Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
July 14, 2014 to August 4, 2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study performed in accordance with OECD test guideline and in compliance with GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2014
Report Date:
2014

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Deviations:
no
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: Clear, yellow liquid
Details on test material:
Date Received: June 16, 2014
Supplier: Chemtura Fords, New Jersey
Amount Received: Approximately 2083.33 (total of 2 containers)
Label Identification: Hatcol 3346
Batch Number: 2013059135
Physical Characteristics: Clear, yellow liquid
Retest Date: May 30, 2017
Storage: Room temperature, protected from light
TMC Number: 1405A8

Test animals

Species:
rat
Strain:
other: CD® [Crl:CD®(SD)]
Sex:
female
Details on test animals and environmental conditions:
Species: RatStrain: CD® [Crl:CD®(SD)]Source: Charles River LaboratoriesExpected Age: 7 weeks of age at arrivalExpected Weight at Arrival: Females weighed 100 to 170 g, as measured within 3 days of arrival. Number Ordered Female: 10Number on Study Female: Up to 9AcclimationDuration: At least 1 weekAcclimation Details: During this acclimation period, all animals were observed daily for any clinical signs of disease, and all animals were given a detailed clinical examination prior to selection for study.Selection for StudyBody Weight Range: ±20% of the mean body weightRandomization: Into treatment groups using a simple randomization procedure. All animals with any evidence of disease or physical abnormalities were not selected for study.Method of Identification: Each animal was assigned an animal number to be used in Provantis™ and was implanted with a microchip bearing a unique identification number. The individual animal number, implant number, and the MPI Research study number comprises a unique identification for each animal. The animal cage was identified by the study number, animal number, group number, and sex.Housing: IndividuallyCaging: Solid bottom cages with nonaromatic bedding. The bedding was sourced from an approved supplier and documented in the study data.Temperature: 68 to 79 °FHumidity: 30 to 70%Lighting: Fluorescent lighting was provided via an automatic timer for approximately 12 hours per day. On occasion, the dark cycle could be interrupted intermittently due to study-related activities.Water: Tap water was supplied ad libitum to all animals via an automatic water system unless otherwise indicated.Diet: The basal diet was block Lab Diet® Certified Rodent Diet #5002, PMI Nutrition International, Inc. This diet was available ad libitum unless designated otherwise. Each lot number used was identified in the study records.Water and Diet Contaminants: There are no known contaminants in the food or water that would interfere with this study. The drinking water used is monitored for specified contaminants at periodic intervals according to MPI Research SOP.Supplemental Enrichment: Animal enrichment was provided as described in MPI Research SOP.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Preparation: Test article was administered neat.Frequency: Day of administrationStorage Conditions: Room temperature
Doses:
Sighting Study: 2000 mg/kg. As no toxicity was noted an additional group was added at 5000 mg/kg.Main Study: 5000 mg/kg
No. of animals per sex per dose:
1 female per dose in the Sighting study4 females in the main study
Control animals:
no
Details on study design:
The 2000 mg/kg dose is specified by regulatory agencies for the limit test. Any additional doses were selected to estimate the LD50.The test article was administered once on Day 1 via oral gavage to one animal. The initial dose level for the sighting study was 2000 mg/kg. Due to there being no toxicity noted, an additional animal was administered the test article at a dose level of 5000 mg/kg. The results of the sighting study determined that 5000 mg/kg was the starting dose for the main study animals. Individual doses were based on the most recent body weight measurements. The test article was administered at a dose volume of 2.08 mL/kg to the initial animal dosed in the sighting study and at a dose volume of 5.21 mL/kg for the second animal in the sighting study and for all main study animals. The animals were fasted overnight prior to test article administration and had food returned following the completion of dosing.Observations for morbidity, mortality, injury, and the availability of food and water were conducted twice daily for all animals. Observations for clinical signs were conducted on Day 1 at 30 minutes, 2, and 4 hours postdose, and daily thereafter. Body weights were measured and recorded prior to dosing on Day 1 and weekly thereafter.At study termination (Day 15), the animals were euthanized by carbon dioxide inhalation. Euthanasia was confirmed via exsanguination via severing the vena cava. Necropsy examinations were performed under procedures approved by a veterinary pathologist on all animals euthanized at the scheduled necropsy. The animals were examined carefully for external abnormalities including palpable masses. The skin was reflected from a ventral midline incision, any subcutaneous masses were identified and correlated with antemortem findings, and the abdominal, thoracic, and cranial cavities were examined. Following the evaluation, the carcasses were discarded and no tissues were saved.
Statistics:
No statistical analyses are required or will be performed for this study.

