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Toxicological information

Acute Toxicity: inhalation

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Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
16 May 2017 to 05 Jul 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2017
Report date:
2017

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1300 (Acute inhalation toxicity)
Version / remarks:
US EPA OPPTS Guideline 870.1300, Acute Inhalation Toxicity, August, 1998
Deviations:
yes
Remarks:
See "Any other informatino on material and methods inc. tables" below
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
OECD Guidelines for the Testing of Chemicals, Section 403, Acute Inhalation Toxicity, September, 2009.
Deviations:
no
GLP compliance:
yes
Test type:
traditional method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Reaction mass of 3-methylphenyl bis(4-methylphenyl) phosphate and bis(3-methylphenyl) 4-methylphenyl phosphate and tris(3-methylphenyl) phosphate
EC Number:
809-930-9
Cas Number:
1330-78-5
Molecular formula:
C21H21O4P
IUPAC Name:
Reaction mass of 3-methylphenyl bis(4-methylphenyl) phosphate and bis(3-methylphenyl) 4-methylphenyl phosphate and tris(3-methylphenyl) phosphate
Test material form:
liquid: viscous
Details on test material:
Identification: Disflamoll TKP-P and Kronitex TCP (1:1 Mixture)
Batch (Lot) No.: CH3/08086 / 2015053500
Log No.: 170108
Receipt Date: 29 Mar 2017
Expiration Date: 08 Aug 2018
Empirical formula: C21H21O4P
Molecular weight: 368.3 g/mol
Physical Description: Clear colorless viscous liquid
Storage Conditions: Kept in a controlled temperature area set to maintain 18°C to 24°C
Specific details on test material used for the study:
A full explanation and analytical report is detailed within Section 13.2 - Material tested for the CoRAP studies

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
Animal Receipt and Acclimation
The Sprague Dawley (Crl:CD[SD]) rats used for this study were received in good health from Charles River Raleigh on 09 May 2017 and 13 Jun 2017. Each animal was inspected by a qualified technician upon receipt. The rats were uniquely identified by ear tags displaying the animal numbers and were acclimated to the laboratory for a minimum of 6 days. During the acclimation period, the rats were observed twice daily for mortality and moribundity.
The animals were subjected to restraint in the nose-only exposure holding tubes for 1 hour on a week day prior to test substance exposure. Following the restraint period, each animal was observed and there were no clinical signs of injury or stress. Animals were held in restraint tubes for at least 15 minutes prior to initiation of exposure after they were delivered to the exposure room.

Animal Housing
Upon arrival, all animals were housed individually in suspended wire-mesh cages. Caging was cleaned at appropriate intervals. The animals were maintained in accordance with Charles River SOPs and the Guide for the Care and Use of Laboratory Animals.1 On the day of exposure, the animals were placed in nose-only exposure holding tubes in the animal room, transported to the exposure room, exposed for the requisite duration, and then returned to their home cages.

Diet, Drinking Water, and Maintenance
The basal diet used in this study, PMI Nutrition International, LLC, Certified Rodent LabDiet® 5002 (block), is a certified feed with appropriate analyses performed by the manufacturer and provided to Charles River Ashland. Reverse osmosis-treated water supplying the facility is analyzed for contaminants according to Charles River SOPs. Filters servicing the automatic watering system are changed regularly according to Charles River SOPs. The results of the diet and water analyses are retained with the Charles River facility data. No contaminants were present in animal feed or water at concentrations sufficient to interfere with the objectives of this study. The basal diet and reverse osmosis-treated water, delivered by an automatic watering system, were provided ad libitum, except during acclimation to the nose-only restraint and during the exposure periods.

Environmental Conditions
The animal room was maintained with controlled temperature, humidity, and fluorescent lighting (12 hours light/12 hours dark). The light status (on or off) was recorded once every 15 minutes. The room temperature and humidity controls were set to maintain conditions of 73°F ± 5°F (approximately 23°C ± 3°C) and 50% ± 20% relative humidity. Room temperature and relative humidity were monitored continuously using the Metasys DDC Electronic Environmental control system and were scheduled for data collection on an hourly basis. Actual mean daily temperature ranged from 71.4°F to 73.5°F (21.9°C to 23.1°C) and mean daily relative humidity ranged from 37.7% to 49.4% during the study. Air handling units were set to provide a minimum of 10 fresh air changes per hour, 100% fresh air.

