Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Experimental start date 07 July 2016 Experimental completion date 26 July 2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016
Report date:
2016

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
fixed dose procedure
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
O,O-dibutyl hydrogen thiophosphate, compound with 1-octylamine (1:1)
EC Number:
300-947-2
EC Name:
O,O-dibutyl hydrogen thiophosphate, compound with 1-octylamine (1:1)
Cas Number:
93964-99-9
Molecular formula:
C8H19N.C8H19O3PS
IUPAC Name:
octan-1-amine dibutyl sulfanylphosphonate
impurity 1
Chemical structure
Reference substance name:
Octylamine
EC Number:
203-916-0
EC Name:
Octylamine
Cas Number:
111-86-4
Molecular formula:
C8H19N
IUPAC Name:
octan-1-amine
Test material form:
liquid
Specific details on test material used for the study:
Identification: X-19575 Phosphorothioic acid, O,O-dibutyl ester, compd. with 1-octanamine, CASRN 93964-99-9
Batch: X-019575-00-00
Purity: >95% (treated as 100%)
Physical state/Appearance: amber colored viscous liquid
Expiry Date: 01 June 2017
Storage Conditions: room temperature in the dark

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
Animal Information
Female Wistar (RccHan™:WIST) strain rats were supplied by Envigo RMS (UK) Limited, Oxon, UK. On receipt the animals were randomly allocated to cages. The females were nulliparous and non pregnant. After an acclimatization period of at least 5 days the animals were selected at random and given a number unique within the study by indelible ink marking on the tail and a number written on a cage card. At the start of the study the animals were 8 to 12 weeks of age. The body weight variation did not exceed ±20% of the mean body weight at the start of treatment.

Animal Care and Husbandry
The animals were housed in groups of up to four in suspended solid floor polypropylene cages furnished with woodflakes. With the exception of an overnight fast immediately before dosing and for approximately 3 to 4 hours after dosing, free access to mains drinking water and food (2014C Teklad Global Rodent diet supplied by Envigo RMS (UK) Limited, Oxon, UK) was allowed throughout the study. The diet, drinking water and bedding were routinely analyzed and were considered not to contain any contaminants that would reasonably be expected to affect the purpose or integrity of the study.
The temperature and relative humidity were set to achieve limits of 19 to 25 °C and 30 to 70% respectively. The rate of air exchange was at least fifteen changes per hour and the lighting was controlled by a time switch to give 12 hours continuous light and 12 hours darkness.
The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Dose volume: 2.09 mL/kg

Doses:
2000 mg/kg starting dose
2000 mg/kg additional group
No. of animals per sex per dose:
Starting dose: 1 animal
Additional group: 4 animals
Control animals:
no
Details on study design:
All animals were dosed once only by gavage, using a metal cannula attached to a graduated syringe. The volume administered to each animal was calculated according to the fasted body weight at the time of dosing. Treatment of animals was sequential. Sufficient time was allowed between each dose group to confirm the survival of the previously dosed animals.
Clinical observations were made 30 minutes, 1, 2, and 4 hours after dosing and then daily for 14 days. Morbidity and mortality checks were made twice daily.
Individual body weights were recorded on Day 0 (the day of dosing) and on Days 7 and 14.
At the end of the observation period the animals were killed by cervical dislocation. All animals were subjected to gross necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.
3.4 Data Evaluation
The test item was classified according to Annex 3 of the OECD Guidelines for Testing of Chemicals No. 420 "Acute Oral Toxicity - Fixed Dose Method" (adopted 17 December 2001) as shown in the Flow Chart in Annex 3.
Evaluation of data included identification of the number of animals that died during the study (or that were killed for humane reasons), and determination of the nature, severity, onset and duration of the toxic effects. If possible, the signs of evident toxicity were described. Evident toxicity refers to the toxic effects of sufficient severity that administration of the next higher dose level could result in development of severe signs of toxicity and probable mortality. Effects on body weights and abnormalities noted at necropsy were also identified.
Using the mortality data obtained, an estimate of the acute oral median lethal dose (LD50) of the test item was made.
Statistics:
The following computerized system was used in the study:
Delta Controls – ORCAview

Results and discussion

Preliminary study:
There was an absence of toxicity in the starting group of one animal
Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be greater than 2000 mg/kg body weight (Globally Harmonized Classification System  Unclassified).
Mortality:
There were no deaths.
Clinical signs:
Hunched posture was noted in three animals 2 and 4 hours after dosing.
No signs of systemic toxicity were noted in the remaining two animals during the observation period.
Body weight:
All animals showed expected gains in body weight over the observation period.
Gross pathology:
No abnormalities were noted at necropsy.

Any other information on results incl. tables

  Individual Clinical Observations and Mortality Data

Dose Level mg/kg

Animal Number and Sex

Effects Noted After Dosing
(Hours)

Effects Noted During Period After Dosing
(Days)

½

1

2

4

1

2

3

4

5

6

7

8

9

10

11

12

13

14

2000

1-0
Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-0
Female

0

H

H

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-1
Female

0

H

H

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-2
Female

0

H

H

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-3
Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

 

  Individual Body Weights and Body Weight Changes

Dose Level
mg/kg

Animal Number
and Sex

Body Weight (g) at Day

Body Weight Gain (g) During Week

0

7

14

1

2

2000

1-0 Female

195

228

240

33

12

2-0 Female

160

171

190

11

19

2-1 Female

163

175

190

12

15

2-2 Female

181

194

214

13

20

2-3 Female

165

179

191

14

12

 

 Individual Necropsy Findings

Dose Level
mg/kg

Animal Number
and Sex

Time of Death

Macroscopic Observations

2000

1-0 Female

Killed Day 14

No abnormalities detected

2-0 Female

Killed Day 14

No abnormalities detected

2-1 Female

Killed Day 14

No abnormalities detected

2-2 Female

Killed Day 14

No abnormalities detected

2-3 Female

Killed Day 14

No abnormalities detected

 


0=   No signs of systemic toxicity

H =  Hunched posture

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be greater than 2000 mg/kg body weight (Globally Harmonized Classification System  Unclassified).
Executive summary:

Introduction

The study was performed to assess the acute oral toxicity of the test item in the Wistar strain rat.

Methods

Following a sighting test at a dose level of 2000 mg/kg, an additional four fasted female animals were given a single oral dose of test item at a dose level of 2000 mg/kg body weight. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy.

Results

Mortality. There were no deaths.

Clinical Observations. Hunched posture was noted in three animals 2 and 4 hours after dosing. There were no other signs of systemic toxicity noted.

Body Weight. All animals showed expected gains in body weight.

Necropsy. No abnormalities were noted at necropsy.

Conclusion

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be greater than 2000 mg/kg body weight (Globally Harmonized Classification System-Unclassified).

Categories Display