Reaction mass of pentyl pyridine-3-carboxylate and 2-methylbutyl pyridine-3-carboxylate

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

16 September - 01 October 2003

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP- guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2003

Report date:

2003

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

2-methylbutyl pyridine-3-carboxylate; pentyl pyridine-3-carboxylate

Molecular formula:

Multi constituent substance

IUPAC Name:

2-methylbutyl pyridine-3-carboxylate; pentyl pyridine-3-carboxylate

Constituent 2

Reference substance name:

Nikotinsäurepentylester

IUPAC Name:

Nikotinsäurepentylester

Test material form:

other: liquid

Details on test material:

- Name of test material (as cited in study report) : Nicotinsäurepentylester HF
- Substance type : organic
- Physical state : pale yellow liquid
- Analytical purity : 95%
- Lot/batch No. : 03030417/005
- Storage condition of test material : room temperature

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source : Elevage JANVIER (53940 Le Genest St Isle — France)
- Age at study initiation : not stated
- Weight at study initiation : 197g - 221g (males) ; 155g - 177g (females)
- Fasting period before study : not stated
- Housing : not stated
- Diet (e.g. ad libitum) : rats&mice maintenance diet
- Water (e.g. ad libitum) : not stated
- Acclimation period : 5-6 days

Group 1 (control) : 3 male rats Rm4019 to Rm4021 ; 3 female rats Rf3980 to Rf3982
Group 2 (treated) : 3 male rats Rm3969 to Rm3971 ; 3 female rats Rf3950 to Rf3952

ENVIRONMENTAL CONDITIONS
- Temperature (°C) : between 19°C and 24°C
- Humidity (%) : between 50% and 66%
- Air changes (per hr) : not stated
- Photoperiod (hrs dark / hrs light) : not stated

Administration / exposure

Route of administration:

other: force-feeding

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

The animals of Group 2, received an effective dose of 2000 mg/kg body weight of item, administered by force-feeding under a volume of 1.923mL/kg body weight using a suitable syringe graduated fitted with an oesophageal metal canula.

Doses:

- 2000 mg/kg bw

No. of animals per sex per dose:

3

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations : not further specified
- Necropsy of survivors performed: yes
- Other examinations performed :
* Spontaneous Activity
* Preyer's Reflex
* Respiratory Rate
* Convulsions
* Tremors
* Body Temperature
* Muscle Tone
* Palpebral Opening
* Pupil Appearance
* Salivation
* Lachrymation
* Righting Reflex
* Back Hair Appearance
• The observations are performed by comparison with the control animals standing in the same environment.
• The temperature of animal is evaluated by touch.

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred during the study.

Clinical signs:

other: No clinical signs related to the administration of the test item were observed.

Gross pathology:

The macroscopical examination of the animals at the end of the study did not reveal treatment-related changes.

Any other information on results incl. tables

Table 1 :

OBSERVATION DATA SHEET No. 1 — Group 2 (treated)

Test item : Nicotinsäurepentylester HF

Dose 2000 mg/kg bw ; Day 0 : 17 September 2003 (male) & 16 September 2003 (female)

OBSERVATIONS  T0 + 1 hour  T0 + 3 hours T0 + 5 hours	MALES			FEMALES
	Rm3969	Rm3970	Rm3971	Rf3950	Rf3951	Rf3952
Spontaneous activity	D*	D*	D*	D*	D*	D*
Preyer´s reflex (noise)	N	N	N	N	N	N
Respiratory rate	N	N	N	N	N	N*
Convulsions	N	N	N	N	N	N
Tremors	N	N	N	N	N	N
Body temperature	N	N	N	N	N	N
Muscle tone	N	N	N	N	N	N
Palpebral opening	N	N	N	N	N	N
Pupil appearance	N	N	N	N	N	N
Salivation	N	N	N	N	N	N
Lachcrymation	N	N	N	N	N	N
Righting reflex	N	N	N	N	N	N
Back hair appearance	N	N	N	N	N	N
MORTALITY	0	0	0	0	0	0
Remarks	D* : recorded at the reading time 1 hour			D* : recorded at the reading time 1 hour N* : noise at breathing at the reading time 3 hours

Table 2 :

OBSERVATION DATA SHEET No. 2 — Group 2 (treated)

Test item : Nicotinsäurepentylester HF

Dose 2000 mg/kg bw ; Day 0 : 17 September 2003 (male) & 16 September 2003 (female)