Enrichment
Each animal was provided devices for environmental enrichment and to aid in maintaining the animals’ oral health (starting during acclimation). Enrichment devices were not available during the restraint acclimation and the exposure periods and were sanitized approximately weekly. Additional enrichment was provided following acclimation to nose-only exposure restraint tubes.

Assignment of Animals to Treatment Groups
Animals used in the study were selected from available stock and assigned to groups using an arbitrary assignment. The animals were selected based on age and body weight requirements and on the appearance of general good health. The selected animals were approximately 8 weeks old at initiation of exposure; body weight values ranged from 296 g to 325 g for males and from 196 g to 236 g for females. Individual body weights at assignment were within ± 20% of the mean for each sex.

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
air
Mass median aerodynamic diameter (MMAD):
>= 2.3 - <= 3 µm
Geometric standard deviation (GSD):
>= 1.93 - <= 1.94
Remark on MMAD/GSD:
Two aerosol particle size measurements were conducted during each exposure using a 7-stage cascade impactor (Model No. 02-100-2L-A, In-Tox Products; Moriarty, NM). Pre-weighed, 22-mm stainless steel discs were used for the collection substrates for stages 1 through 7.
A 25-mm glass-fiber filter (Type A/E, PALL Corporation) was used as the collection substrate for the final stage. The sample flow rate was measured using a Mini-Buck Calibrator (Model M-5). Samples were collected at approximately 2.0 LPM for 0.5 and 0.25 minutes for the 1.3 and 5.2 mg/L groups, respectively. The substrates and filter were re-weighed and the particle size was calculated based on the impactor stage cut-offs. The aerosol size was expressed as the mass median aerodynamic diameter (MMAD) and the geometric standard deviation (GSD).
Details on inhalation exposure:
Exposure Methods
Exposures were conducted using a 7.9-L stainless steel, conventional nose-only exposure system with grommets in exposure ports to engage the animal holding tubes (designed and fabricated by Charles River). Animals were restrained in nose-only exposure holding tubes during exposure.
Airflow rates through the system were determined from the airflow required for aerosol generation and the dilution airflow, and provided sufficient volumes for the number of animals to be exposed and for exposure atmosphere sampling. Airflow to the exposure system was provided using a dry, breathing quality, in-house, compressed air source and an in-house supply air source utilizing HEPA filtration and activated charcoal to pre-treat room air.
Exposure atmosphere environmental conditions were recorded at approximately 60-minute intervals during the exposure. A temperature and relative humidity transmitter probe (Model No. HX94C, Omega Engineering, Inc.; Stamford, CT) was used with a display unit to monitor temperature and percent relative humidity.
Oxygen content was measured during the pre-exposure method development phase using a Dräger PAC III equipped with a calibrated oxygen sensor (Draeger Safety, Inc.; Pittsburgh, PA).
The oxygen content was 20.9% for both target concentrations.
The time required to attain 99% of the equilibrium concentration (or clearance time for the concentration to decrease from the equilibrium concentration) was calculated.
The calculated t99 equilibrium time for this study was approximately 1 minute. The start of the 4-hour animal exposure began when animals were placed on the system and the generation was initiated. The exposure period was terminated after 4 hours when the test substance generation was stopped.

Exposure Atmosphere Generation Methods
The system operated as follows. A 3-jet and 6-jet Collison nebulizer (BGI, Inc.; Waltham, MA) was used for the 1.3 and 5.2 mg/L groups, respectively. The test substance was metered at a known flow rate via 1/8-inch Teflon tubing using a Razel syringe pump (Model No. A-99.EJM, Razel Scientific Instruments, Inc.; Stamford, CT) and a 20-mL and 60-mL BD plastic syringe (Becton Dickinson and Co.; Franklin Lakes, NJ) for the 1.3 and 5.2 mg/L groups, respectively. Using a regulator (Model No. 8802K, Coilhose Pneumatics Inc.; East Brunswick, NJ), dry, breathing quality, in-house, compressed air at a controlled pressure was supplied to the air port of the nebulizer to effect atomization of the test substance.
The aerosol was delivered to the nose-only exposure system through 22-mm respiratory tubing.
For the 5.2 mg/L group, the test substance aerosol was directed to a 4.5-L glass chromatography jar where larger particles were removed prior to entering nose-only exposure system. Using a rotameter-type flowmeter (Model No. 127mm, Barnant Co./Gilmont Instruments; Barrington, IL), humidified supply air was added at a tee fitting placed in-line prior to the exposure system. Exhaust atmosphere was filtered using a Solberg filter (Solberg Manufacturing, Inc.; Itasca, IL) prior to entering the facility exhaust system, which consists of redundant exhaust blowers preceded by activated-charcoal and HEPA-filtration units. Negative pressure within the exposure system was checked at an open T-fitting in-line prior to the Solberg filter.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
Actual exposure concentrations were determined approximately every 17 to 45 minutes using standard gravimetric methods.
Duration of exposure:
4 h
Remarks on duration:
As per the test guideline.
Concentrations:
Two range-finding exposures were conducted at mean concentrations of 1.3 and 4.8 mg/L.
For the definitive study, the test substance was administered tat concentrations of 1.3 and 5.2 mg/L.

