute toxicity studies

Deviations:

not specified

Qualifier:

according to guideline

Guideline:

other: EPA Pesticide Assessment Guidelines, Subdivision F. Hazard Evaluation: Human and Domestic Animals 81-1 Acute oral toxicity study (Revised Edition November 1984). Subdivision F provides detailed information relating to data requirements of 40 CFR Part 158.

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan UK Ltd, Bicester, Oxon, England
- Age at study initiation: approximately 7 to 8 weeks
- Weight at study initiation: 200 to 249 g
- Fasting period before study: Animals were fasted overnight before dosing and for approximately 4 hours after dosing.
- Housing: Housed in groups of up to five rats of the same sex in metal cages with wire mesh floors
- Diet: A standard laboratory rodent diet provided ad libitum
- Water: Drinking water was provided ad libitum
- Acclimation period: At least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.5 to 23°C
- Humidity (%): 38-57% RH
- Air changes (per hr): 10 to 15
- Photoperiod (hrs dark / hrs light): 12 hours light per 24 hour period

IN-LIFE DATES: From: 25 February 1997 To: 25 March 1997

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

VEHICLE
- Concentration in vehicle: Not applicable - administered as supplied by sponsor.


MAXIMUM DOSE VOLUME APPLIED: 5.714 mL/kg (6400 mg/kg group)

Doses:

3200 mg/kg (Preliminary test, one animal per sex)
2000, 3200, 5000 and 6400 mg/kg (main test groups - 5 animals per sex per group, except 3200 mg/kg : 5 females only, 6400 mg/kg : 5 males only).

No. of animals per sex per dose:

5, except for the dose rates of 2000 mg/kg and 5000 mg/kg for which 10 rats were used, 5 female and 5 male.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations (clinical signs) taken frequently on day of dosing then twice daily for remainder of
observation period. Bodyweights recorded on days 1 (day of dosing), 8, and 15, or on death.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, macroscopic pathology.

Statistics:

The acute median lethal oral dose (LD50) to male and female rats was calculated using the method of Finney [FINNEY, D.J. (1971) Probit Analysis, 3rd ed., Cambridge University Press, Cambridge]

Sex:

male

Dose descriptor:

LD50

Effect level:

5 072 mg/kg bw

95% CL:

4 455 - 5 774

Sex:

female

Dose descriptor:

LD50

Effect level:

3 295 mg/kg bw

95% CL:

2 857 - 3 801

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

3 914 mg/kg bw

95% CL:

2 957 - 4 844

Mortality:

Two females at 3200 mg/kg, two males and all females at 5000 mg/kg and all males at 6400 mg/kg died during the study. All deaths occurred within three days of dosing.

Clinical signs:

other: Refer to full list of clinical signs in "Remarks on results" section, below.

Gross pathology:

Macroscopic examination of males at 5000 mg/kg that survived treatment and killed at study termination revealed congestion (characterised by dark tissue and prominent blood vessels) in the brain. No abnormalities were observed among all other animals surviving treatment and killed at study termination.

Piloerection was observed in all rats within fifteen minutes of dosing. This sign persisted and was accompanied in rats later during the study by;hunched posture, waddling/unsteady gait, lethargy and pallor of the extremities in all rats;partially closed eyelids in three males at 2000 mg/kg four females at 3200 mg/kg, in all rats at 5000 mg/kg and in all males at 6400 mg/kg; increased salivation in all males at 2000 mg/kg, one female at 3200 mg/kg. all rats at 5000 mg/kg and three males at 6400 mg/kg; walking on toes in all rats at 2000 and 5000 mg/kg and four females at 3200 mg/kg; ungroomed appearance in all males at 2000 and 6400 mg/kg, four females at 3200 mg/kg and in all rats at 5000 mg/kg; respiratory distress (characterised by increased or decreased respiration) in all males at 2000 mg/kg, four females at 3200 mg/kg and in all rats at 5000 mg/kg; soft to liquid faeces in one female at 2000 mg/kg; clonic convulsions in three males at 5000 mg/kg; increased lacrimation and body tremors in three females at 3200 mg/kg and all rats at 5000 mg/kg; cold body surfaces in three males and all females at 2000 mg/kg, four females at 3200 mg/kg and all rats at 5000 mg/kg; prostration in one female at 3200 mg/kg and two males and two females at 5000 mg/kg; red brown stain around the muzzle in four females at 3200 mg/kg and two males and one female at 5000 mg/kg; red brown stain around the urogenital area in three females at 3200 mg/kg and one male at 5000 mg/kg; sensitivity to handling in four females at 3200 mg/kg and two males at 5000 mg/kg; aggressive behaviour to cagemates in three females at 3200 mg/kg; brown staining on dorsal area in three females at 3200 mg/kg; Recovery of surviving rats was complete with the exception of piloerection, by either Day 4 (females 2000 mg/kg), Day 5 males (2000 mg/kg), Day 8 (males 5000 mg/kg) or Day 15 (females 3200 mg/kg).

