N-(2-ethylhexyl)-8,9,10-trinorborn-5-ene-2,3-dicarboximide

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

17 November 2004 to 21 April 2005

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2005

Report date:

2005

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

May 12, 1981

Deviations:

not specified

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Version / remarks:

August 1998

Deviations:

not specified

GLP compliance:

yes

Test type:

traditional method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

N-(2-ethylhexyl)-8,9,10-trinorborn-5-ene-2,3-dicarboximide

EC Number:

204-029-1

EC Name:

N-(2-ethylhexyl)-8,9,10-trinorborn-5-ene-2,3-dicarboximide

Cas Number:

113-48-4

Molecular formula:

C17H25NO2

IUPAC Name:

N-(2-ethylhexyl)-8,9,10-trinorborn-5-ene-2,3-dicarboximide

impurity 1

Reference substance name:

(E)-1,4-Bis(2-ethylhexylamino)-2-butene-1,4-dione

Molecular formula:

C20H38N2O2

IUPAC Name:

(E)-1,4-Bis(2-ethylhexylamino)-2-butene-1,4-dione

impurity 2

Reference substance name:

1-(2-ethylhexyl)-1H-pyrrole-2,5-dione

Molecular formula:

C12H19NO2

IUPAC Name:

1-(2-ethylhexyl)-1H-pyrrole-2,5-dione

Test material form:

liquid

Details on test material:

Purity and characterisation analysis conducted on the following sample; Supplier: McLaughlin Gormley King ; Batch Number: AB9500

Specific details on test material used for the study:

MGK® 264
Lot No.: AA7093
Purity: 95.2% MGK 264 (From CofA)

Lot No. AA7207 - addtional shipment required to complete the study
Purity: 99.04%

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Animals
Young adult, Hsd: Sprague Dawley SD rats were received from Harlan Sprague Dawley Inc., Indianapolis, Indiana.
Environment
The animal room temperature and relative humidity ranges were 65-72°F (18-22°C) and 34-59%, respectively. Environmental control equipment was monitored and adjusted as necessary to minimize fluctuations in the animal room environment. Light timers were set to maintain a 12-hour light/12-hour dark cycle and room ventilation was set to produce 10-15 air changes/hour. The animal room temperature and relative humidity were recorded a minimum of once daily.

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

other: Conditioned external air

Mass median aerodynamic diameter (MMAD):

>= 2.2 - <= 3.6 µm

Geometric standard deviation (GSD):

>= 1.94 - <= 2.46

Remark on MMAD/GSD:

For 0.55mg/L dose MMAD = 2.2µ, GSD=1.94
For 0.55mg/L dose MMAD = 3.6µ, GSD=2.10
For 0.55mg/L dose MMAD = 3.0µ, GSD=2.46

Details on inhalation exposure:

The aerosol exposures consisted of a 21-minute (0.55 and 2.23 mg/L dose level) or an 18-minute (1.01 mg/L dose level) T99 equilibration period, a 240-minute exposure period and a 21-minute (0.55 and 2.23 mg/L dose level) or an 18-minute (1.01 mg/L dose level) de-equilibration period equal to the T99 equilibration period. After the aerosol exposure, the animals were removed from the chamber and residual test article was removed from the animal's exterior surfaces (where practical) by rinsing the haircoat with lukewarm tap water and wiping the haircoat with a dry towel. The animals were then returned to ad libitum feed and water.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

the concentration of the test item aerosol was ollected in the inhalation chamber by gravimetric technique.

Duration of exposure:

240 min

Concentrations:

0.55, 1.01 and 2.23 mg/L

No. of animals per sex per dose:

5 Male, 5 Female per dose level

Control animals:

no

Details on study design:

The 4h whole-body inhalation toxicity of MGK® 264 was evaluated in Sprague Dawley rats. A LC50 study was performed in which three groups of five male and five female rats received a 4h whole-body inhalation exposure to a time-weighted average aerosol concentration (gravimetrically determined). Following the exposure, the rats were observed daily and weighed weekly. A gross necropsy examination was performed on all test animals at the time of scheduled euthanasia (day 14).

Statistics:

The LC50 and 95% confidence intervals were calculated separately for males, females and the combined sexes using a computer adaptation of the method of Litchfield and Wilcoxon.

Body weight means and standard deviations were calculated separately for males and females. The aerodynamic particle-size distribution of the test article aerosol was plotted using an Excel computer adaptation of the three cycle logarithmic probability paper as per the ITP Cascade Impactor instruction manual. The mass median aerodynamic diameter, geometric standard deviation and particles S 4.0 11 were determined based on the plotted distribution.

