Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
March 2009 - April 2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP Guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2009
Report Date:
2009

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
GLP compliance:
yes
Test type:
up-and-down procedure

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Daltolac XR 159
- Lot/batch No.: RZW023
- Expiration date of the lot/batch: Twenty-one months at customer
- Physical Description: Light yellow viscous liquid
- Composition/Purity: Reaction mass of 2,2'-Oxydiethanol, propoxylated and formaldehyde polymer with benzenamine and 2-methyloxirane
Stability: The test article was expected to be stable under standard laboratory conditions for the duration of testing.
Storage Conditions: Room temperature (10-30ºC)

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
Total Number: Six
Gender: Female
Age Range: 7 to 12 weeks at start of dosing; records of dates of birth for animals used in this study are retained in the Calvert archives.
Body Weight Range: 152 to 219 grams
Animal Source: Harlan
Experimental History: Purpose-bred and experimentally naïve at the outset of the study.
Identification: Ear tag and cage card.

ENVIRONMENTAL CONDITIONS
Housing: Animals were group housed by sex upon receipt and individually housed upon assignment to study in compliance with the National Research Council “Guide for the Care and Use of Laboratory Animals”. Calvert is a USDA registered and fully AAALAC accredited facility. The room in which the animals were kept was documented in the study records. No other species were kept in the same room.
Lighting: 12 hours light/12 hours dark
Room Temperature: 17.2 to 26.7°C
Relative Humidity: 10 to 67%
Food: All animals had access to Harlan Teklad Rodent Diet (certified) as per Calvert SOP. Animals were fasted overnight prior to dose administration. Food was returned to the animals ~30 minutes after dosing. The lot number(s) and specifications of each lot used are archived at Calvert. No contaminants were known to be present in the certified diet at levels that would be expected to interfere with the results of this study. Analysis of the diet was limited to that performed by the manufacturer, records of which are maintained in the Calvert archives.
Water: Tap water was available ad libitum, to each animal via an automatic watering device. The water is routinely analyzed for contaminants as per Calvert SOP’s. No contaminants were known to be present in the water at levels that would be expected to interfere with the results of this study. Results of the water analysis are maintained in the Calvert archives.
Acclimation: Study animals were acclimated to their housing for a minimum of 5 days prior to dosing.

IN-LIFE DATES: From: 5 April 2009 To: 13 May 2009

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: Mineral oil
Details on oral exposure:
VEHICLE
- Physical Description: Clear semi-viscous liquid
- Lot/batch no. (if required): 066K0086 (exp. September 2011)
- Storage: Room temperature
- Dosing: The 175, 550 mg/kg dose level was prepared at 35 mg/ml and 110 mg/ml to be dosed at 5 ml/kg (dose volume) and the 2000 and 5000 mg/kg levels were dosed as received at 2 or 5 ml/kg, respectively. The 175 and 550 mg of test article were brought to a volume of 5 ml with the vehicle, respectively. Each preparation was made daily on the day of dosing. The stock bottle was inverted several times prior to dispensing. The 175 and 550 mg/kg formulations were described as cloudy suspensions.
Doses:
175, 550, 2000 and 5000 mg/kg
No. of animals per sex per dose:
Dose No. of
Treatment (mg/kg) Sex Rats
Daltolac XR 159 175 F 1
550 F 1
2000 F 3
5000 F 1
Control animals:
no
Details on study design:
The test article/dosing suspensions were administered on Day 1 to each rat as a single dose via oral gavage. Animals were fasted overnight prior to dose administration. Each animal received its designated dose based on fasted body weight determined just prior to dosing. The dose volume was 2 or 5 ml/kg.

A total of four rats received the test article at dose levels of 175, 550, 2000 or 5000 mg/kg. Mortality checks were made once daily. Clinical observations were recorded prior to dosing and at 30 minutes and 4 hours post-dose, and daily thereafter (Days 2-15). Body weights were recorded prior to dosing, on the day of dosing (Day 1), and on Days 8 and 15. All rats were euthanized by CO2 asphyxiation and necropsied on Day 15.
Statistics:
The design of this study was such that statistical analysis was not necessary.