Interpretation of results:

other: Not classified

Remarks:

According to Directive 67/548/EEC Criteria used for interpretation of results: EU

Conclusions:

The acute median lethal oral dose (LD50) and 95% confidence limits to male and female rats of DPGDB were calculated to be:
Males only: 5072 (4455 to 5774) mg/kg bodyweight
Females only: 3295 (2857 to 3801) mg/kg bodyweight
Combined sexes: 3914 (2957 to 4844) mg/kg bodyweight.

Executive summary:

Key data is available for propylene glycol dibenzoate (PGDB). This data is supported by relevant information available from a structural analogue Dipropylene glycol dibenzoate (DPGDB). The justification for read across is presented as an attachment included in Section 13 of the IUCLID dossier.

 

A study was performed to assess the acute oral toxicity of the test material DPGDB when administered to rats. The study was conducted according to OECD,

EC, EPA, OECD and Japanese (MITI) test guidelines, and in compliance with GLP.

 

In the definitive test, ten rats (five male and five female) were dosed at 2000 and 5000 mg/kg bodyweight. Five females were dosed at 3200 mg/Kg bodyweight

and five males were dosed at 6400 mg/Kg bodyweight. Doses were administered by oral gavage. Observations were taken for 14 days following dosing, and macroscopic pathology was performed on all animals.

 

Two females at 3200 mg/Kg, two males and all females at 5000 mg/Kg and all males at 6400 mg/Kg died during the study. All deaths occurred within three

days of dosing. Macroscopic examination revealed a generalised congestion in the majority of organs and tissues. Macroscopic examination of males at 5000 mg/Kg that survived treatment and killed at study termination revealed congestion characterised by dark tissue and prominent blood vessels in the brain. No abnormalities were observed among all other animals surviving treatment and were killed at study termination.

 

The acute median lethal oral doses (LD50) to male and female rats of DPGDB were calculated to be: 5072 mg/Kg bodyweight (males), 3295 mg/Kg

bodyweight (females), and 3914 mg/Kg bodyweight (both sexes).

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1998

Report date:

1998

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

EPA OTS 798.1175 (Acute Oral Toxicity)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: Japan Ministry of International Trade and Industry MITI Directive concerning the conduct of acute toxicity studies

Deviations:

not specified

Test guideline 5

Qualifier:

according to guideline

Guideline:

other: EPA Pesticide Assessment Guidelines, Subdivision F. Hazard Evaluation: Human and Domestic Animals 81-1 Acute oral toxicity study (Revised Edition November 1984). Subdivision F provides detailed information relating to data requirements of 40 CFR Part 158.

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Benzoflex 9-88

IUPAC Name:

Benzoflex 9-88

Constituent 2

Reference substance name:

Oxydipropyl dibenzoate

EC Number:

248-258-5

EC Name:

Oxydipropyl dibenzoate

Cas Number:

27138-31-4

Molecular formula:

C20H22O5

IUPAC Name:

oxydipropyl dibenzoate

Details on test material:

- Name of test material (as cited in study report): Benzoflex 9-88 (Dipropylene glycol dibenzoate DPGDB)
- Physical state: Clear colourless liquid
- Storage condition of test material: Room temperature

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan UK Ltd, Bicester, Oxon, England
- Age at study initiation: approximately 7 to 8 weeks
- Weight at study initiation: 200 to 249 g
- Fasting period before study: Animals were fasted overnight before dosing and for approximately 4 hours after dosing.
- Housing: Housed in groups of up to five rats of the same sex in metal cages with wire mesh floors
- Diet: A standard laboratory rodent diet provided ad libitum
- Water: Drinking water was provided ad libitum
- Acclimation period: At least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.5 to 23°C
- Humidity (%): 38-57% RH
- Air changes (per hr): 10 to 15
- Photoperiod (hrs dark / hrs light): 12 hours light per 24 hour period

IN-LIFE DATES: From: 25 February 1997 To: 25 March 1997

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

VEHICLE
- Concentration in vehicle: Not applicable - administered as supplied by sponsor.


MAXIMUM DOSE VOLUME APPLIED: 5.714 mL/kg (6400 mg/kg group)

Doses:

3200 mg/kg (Preliminary test, one animal per sex)
2000, 3200, 5000 and 6400 mg/kg (main test groups - 5 animals per sex per group, except 3200 mg/kg : 5 females only, 6400 mg/kg : 5 males only).

No. of animals per sex per dose:

5, except for the dose rates of 2000 mg/kg and 5000 mg/kg for which 10 rats were used, 5 female and 5 male.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations (clinical signs) taken frequently on day of dosing then twice daily for remainder of
observation period. Bodyweights recorded on days 1 (day of dosing), 8, and 15, or on death.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, macroscopic pathology.