Nominal Exposure Concentrations
A nominal exposure concentration was calculated from the total amount of test substance used during the generation period and the total volume of air that passed through the exposure system.
The amount of test substance removed using the chromatography jar was not accounted for in the nominal calculation for the 5.2 mg/L group.

Actual Exposure Concentrations
Actual exposure concentrations were determined approximately every 17 to 45 minutes using standard gravimetric methods. Samples were collected on pre-weighed, 25-mm glass-fiber filters (Type A/E, PALL Corporation; Ann Arbor, MI) held in a closed-faced filter holder positioned in the animal exposure port (i.e. in the breathing zone of the animal) of the nose-only exposure system. A measured volume of the exposure atmosphere was pulled through the filter to quantitatively collect aerosol particles. The sample flow rate was controlled using a sapphire critical orifice (Model No. 24, O’Keefe Controls Co.; Trumbull, CT) and measured using a Mini-Buck Calibrator (Model No. M-5, A.P. Buck Inc.; Orlando, FL) prior to each sample.
Samples were collected at approximately 430 mL/minute for 2 and 1 minute for the 1.3 and 5.2 mg/L groups, respectively. Following sample collection, the filters were re-weighed and the concentration calculated as the filter weight difference divided by the sample volume.
No. of animals per sex per dose:
Two range-finding exposures were conducted using 2 rats/sex at mean concentrations of 1.3 and 4.8 mg/L.
For the definitive study, the test substance was administered to 2 groups of 5 male and 5 female Sprague Dawley rats via nose-only inhalation exposure as a liquid droplet aerosol at concentrations of 1.3 and 5.2 mg/L.
Control animals:
no
Details on study design:
The selected route of administration was nose-only exposure methods as a means of reducing the potential for dermal exposure or oral exposure resulting from grooming. The animal model, the albino rat, is generally recognized as appropriate for acute inhalation toxicity studies.

Mortality
All animals were observed for mortality, abnormalities, and signs of pain and distress twice daily for 14 days (once in the morning and once in the afternoon, except on the day of scheduled necropsy).

Clinical Observations
All animals were observed once during the exposure, where only clinical signs visible in nose-only exposure restraint tubes were recorded. All animals were observed for clinical signs of toxicity after the 4-hour exposure when removed from exposure system, once 1 to 2 hours post-exposure, and once daily for 14 days following exposure. Observations were recorded and included, but were not limited to: changes in the skin and fur, eyes and mucous membranes and also changes to the respiratory, circulatory, autonomic and central nervous systems, somatomotor activity, and behavior pattern.

Body Weights
Body weights were obtained prior to exposure on Study Day 0 and on Post-Exposure Days 1, 3, 7, and 14.