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 - < 5 000 mg/kg bw
Based on:
test mat.
Mortality:
Mortality was not observed in any of the animals dosed at 175, 550, 2000 or 5000 mg/kg of the test article. The single female dosed at 5000 mg/kg was found dead on Day 2.

Clinical signs:
All animals appeared normal throughout the study at 175 and 550 mg/kg. Clinical signs of hunched posture, poor grooming, piloerection and wet and/or discoloured fur of the lower ventral area were observed in one of the three animals dosed at 2000 mg/kg. At 5000 mg/kg, abnormal gait and stance, decreased body tone, decreased activity, poor grooming and piloerection were observed on Day 1.
Body weight:
No biologically significant effect was seen on body weights of animals on Days 8 and 15.
Gross pathology:
Terminal necropsy revealed no visible lesions in any of the animals at 175, 550 or 2000mg/kg. At 5000 mg/kg, necropsy revealed red fluid-filled intestines in the animal found dead on Day 2.

Any other information on results incl. tables

 

Dose

 

No. of

Observation Period

Total

Treatment

(mg/kg)

Sex

Rats

Day

1

Day

2

Day

3

Day

4

Day

5

Day

6

Day

7

Day

8

Day

9

Day

10

Day

11

Day

12

Day

13

Day

14

Day

15

Mortality

Daltolac XR 159

175

F

1

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0/1

550

F

1

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0/1

2000

F

3

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0/3

5000

F

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

1/1

Animal ID#

Observation Period (Day)

Treatment

175 mg/kg

Day 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

30 Min

4 Hr

1873F

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

 

 

Animal ID#

Observation Period (Day)

Treatment

550 mg/kg

Day 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

30 Min

4 Hr

1874F

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

 

 

Animal ID#

Observation Period (Day)

Treatment

5000 mg/kg

Day 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

30 Min

4 Hr

1875F

AN

HP

PIL PG LWF

PG FYL

PG FYL

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

3116F

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

3117F

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

 

All animals appeared normal prior to dosing       AN = Appears normal     HP = Hunched posture PIL = Piloerection PG = Poor grooming LWF = Lower ventral area wer fur FYC = Fur yellow lower ventral area

 

Animal ID#

Observation Period (Day)

Treatment

2000 mg/kg

Day 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

30 Min

4 Hr

1556F

AGS DBT

DBT ACD AGS PG PIL

FD

-

-

-

-

-

-

-

-

-

-

-

-

-

 

All animals appeared normal prior to dosing   ACD = Decrease activity AGS = Abnormal gait and stance DBT = Decreased body tone FD = Found dead PIL = Piloerection PG = Poor grooming     

Applicant's summary and conclusion

Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: OECD GHS
Conclusions:
Based on the results of this study, the oral LD50 for Daltolac XR 159 in rats was estimated to be greater than 2000 mg/kg and less than 5000 mg/kg.
Executive summary:

Initially, one female Sprague Dawley rat was dosed at 175 mg/kg. No mortality was observed at 175 mg/kg and dosing continued in another female at 550 mg/kg. Dosing continued in three additional female at 2000 mg/kg as per protocol guidelines and then in one female at 5000 mg/kg. A total of 6 females were dosed. Mortality checks were made once daily. Clinical observations were recorded prior to dosing, as well at 30 minutes, 4 hours post-dose, and daily thereafter through Day 15. Body weights were recorded on the day of dosing (Day 1), and on Days 8 and 15 or upon death. Necropsy was performed on animals dying on study. All rats were euthanized by CO2 asphyxiation and necropsied on Day 15.

 

For doses of 175, 550 or 2000 mg/kg, no mortality was observed. The single animal dosed at 5000 mg/kg was found dead on Day 2. All animals appeared normal throughout the study at 175 and 550 mg/kg. Clinical signs of hunched posture, poor grooming, piloerection and wet and/or discoloured fur of the lower ventral area were observed in one of the three animals dosed at 2000 mg/kg. At 5000 mg/kg, abnormal gait and stance, decreased body tone, decreased activity, poor grooming and piloerection were observed on Day 1. No biologically significant effect was seen on body weights on Days 8 and 15.  Furthermore, terminal necropsy revealed no visible lesions in any of the animals at 175, 550 or 2000 mg/kg. At 5000 mg/kg, necropsy revealed red-filled intestines in the animal found dead on Day 2.