Reaction products of neodecanoic acid and titanium (IV) isopropoxide

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

The study was performed between 20 October 2009 and 01 December 2009.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted to GLP and in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not effect the quality of the relevant results.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2010

Report date:

2010

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

Date of GLP inspection: 28 January 2010 Date of Signature on GLP certificate: 26 November 2009

Test type:

fixed dose procedure

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

E0286P/040A

IUPAC Name:

E0286P/040A

Details on test material:

Sponsor's identification : E0286P/040A
Description : amber coloured viscous liquid
Batch number : E0286P/040A/01
Date received : 20 July 2009
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:

TEST ANIMALS
- Source:
Harlan UK Limited, Bicester, Oxon, UK.

- Age at study initiation:
At the start of the study the animals were eight to twelve weeks of age.

- Weight at study initiation:
The bodyweight variation did not exceed ± 20% of the initial/mean bodyweight of any previously dosed animal(s).

- Fasting period before study:
overnight fast immediately before dosing

- Housing:
The animals were housed in groups of up to four in suspended solid floor polypropylene cages furnished with woodflakes.

- Diet (e.g. ad libitum):
(2014 Teklad Global Rodent diet supplied by Harlan Teklad, Blackthorn, Bicester, Oxon, UK) was allowed ad libitum throughout the study.

- Water (e.g. ad libitum):free access to mains drinking water

- Acclimation period:acclimatisation period of at least five days


ENVIRONMENTAL CONDITIONS
- Temperature (°C):
19 to 25°C

- Humidity (%):
30 to 70%

- Air changes (per hr):
The rate of air exchange was at least fifteen changes per hour.

- Photoperiod (hrs dark / hrs light):
lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness.


IN-LIFE DATES: From: Day 1 To: Day 14

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

arachis oil

Remarks:

Arachis oil BP was used because the test material did not dissolve/suspend in distilled water.

Details on oral exposure:

VEHICLE
- Concentration in vehicle:
For the purpose of the study the test material was freshly prepared, as required, as a solution in arachis oil BP to give dose levels of 300 and 2000mg/kg bodyweight.

- Amount of vehicle (if gavage):
Not stated

- Justification for choice of vehicle:
Arachis oil BP was used because the test material did not dissolve/suspend in distilled water.

- Lot/batch no. (if required):
Not stated

- Purity:
Not stated


MAXIMUM DOSE VOLUME APPLIED:
10ml/kg


DOSAGE PREPARATION (if unusual):
Not applicable

CLASS METHOD (if applicable)

- Rationale for the selection of the starting dose:
In the absence of data regarding the toxicity of the test material, 300 mg/kg was chosen as the starting dose.

Doses:

Following a sighting test at dose levels of 300 mg/kg and 2000 mg/kg, a further group of four fasted females was given a single oral dose of test material, as a solution in arachis oil BP, at a dose level of 2000 mg/kg bodyweight. Based on the results of this, a further group of four fasted females was given a single oral dose of test material, as a solution in arachis oil BP, at a dose level of 300 mg/kg bodyweight. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

No. of animals per sex per dose:

EXAMPLE:
5 females at 300 mg/kg
5 females at 2000 mg/kg
EXAMPLE:

Control animals:

no

Details on study design:

- Duration of observation period following administration:
14 days

- Frequency of observations and weighing:
Clinical observations were made ½, 1, 2, and 4 hours after dosing and then daily for fourteen days. Morbidity and mortality checks were made twice daily. Individual bodyweights were recorded on Day 0 (the day of dosing) and on Days 7 and 14.

- Necropsy of survivors performed:
Yes

- Other examinations performed:
Clinical signs, body weight.

Results and discussion

Preliminary study:

A sighting test sighting test at dose levels of 300 mg/kg and 2000 mg/kg was performed.

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

300 - 2 000 mg/kg bw

Mortality:

300 mg/kg: There were no deaths.

2000 mg/kg: Four animals treated at a dose level of 2000 mg/kg were humanely killed two hours after dosing.

Clinical signs:

other: 300 mg/kg: Increased salivation was noted in one animal during the day of dosing. No other signs of systemic toxicity were noted. 2000 mg/kg: Signs of systemic toxicity noted were ataxia, lethargy, pilo-erection, splayed gait, prostration, decreased r

Gross pathology:

300 mg/kg: No abnormalities were noted at necropsy.

2000 mg/kg: Yellow liquid present in the stomach was noted at necropsy of animals that were humanely killed during the study. No abnormalities were noted at necropsy of the animal that was killed at the end of the study.