Necropsy
Animals at the scheduled necropsy were euthanized by isoflurane anesthesia followed by exsanguination and subject to necropsy. The major organ systems of the cranial, thoracic, and abdominal cavities were examined for all animals. No tissue or organs were retained and the carcasses were discarded after necropsy.
Statistics:
Not specified

Results and discussion

Preliminary study:
None of the animals in the range-finding groups died during the study.
Effect levels
Key result
Sex:
male/female
Dose descriptor:
LC0
Effect level:
> 5.2 mg/L air
Based on:
test mat.
Exp. duration:
4 h
Mortality:
None of the animals died during exposure or during the 14-day post-exposure observation period.
Clinical signs:
other: There were no clinical observations noted during the exposure. Following exposure, increased respiration was observed for 1 male in the 5.2 mg/L group and vocalization upon handling was observed for 1 female in the 1.3 mg/L group. At the 1 to 2 hour post-
Body weight:
There were no remarkable changes in body weight in the 1.3 and 5.2 mg/L groups. From Study Day 0 to Study Day 1, 1 male and 2 females in the 1.3 mg/L group lost 2 to 4 grams and 5 males and 4 females in the 5.2 mg/L group lost 3 to 12 grams. All animals surpassed their initial (Study Day 0) body weight by Study Day 14 and were considered normal.
Gross pathology:
Macroscopic findings noted for animals at the scheduled necropsy were enlarged mandibular lymph node for 1 male in the 1.3 mg/L group and 1 male in the 5.2 mg/L group, dark red discoloration of the mandibular lymph node for 1 female in the 5.2 mg/L group and clear fluid contents in the uterus for 2 females in the 5.2 mg/L group. There were no other macroscopic findings for animals at the scheduled necropsy.

Any other information on results incl. tables

Mean Exposure System Environmental Conditions

Group (mg/L):

1.3

5.2

Temperature (°C)

23

21

Standard Deviation:

0.5

1.4

 

 

 

Relative Humidity (%):

40

25

Standard Deviation:

2.5

2.6

 

 

 

Airflow Rate (LPM):

44.7

41.8

Standard Deviation:

1.59

1.73

 

 

 

N:

4

4

 

Nominal Exposure Concentrations

Group (mg/L):

1.3

5.2

Test Substance Used (g):

16.7

68.4

Nominal Concentration (mg/L):

1.6

6.8

 

Mean Actual Exposure Concentrations

Group (mg/L):

1.3

5.2

Target Concentration (mg/L):

1.2

5.0

Mean Concentration (mg/L):

1.3

5.2

Standard Deviation:

0.10

0.34

N:

6

5

 

Mean Particle Size

Group (mg/L):

1.3

5.2

Mean MMAD (microns):

3.0

2.3

Mean GSD:

1.93

1.94

N:

2

2

 

INH.TOX. STUDY OF DISFLAMOLL TKP-P AND KRONITEX TCP IN RATS

SUMMARY OF CLINICAL FINDINGS: TOTAL OCCURRENCE/NO. OF ANIMALS

---- MALE ----

 

DAY 0 POST-EXPOSURE

GROUP:

1

2

BODY / INTEGUMENT

-WET CLEAR MATERIAL DORSAL HEAD

-WET CLEAR MATERIAL FACIAL AREA

-WET CLEAR MATERIAL DORSAL NECK

-WET CLEAR MATERIAL VENTRAL NECK

-WET CLEAR MATERIAL FORELIMB(S)

-WET CLEAR MATERIAL LEFT LATERAL TRUNK

-WET CLEAR MATERIAL RIGHT LATERAL TRUNK

-WET CLEAR MATERIAL VENTRAL TRUNK

-WET CLEAR MATERIAL UROGENITAL AREA

 

1/ 1

3/ 3

0/ 0

0/ 0

1/ 1

2/ 2

1/ 1

5/ 5

0/ 0

 

0/ 0

1/ 1

3/ 3

5/ 5

0/ 0

3/ 3

3/ 3

3/ 3

5/ 5

CARDIO-PULMONARY

-INCREASED RESPIRATION

 

0/ 0

 

1/ 1

EYES/EARS/NOSE

-WET RED MATERIAL AROUND NOSE

-DRIED RED MATERIAL AROUND LEFT EYE

-DRIED RED MATERIAL AROUND RIGHT EYE

 

0/ 0

0/ 0

0/ 0

 

1/ 1

1/ 1

1/ 1

ORAL/DENTAL

-WET CLEAR MATERIAL AROUND MOUTH

-WET RED MATERIAL AROUND MOUTH

 

0/ 0

0/ 0

 

3/ 3

1/ 1

ACUTES

-WET RED MATERIAL VENTRAL NECK

 

1/ 1

 

0/ 0

---- FEMALE ----

 

DAY 0 POST-EXPOSURE

GROUP:

1

2

BEHAVIOR/CNS

-VOCALIZATION UPON HANDLING

 