Results and discussion

Preliminary study:
The test article was administered once on Day 1 via oral gavage to one animal. The initial dose level for the sighting study was 2000 mg/kg. Due to there being no toxicity noted, an additional animal was administered the test article at a dose level of 5000 mg/kg. The results of the sighting study determined that 5000 mg/kg was the starting dose for the main study animals.
Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
All animals survived to the scheduled necropsy.
Clinical signs:
No adverse clinical findings indicative of systemic toxicity were noted. Yellow discoloured hair was noted in the anogenital region on Day 1 at 4 hours postdose for animal number 8002. This is a common finding in an animal of this age, sex, and strain, thus deemed not test article-related.
Body weight:
There were no adverse test article-related effects on body weight. Body weights were within normal range for this species.
Gross pathology:
The tissues of all animals examined at necropsy were within normal limits.
Other findings:
No further findings detailed in the study report.

Any other information on results incl. tables

Record of Animal Fate and Disposition – Sighting Study - FEMALE

Group,

Animal Number

Fate

Day

2000 mg/kg

8001

 

Terminal necropsy

 

15

5000 mg/kg

8002

 

Terminal necropsy

 

15

 

Record of Animal Fate and Disposition – Main Study - FEMALE

Group,

Animal Number

Fate

Day

5000 mg/kg

8003

8004

8005

8006

 

Terminal necropsy

Terminal necropsy

Terminal necropsy

Terminal necropsy

 

15

15

15

15

 

Individual Detailed Clinical Observations – Sighting Study – FEMALE

30 minute & 2 hour post dose

Group,

Animal Number

Day(s) Sign Present

2000 mg/kg

8001      No abnormalities detected

 

1

5000 mg/kg

8002      No abnormalities detected

 

1

 

Individual Detailed Clinical Observations – Sighting Study – FEMALE

4 hour post dose

Group,

Animal Number

Day(s) Sign Present

2000 mg/kg

8001     No abnormalities detected

 

1

5000 mg/kg

8002      Hair discoloured, Yellow, Anogenital region

 

1

 

Individual Detailed Clinical Observations – Sighting Study – FEMALE

Group,

Animal Number

Day(s) Sign Present

2000 mg/kg

8001      No abnormalities detected

 

2 - 14

5000 mg/kg

8002      No abnormalities detected

 

2- 14

 

Individual Detailed Clinical Observations – Main Study – FEMALE

30 minute, 2 and 4 hour post dose

Group,

Animal Number

Day(s) Sign Present

5000 mg/kg

8003      No abnormalities detected

8004      No abnormalities detected

8005      No abnormalities detected

8006      No abnormalities detected

 

1

1

1

1

 

Individual Detailed Clinical Observations – Main Study – FEMALE

Group,

Animal Number

Day(s) Sign Present

5000 mg/kg

8003      No abnormalities detected

8004      No abnormalities detected

8005      No abnormalities detected

8006      No abnormalities detected

 

2 – 14

2 – 14

2 – 14

2 – 14

 

Individual Body Weight Values – Sighting Study, g - FEMALE

Group,

Animal Number

Study Interval (Week)

1

2

3

2000 mg/kg

8001

 

176

 

218

 

248

5000 mg/kg

8002

 

167

 

185

 

199

 

Individual Body Weight Values – Main Study, g - FEMALE

Group,

Animal Number

Study Interval (Week)