Statistics:

The acute median lethal oral dose (LD50) to male and female rats was calculated using the method of Finney [FINNEY, D.J. (1971) Probit Analysis, 3rd ed., Cambridge University Press, Cambridge]

Results and discussion

Effect levels

Effect levels 1

Sex:

male

Dose descriptor:

LD50

Effect level:

5 072 mg/kg bw

95% CL:

4 455 - 5 774

Effect levels 2

Sex:

female

Dose descriptor:

LD50

Effect level:

3 295 mg/kg bw

95% CL:

2 857 - 3 801

Effect levels 3

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

3 914 mg/kg bw

95% CL:

2 957 - 4 844

Mortality:

Two females at 3200 mg/kg, two males and all females at 5000 mg/kg and all males at 6400 mg/kg died during the study. All deaths occurred within three days of dosing.

Clinical signs:

other: Refer to full list of clinical signs in "Remarks on results" section, below.

Gross pathology:

Macroscopic examination of males at 5000 mg/kg that survived treatment and killed at study termination revealed congestion (characterised by dark tissue and prominent blood vessels) in the brain. No abnormalities were observed among all other animals surviving treatment and killed at study termination.

Any other information on results incl. tables

Piloerection was observed in all rats within fifteen minutes of dosing. This sign persisted and was accompanied in rats later during the study by;hunched posture, waddling/unsteady gait, lethargy and pallor of the extremities in all rats;partially closed eyelids in three males at 2000 mg/kg four females at 3200 mg/kg, in all rats at 5000 mg/kg and in all males at 6400 mg/kg; increased salivation in all males at 2000 mg/kg, one female at 3200 mg/kg. all rats at 5000 mg/kg and three males at 6400 mg/kg; walking on toes in all rats at 2000 and 5000 mg/kg and four females at 3200 mg/kg; ungroomed appearance in all males at 2000 and 6400 mg/kg, four females at 3200 mg/kg and in all rats at 5000 mg/kg; respiratory distress (characterised by increased or decreased respiration) in all males at 2000 mg/kg, four females at 3200 mg/kg and in all rats at 5000 mg/kg; soft to liquid faeces in one female at 2000 mg/kg; clonic convulsions in three males at 5000 mg/kg; increased lacrimation and body tremors in three females at 3200 mg/kg and all rats at 5000 mg/kg; cold body surfaces in three males and all females at 2000 mg/kg, four females at 3200 mg/kg and all rats at 5000 mg/kg; prostration in one female at 3200 mg/kg and two males and two females at 5000 mg/kg; red brown stain around the muzzle in four females at 3200 mg/kg and two males and one female at 5000 mg/kg; red brown stain around the urogenital area in three females at 3200 mg/kg and one male at 5000 mg/kg; sensitivity to handling in four females at 3200 mg/kg and two males at 5000 mg/kg; aggressive behaviour to cagemates in three females at 3200 mg/kg; brown staining on dorsal area in three females at 3200 mg/kg; Recovery of surviving rats was complete with the exception of piloerection, by either Day 4 (females 2000 mg/kg), Day 5 males (2000 mg/kg), Day 8 (males 5000 mg/kg) or Day 15 (females 3200 mg/kg).

Applicant's summary and conclusion

Interpretation of results:

other: Not classified

Remarks:

According to Directive 67/548/EEC Criteria used for interpretation of results: EU

Conclusions:

The acute median lethal oral dose (LD50) and 95% confidence limits to male and female rats of DPGDB were calculated to be:
Males only: 5072 (4455 to 5774) mg/kg bodyweight
Females only: 3295 (2857 to 3801) mg/kg bodyweight
Combined sexes: 3914 (2957 to 4844) mg/kg bodyweight.

Executive summary:

Key data is available for propylene glycol dibenzoate (PGDB). This data is supported by relevant information available from a structural analogue Dipropylene glycol dibenzoate (DPGDB). The justification for read across is presented as an attachment included in Section 13 of the IUCLID dossier.

 

A study was performed to assess the acute oral toxicity of the test material DPGDB when administered to rats. The study was conducted according to OECD, EC, EPA, OECD and Japanese (MITI) test guidelines, and in compliance with GLP.

 

In the definitive test, ten rats (five male and five female) were dosed at 2000 and 5000 mg/kg bodyweight. Five females were dosed at 3200 mg/Kg bodyweight and five males were dosed at 6400 mg/Kg bodyweight. Doses were administered by oral gavage. Observations were taken for 14 days following dosing, and macroscopic pathology was performed on all animals.

 

Two females at 3200 mg/Kg, two males and all females at 5000 mg/Kg and all males at 6400 mg/Kg died during the study. All deaths occurred within three days of dosing. Macroscopic examination revealed a generalised congestion in the majority of organs and tissues. Macroscopic examination of males at 5000 mg/Kg that survived treatment and killed at study termination revealed congestion characterised by dark tissue and prominent blood vessels in the brain. No abnormalities were observed among all other animals surviving treatment and were killed at study termination.

 

The acute median lethal oral doses (LD50) to male and female rats of DPGDB were calculated to be: 5072 mg/Kg bodyweight (males), 3295 mg/Kg bodyweight (females), and 3914 mg/Kg bodyweight (both sexes).