1/ 1

 

0/ 0

BODY/INTEGUMENT

-WET CLEAR MATERIAL DORSAL HEAD

-WET CLEAR MATERIAL FACIAL AREA

-WET CLEAR MATERIAL DORSAL NECK

-WET CLEAR MATERIAL VENTRAL NECK

-WET CLEAR MATERIAL FORELIMB(S)

-WET CLEAR MATERIAL LEFT LATERAL TRUNK

-WET CLEAR MATERIAL RIGHT LATERAL TRUNK

-WET CLEAR MATERIAL VENTRAL TRUNK

-WET CLEAR MATERIAL DORSAL RUMP

WET-CLEAR MATERIAL UROGENITAL AREA

-WET CLEAR MATERIAL HINDLIMB(S)

 

3/ 3

3/ 3

4/ 4

1/ 1

5/ 5

1/ 1

0/ 0

5/ 5

1/ 1

4/ 4

0/ 0

 

1/ 1

3/ 3

5/ 5

5/ 5

5/ 5

3/ 3

2/ 2

5/ 5

3/ 3

4/ 4

3/ 3

ORAL/DENTAL

-WET CLEAR MATERIAL AROUND MOUTH

 

0/ 0

 

3/ 3

ACUTES

-WET RED MATERIAL FACIAL AREA

 

1/ 1

 

0/ 0

---- MALE ----

TABLE RANGE:

DAY 1 TO DAY 14

GROUP:

1

2

NORMAL

-NO SIGNIFICANT CLINICAL OBSERVATIONS

 

68/ 5

 

68/ 5

DISPOSITION

-SCHEDULED NECROPSY

 

5/ 5

 

5/ 5

DERMAL OBSERVATIONS

-HAIR LOSS FORELIMB(S)

 

2/ 1

 

2/ 1

---- FEMALE ----

TABLE RANGE:

DAY 1 TO DAY 14

GROUP:

1

2

NORMAL

-NO SIGNIFICANT CLINICAL OBSERVATIONS

 

61/ 5

 

64/ 5

DISPOSITION

-SCHEDULES NECROPSY

 

5/ 5

 

5/ 5

BODY INTEGUMENT

-DRIED CLEAR MATERIAL DORSAL HEAD

-DRIED CLEAR MATERIAL DORSAL NECK

-DRIED CLEAR MATERIAL VENTRAL TRUNK

-DRIED CLEAR MATERIAL DORSAL RUMP

-DRIED CLEAR MATERIAL UROGENITAL AREA

 

1/ 1

8/ 3

0/ 0

0/ 0

0/ 0

 

1/ 1

4/ 4

1/ 1

3/ 3

1/ 1

DERMAL OBSERVATIONS

-HAIR LOSS FORELIMB(S)

 

1/ 1

 

0/ 0

1 – 1.3 MG/L    2 – 5.2 MG/L

 

(1-2 HOUR POST-EXPOSURE)

INH.TOX. STUDY OF DISFLAMOLL TKP-P AND KRONITEX TCP IN RATS

SUMMARY OF CLINICAL FINDINGS: TOTAL OCCURRENCE/NO. OF ANIMALS

---- MALE ----

TABLE RANGE:

DAY 0 TO DAY 14

GROUP:

1

2

NORMAL

-NO SIGNIFICANT CLINICAL OBSERVATIONS

 

1/ 1

 

1/ 1

BEHAVIOR/CNS

-VOCALIZATION UPON HANDLING

 

0/ 0

 

2/ 2

BODY / INTEGUMENT

-DRIED CLEAR MATERIAL FACIAL AREA

-DRIED CLEAR MATERIAL DORSAL NECK

-DRIED CLEAR MATERIAL FORELIMB(S)

-DRIED CLEAR MATERIAL LEFT LATERAL TRUNK

-DRIED CLEAR MATERIAL RIGHT LATERAL TRUNK

-DRIED CLEAR MATERIAL VENTRAL TRUNK

-DRIED CLEAR MATERIAL UROGENITAL AREA

 

2/ 2

0/ 0

0/ 0

1/ 1

0/ 0

1/ 1

1/ 1

 

1/ 1

1/ 1

1/ 1

3/ 3

2/ 2

1/ 1

1/ 1

CARDIO-PULMONARY

-RAPID RESPIRATION

 