1

2

3

5000 mg/kg

8003

8004

8005

8006

 

194

205

196

192

 

217

240

225

217

 

227

269

236

234

 

Individual Animal Data Record: Pathology – Sighting Study, FEMALE

Terminal

Group,

Animal Number

 

Fate

Tissue

Observations

2000 mg/kg

8001

 

S

Macroscopic

All tissues

 

- within normal limits

5000 mg/kg

8002

 

S

Macroscopic

All tissues

 

- within normal limits

S – Scheduled necropsy

 

Individual Animal Data Record: Pathology – Main Study - FEMALE

Group,

Animal Number

 

Fate

 

Tissue

 

Observations

5000 mg/kg

8003

S

Macroscopic

All tissues

 

- within normal limits

8004

S

Macroscopic

All tissues

 

- within normal limits

8005

S

Macroscopic

All tissues

 

- within normal limits

8006

S

Macroscopic

All tissues

 

- within normal limits

S – Scheduled necropsy

Applicant's summary and conclusion

Interpretation of results:
study cannot be used for classification
Remarks:
Migrated information
Conclusions:
Under the conditions of this study, where Hatcol 3346, was administered as a single oral dose to rats, the LD50 was greater than 5000 mg/kg.
Executive summary:

This study was conducted for the sponsor to evaluate the potential oral acute toxicity of the test article, Hatcol 3346. This study was conducted in accordance with Standard Operating Procedures (SOPs) and the protocol as approved by the Sponsor. No protocol or SOP deviations occurred. This study was based on the Organization for Economic Cooperation and Development (OECD) Guideline 420 (2001) and the Guide for the Care and Use of Laboratory Animals, Institute of Laboratory Animal Resources, National Academy Press, Washington, D.C., 2011.

 

The 2000 mg/kg dose is specified by regulatory agencies for the limit test. Any additional doses were selected to estimate the LD50.

The test article was administered once on Day 1 via oral gavage to one animal. The initial dose level for the sighting study was 2000 mg/kg. Due to there being no toxicity noted, an additional animal was administered the test article at a dose level of 5000 mg/kg. The results of the sighting study determined that 5000 mg/kg was the starting dose for the main study animals. Individual doses were based on the most recent body weight measurements. The test article was administered at a dose volume of 2.08 mL/kg to the initial animal dosed in the sighting study and at a dose volume of 5.21 mL/kg for the second animal in the sighting study and for all main study animals. The animals were fasted overnight prior to test article administration and had food returned following the completion of dosing.

Observations for morbidity, mortality, injury, and the availability of food and water were conducted twice daily for all animals. Observations for clinical signs were conducted on Day 1 at 30 minutes, 2, and 4 hours postdose, and daily thereafter. Body weights were measured and recorded prior to dosing on Day 1 and weekly thereafter.

At study termination (Day 15), the animals were euthanized by carbon dioxide inhalation. Euthanasia was confirmed via exsanguination via severing the vena cava. Necropsy examinations were performed under procedures approved by a veterinary pathologist on all animals euthanized at the scheduled necropsy. The animals were examined carefully for external abnormalities including palpable masses. The skin was reflected from a ventral midline incision, any subcutaneous masses were identified and correlated with antemortem findings, and the abdominal, thoracic, and cranial cavities were examined. Following the evaluation, the carcasses were discarded and no tissues were saved.

 

All animals survived to the scheduled necropsy.

No adverse clinical findings indicative of systemic toxicity were noted. Yellow discoloured hair was noted in the anogenital region on Day 1 at 4 hours postdose for animal number 8002. This is a common finding in an animal of this age, sex, and strain, thus deemed not test article-related.

There were no adverse test article-related effects on body weight. Body weights were within normal range for this species.

The tissues of all animals examined at necropsy were within normal limits.

 

Under the conditions of this study, where Hatcol 3346, was administered as a single oral dose to rats, the LD50 was greater than 5000 mg/kg. No classification is applicable.