Results and discussion

Effect levels

Effect levels 1

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

1.98 mg/L air

Based on:

test mat.

95% CL:

> 1.506 - < 2.606

Exp. duration:

240 min

Effect levels 2

Key result

Sex:

male

Dose descriptor:

LC50

Effect level:

1.94 mg/L air

Based on:

test mat.

95% CL:

> 1.233 - < 3.043

Exp. duration:

240 min

Effect levels 3

Key result

Sex:

female

Dose descriptor:

LC50

Effect level:

1.94 mg/L air

Based on:

test mat.

95% CL:

> 1.233 - < 3.043

Exp. duration:

240 min

Mortality:

No mortality occurred at the 0.55 and 1.01 mglL dose levels.
Mortality occurred by study day 2 for the 2.23 mgIL dose level. 3/5 Males deceased, 3/5 Females deceased.

Clinical signs:

other: For the 0.55 mg/L dose level, clinical abnormalities included breathing abnormalities, decreased defecation, rough haircoat, hunched posture, urine stain, unkempt appearance, swelling around nose, nasal discharge and dark material around the facial area.

Body weight:

For the 0.55 mg/L dose level, body weight gain was noted for all animals during the test period.

For the 1.01 mg/L dose level, slight body weight loss was noted in four males and one female during the day 0 to 7 body weight interval. Body weight gain/maintenance was noted for all other animals during the test period. All animals exceeded their initial body weight by study termination.

For the 2.23 mg/L dose level, slight body weight loss was noted in two surviving males during the day 0 to 7 body weight interval. Body weight gain was noted for all other surviving animals during the test period. All surviving animals exceeded their initial body weight by study termination.

Gross pathology:

For the 0.55 mg/L dose level, no significant gross internal findings were observed at necropsy on study day 14.

For the 1.01 mg/L dose level, no significant gross internal findings were observed at necropsy on study day 14.

For the 2.23 mg/L dose level, the most notable gross internal findings were noted in the animals that died and included foci on the stomach, mottled lung lobes, abnormal content of the digestive tract/trachea/nasal tissues/larynx/urinary bladder, pale liver lobes and dark red kidney. No significant gross internal findings were observed at necropsy on study day 14.

Applicant's summary and conclusion

Interpretation of results:

other: EC 1272/2008 this would be classified as a category 4 toxicity hazard for inhalation

Conclusions:

Under the conditions of this test, the acute inhalation LC50 of MGK 264 in the male rat was determined to be 1.94 mg/L. In the female rat, the acute inhalation LC50 was determined to be 1.94 mg/L. In the sexes combined, the LC50 was determined to be 1.98 mg/L.

The acute inhalation lethal dose (LC50) of the test material, in female Sprague-Dawley rats (1.94 mg/L) was found to be between 1.0 and 5.0 mg/l. According to EC 1272/2008 this would be classified as a category 4 toxicity hazard for inhalation.

Signal Word: Warning
Hazard Statement: H332: Harmful if inhaled

Executive summary:

The 4h whole-body inhalation toxicity of MGK® 264 was evaluated in Sprague Dawley rats. A LC50 study was performed in which three groups of five male and five female rats received a 4h whole-body inhalation exposure to a time-weighted average aerosol concentration (gravimetrically determined) of 0.55, 1.01 and 2.23 mg/L, respectively. The mass median aerodynamic diameter and geometric standard deviation of the sampled particles were 2.2 µand 1.94, 3.6 µand 2.1 0, and 3.0 µand 2.46, respectively. The percentage of particles ≤ 4.0 µ was determined to be 82%, 56% and 62%, respectively. Following the exposure, the rats were observed daily and weighed weekly. A gross necropsy examination was performed on all test animals at the time of scheduled euthanasia (day 14).

Under the conditions of this test, the acute inhalation LC50 of MGK 264 in the male rat was determined to be 1.94 mg/L. In the female rat, the acute inhalation LC50 was determined to be 1.94 mg/L. In the sexes combined, the LC50 was determined to be 1.98 mg/L. The test article would be assigned an EPA-OPPTS Toxicity Category III for labelling.

The acute inhalation lethal dose (LC50) of the test material, in female Sprague-Dawley rats (1.94 mg/L) was found to be between 1.0 and 5.0 mg/l. According to EC 1272/2008 this would be classified as a category 4 toxicity hazard for inhalation.

Signal Word: Warning

Hazard Statement: H332: Harmful if inhaled