0/ 0

 

2/ 2

EYES/EARS/NOSE

-DRIED RED MATERIAL AROUND LEFT EYE

-DRIED RED MATERIAL AROUND RIGHT EYE

 

1/ 1

1/ 1

 

0/ 0

0/ 0

---- FEMALE ----

TABLE RANGE:

DAY 0 TO DAT 14

GROUP:

1

2

BEHAVIOR/CNS

-VOCALIZATION UPON HANDLING

 

0/ 0

 

2/ 2

BODY/INTEGUMENT

-DRIED CLEAR MATERIAL DORSAL HEAD

-DRIED CLEAR MATERIAL FACIAL AREA

-DRIED CLEAR MATERIAL DORSAL NECK

-DRIED CLEAR MATERIAL VENTRAL NECK

-DRIED CLEAR MATERIAL FORELIMB(S)

-DRIED CLEAR MATERIAL LEFT LATERAL TRUNK

-DRIED CLEAR MATERIAL RIGHT LATERAL TRUNK

-DRIED CLEAR MATERIAL VENTRAL TRUNK

-DRIED CLEAR MATERIAL DORSAL RUMP

-DRIED CLEAR MATERIAL UROGENITAL AREA

 

2/ 2

2/ 2

4/ 4

1/ 1

2/ 2

0/ 0

0/ 0

4/ 4

0/ 0

3/ 3

 

0/ 0

2/ 2

3/ 3

2/ 2

1/ 1

1/ 1

2/ 2

5/ 5

3/ 3

2/ 2

CARDIO-PULMONARY

-RAPID RESPIRATION

 

0/ 0

 

1/ 1

1 – 1.3 MG/L    2 – 5.2 MG/L

 

INH.TOX. STUDY OF DISFLAMOLL TKP-P AND KRONITEX TCP IN RATS

SUMMARY OF BODY WEIGHTS [G]

MALES

GROUP:

1.3 MG/L

5.2 MG/L

DAY

0

 

MEAN

S.D.

N

 

302.

7.2

5

 

314.

6.0

5

1

 

MEAN

S.D.

N

 

304.

6.3

5

 

307.

6.9

5

3

 

MEAN

S.D.

N

 

319.

4.1

5

 

326.

10.3

5

7

 

MEAN

S.D.

N

 

342.

5.7

5

 

359.

10.0

5

14

 

MEAN

S.D.

N

 

389.

11.9

5

 

409.

10.9

5

FEMALES

GROUP:

1.3 MG/L

5.2 MG/L

DAY

0

 

MEAN

S.D.

N

 

203.

6.6

5

 

227.

6.2

5

1

 

MEAN

S.D.

N

 

205.

5.4

5

 

223.

9.3

5

3

 

MEAN

S.D.

N

 

212.

7.5

5

 

230.

10.4

5

7

 

MEAN

S.D.

N

 

220.

9.6

5

 

236.

10.2

5

14

 

MEAN

S.D.

N

 

235.

14.1

5

 

256.

9.0

5

 

INH.TOX. STUDY OF DISFLAMOLL TKP-P AND KRONITEX TCP IN RATS

SUMMARY OF BODY WEIGHT CHANGES [G]

MALES

GROUP:

1.3 MG/L

5.2 MG/L

DAY

0 TO 1

 

 

 

MEAN

S.D.

N

1.

3.1

5

-8.

2.4

5

1 TO 3

 

 

 

MEAN

S.D.

N

15.

3.2

5

19.

3.5

5

3 TO 7

 

 

 

MEAN

S.D.

N

24.

1.8

5

33.

3.9

5

7 TO 14

 

 

 

MEAN

S.D.

N

46.

7.5

5

50.

6.4

5

FEMALES

GROUP:

1.3 MG/L

5.2 MG/L

DAY

0 TO 1

 

 

 

MEAN

S.D.

N

2.

5.7

5

-4.

5.0

5

1 TO 3

 

 

 

MEAN

S.D.

N

7.

5.9

5

7.

4.7

5

3 TO 7

 

 

 

MEAN

S.D.

N

8.

2.6

5

6.

3.8

5

7 TO 14

 

 

 

MEAN

S.D.

N

15.

8.1

5

20.