Other findings:

- Organ weights:
EXAMPLE: Not recorded

- Histopathology: N/A


- Potential target organs:
EXAMPLE: Not recorded

- Other observations:
EXAMPLE: None

Any other information on results incl. tables

Table1              Individual Clinical Observations and Mortality Data - 2000 mg/kg

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	2-0 Female	AWs		ALP	A	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	3-0 Female	PrRdRlLWs	PrRdRlLWs	CoRdRlWsX*
	3-1 Female	PrRdRlLWs	PrRdRlLWs	CoRdRlWsX*
	3-2 Female	PrRdRlLWs	PrRdRlLWs	CoRdRlWsX*
	3-3 Female	PrRdRlLWs	PrRdRlLWs	CoRdRlWsX*

0= No signs of systemic toxicity

A= Ataxia

L = Lethargy

P = Pilo-erection

Ws = Splayed gait

Pr = Prostration

Rd = Decreased respiratory rate

Rl = Laboured respiration

Co = Comatose

X* = Animal humanely killed

Table2              Individual Bodyweights and Bodyweight Changes - 2000 mg/kg

Dose Level mg/kg	Animal Number and Sex	Bodyweight (g) at Day			Bodyweight (g) at Death	Bodyweight Gain (g) During Week
		0	7	14		1	2
2000	2-0 Female	203	209	221		6	12
	3-0 Female	184	-	-	184	-	-
	3-1 Female	180	-	-	176	-	-
	3-2 Female	181	-	-	181	-	-
	3-3 Female	165	-	-	163	-	-

 

Table3              Individual Necropsy Findings - 2000 mg/kg

Dose Level mg/kg	Animal Number and Sex	Time of Death	Macroscopic Observations
2000	2-0 Female	Killed Day 14	No abnormalities detected
	3-0 Female	Humanely killed Day 0	Stomach: yellow liquid present
	3-1 Female	Humanely killed Day 0	Stomach: yellow liquid present
	3-2 Female	Humanely killed Day 0	Stomach: yellow liquid present
	3-3 Female	Humanely killed Day 0	Stomach: yellow liquid present

Table4              Individual Clinical Observations and Mortality Data -300mg/kg

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
300	1-0 Female	S	S	S	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	4-0 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	4-1 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	4-2 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	4-3 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

0= No signs of systemic toxicity

S = Increased salivation

Table5              Individual Bodyweights and Bodyweight Changes-300mg/kg

Dose Level mg/kg	Animal Number and Sex	Bodyweight (g) at Day			Bodyweight Gain (g) During Week
		0	7	14	1	2
300	1-0 Female	176	185	198	9	13
	4-0 Female	179	188	196	9	8
	4-1 Female	173	182	190	9	8
	4-2 Female	173	178	183	5	5
	4-3 Female	170	179	184	9	5

Table6              Individual Necropsy Findings-300mg/kg

Dose Level mg/kg	Animal Number and Sex	Time of Death	Macroscopic Observations
300	1-0 Female	Killed Day 14	No abnormalities detected
	4-0 Female	Killed Day 14	No abnormalities detected
	4-1 Female	Killed Day 14	No abnormalities detected
	4-2 Female	Killed Day 14	No abnormalities detected
	4-3 Female	Killed Day 14	No abnormalities detected

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Remarks:

Migrated information: The acute oral median lethal dose (LD50) of the test material in the female Wistar strain rat was estimated to be in the range of 300 2000 mg/kg bodyweight (Globally Harmonised Classification System  Category 4).

Conclusions:

The acute oral median lethal dose (LD50) of the test material in the female Wistar strain rat was estimated to be in the range of 300 2000 mg/kg bodyweight (Globally Harmonised Classification System - Category 4).

Executive summary:

Introduction. The study was performed to assess the acute oral toxicity of the test material in the Wistar strain rat. The method was designed to meet the requirements of the following:

        OECD Guidelines for Testing of Chemicals No 420 “Acute Oral Toxicity - Fixed Dose Method” (2001)

      Method B1 bisAcute Toxicity (Oral) of CommissionRegulation (EC) No. 440/2008

Method. Following a sighting test at dose levels of 300 mg/kg and2000 mg/kg, a further group of four fasted females was given a single oral dose of test material, as asolutioninarachis oil BP, at a dose level of 2000 mg/kg bodyweight. Based on the results of this, a further group of four fasted females was given a single oral dose of test material, as asolutioninarachis oil BP, at a dose level of 300 mg/kg bodyweight. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

Mortality. Four animals treated at a dose level of 2000 mg/kg were humanely killed two hours after dosing. There were no deaths noted at a dose level of 300 mg/kg.

Clinical Observations. Signs of systemic toxicity noted in animals treated at a dose level of 2000 mg/kg were ataxia, lethargy, pilo-erection, splayed gait, prostration, decreased respiratory rate and laboured respiration. Four animals treated at a dose level of 2000 mg/kg were comatose two hours after dosing. The surviving animal treated at a dose level of 2000 mg/kg appeared normal one day after dosing. Increased salivation was noted in one animal treated at a dose level of 300 mg/kg. No other signs of systemic toxicity were noted in animals treated at a dose level of 300 mg/kg.

Bodyweight. Surviving animals showed expected gains in bodyweight.

Necropsy. Yellow liquid present in the stomach was noted at necropsy of animals treated at a dose level of 2000 mg/kg that were humanely killed during the study. No abnormalities were noted at necropsy of animals that were killed at the end of the study.

Conclusion. The acute oral median lethal dose (LD₅₀) of the test material in the female Wistar strain rat was estimated to be in the range of 300 - 2000 mg/kg bodyweight (Globally Harmonised Classification System-Category 4).