3.5

5

 

INH.TOX. STUDY OF DISFLAMOLL TKP-P AND KRONITEX TCP IN RATS

SUMMARY OF MACROSCOPIC FINDINGS

---- MALE ----

GROUP:

1

2

NUMBER OF ANIMALS IN DOSE GROUP

NUMBER OF ANIMALS TERMINALLY EUTHANIZED

5

5

5

5

MANDIBULAR, LN

-ENLARGED

 

1

 

1

NO SIGNIFICANT CHANGES OBSERVED – ALL EXAMINED TISSUES

4

4

---- FEMALE ----

GROUP:

1

2

NUMBER OF ANIMALS IN DOSE GROUP

NUMBER OF ANIMALS TERMINALLY EUTHANIZED

5

5

5

5

MANDIBULAR, LN

-DISCOLORATION, DARK RED

 

0

 

1

UTERUS

-CONTENTS, CLEAR FLUID

 

0

 

2

NO SIGNIFICANT CHANGES OBSERVED – ALL EXAMINED TISSUES

5

2

1 – 1.3 MG/L    2 - 5.2 MG/L

Deviations

A GLP deviation from 40 CFR Sections 160.130( e) and 792.130( e) occurred.

The individual inputting data in an automated data collection system was not identified at the time of that data input. On 18 May 2017, Operator No. 1122 collected data using the electronic log-in for Operator No. 247. The data was still recorded, but not by the person logged into the computer system. Therefore, there was no impact on the collected study data.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Based on the results of this study, the LC50 of Disflamoll TKP-P and Kronitex TCP (1:1 Mixture) was > 5.2 mg/L when male and female Crl:CD(SD) rats were exposed to an aerosol of the test substance as a single, 4-hour, nose-only exposure.
Executive summary:

SUMMARY

Objective

The objective of this study was to determine the acute inhalation toxicity of Disflamoll TKP-P and Kronitex TCP (1:1 Mixture) when administered as a single, 4-hour, nose-only inhalation exposure to rats.

 

Test Guidelines

The protocol was designed in accordance with the US EPA OPPTS Guideline 870.1300, Acute Inhalation Toxicity, August, 1998 and the OECD Guidelines for the Testing of Chemicals, Section 403, Acute Inhalation Toxicity, September, 2009.

 

Study Design

The acute inhalation toxicity of Disflamoll TKP-P and Kronitex TCP (1:1 Mixture) was evaluated in this 4-hour, single-exposure study in rats. Two range-finding exposures were conducted using 2 rats/sex at mean concentrations of 1.3 and 4.8 mg/L. For the definitive study, the test substance was administered to 2 groups of 5 male and 5 female Sprague Dawley rats via nose-only inhalation exposure as a liquid droplet aerosol at concentrations of 1.3 and 5.2 mg/L. Mean mass median aerodynamic diameter ± the geometric standard deviation were 3.0 ± 1.93 and 2.3 ± 1.94 μm for the 1.3 and 5.2 mg/L groups, respectively.

Mortality, clinical observations, body weights, and body weight changes were evaluated over a 14-day post-exposure observation period. Necropsies were conducted on all animals.

 

Results

None of the animals in the range-finding nor the definitive groups died during the study.

Significant clinical observations following exposure included increased respiration for the 5.2 mg/L group and vocalization upon handling for the 1.3 mg/L group. Significant clinical observations at the 1 to 2 hour post-exposure period included rapid respiration and vocalization upon handling for the 5.2 mg/L group. There were no significant clinical observations during the 14-day post-exposure observation period. All animals were considered clinically normal by Study Day 1.

One male and 2 females in the 1.3 mg/L group and 5 males and 4 females in the 5.2 mg/L group lost weight from Study Day 0 to Study Day 1. All animals surpassed their initial (Study Day 0) body weight by Study Day 14.

Macroscopic findings noted for animals at the scheduled necropsy were enlarged mandibular lymph node for the 1.3 and 5.2 mg/L groups and dark red discoloration of the mandibular lymph node and clear fluid contents in the uterus for the 5.2 mg/L group. There were no other macroscopic findings for animals at the scheduled necropsy.

 

Conclusions

Based on the results of this study, the LC50 of Disflamoll TKP-P and Kronitex TCP (1:1 Mixture) was > 5.2 mg/L when male and female Sprague Dawley rats were exposed to an aerosol of the test substance as a single, 4-hour, nose-only exposure.