OBSERVATIONS  T0 + 24 hours T0 + 48 hours	MALES			FEMALES
	Rm3969	Rm3970	Rm3971	Rf3950	Rf3951	Rf3952
Spontaneous activity	N	N	N	N	N	N
Preyer´s reflex (noise)	N	N	N	N	N	N
Respiratory rate	N	N	N	N*	N*	N*
Convulsions	N	N	N	N	N	N
Tremors	N	N	N	N	N	N
Body temperature	N	N	N	N	N	N
Muscle tone	N	N	N	N	N	N
Palpebral opening	N	N	N	N	N	N
Pupil appearance	N	N	N	N	N	N
Salivation	N	N	N	N	N	N
Lachcrymation	N	N	N	N	N	N
Righting reflex	N	N	N	N	N	N
Back hair appearance	N	N	N	N	N	N
MORTALITY	0	0	0	0	0	0
Remarks	None			N* : noise at breathing at the reading time 24 hours

Toxicity Lexicon

* Spontaneous Activity :Normal (N) / Decrease (D) / Increased (A)

* Preyer's Reflex :Normal (N) / None (0)

*Respiratory Rate :Normal (N) / Dyspnea (D) / Bradypnea (B) / Polypnea (P)

* Convulsions : None (N) / Tonic (T) / Clonic (C)

* Tremors :None (N) / Tremors (Tr)

* Body Temperature :Normal (N) / Hypothermia (D) / Hyperthermia (A)

* Muscle Tone : Normal (N) / Decreased (D) / Increased (A)

* Palpebral Opening :Normal (N) / Eyes partly closed (Pc) / Eyes completely closed (Cc)

* Pupil Appearance :Normal (N) / Mydriasis (Md) / Myosis (Ms)

* Salivation : Normal (N) / Increased (A)

* Lachrymation : Normal (N) / Increased (A)

* Righting Reflex :Normal (N) / Limited (D) / None (0)

* Back Hair Appearance :Normal (N) / Piloerection (Pi)

NOTES:

•The observations are performed by comparison with the controlanimals standing in the same environment.

• The temperature of animal is evaluated by touch.

Table 3:

Body weight evolution - Group 1 (Control)

Control product : Distilled water

(Body weight and weight gain in grams)

MALES	D0			D2	D2-D0			D7	D7-D0					D14		D14-D0
Rm 4019	204			233	29			284	80					337		133
Rm 4020	210			237	27			293	83					349		139
Rm 4021	214			253	39			306	92					369		155
MEAN	209,3			241,0	31,7			294,3	85,0					351,7		142,3
Standard deviation	5,0			10,6	6,4			11,1	6,2					16,2		11,4
FEMALES
Rf 3980	172			194	22			215	43					237		65
Rf 3981	155			174	19			189	34					205		50
Rf 3982	160			185	25			204	44					236		76
MEAN	162,3			184,3	22,0			202,7	40,3					226,0		63,7
Standard deviation	8,7			10,0	3,0			13,1	5,5					18,2		13,1

Table 4:

Body weight evolution - Group 2 (treated)

Test item : Nicotinsäurepentylester

(Body weight and weight gain in grams)

MALES	D0			D2	D2-D0			D7	D7-D0				D14	D14-D0
Rm 3969	213			247	34			305	92				366	153
Rm 3970	221			258	37			327	106				395	174
Rm 3971	197			222	25			270	73				320	123
MEAN	210,3			242,3	32,0			300,7	90,3				360,3	150,0
Standard deviation	12,2			18,4	6,2			28,7	16,6				37,8	25,6
FEMALES
Rf 3950	173			185	12			211	38				238	65
Rf 3951	177			175	-2			207	30				212	35
Rf 3952	176			186	10			212	36				246	70
MEAN	175,3			182,0	6,7			210,0	34,7				232,0	56,7
Standard deviation	2,1			6,1	7,6			2,6	4,2				17,8	18,9

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The study was performed according to the O.E.C.D. guideline N° 423 dated March 22nd, 1996 concerning acute oral toxicity and the test method B.1ter of the Directive N° 96/54/EC dated July 30th, 1996 without deviations and therefore considered to be of the highest quality (reliability Klimisch 1).The test material Nicotinsäurepentylester HF did not induce any signs of acute oral toxicity.

In conclusion, the LD50 of the item Nicotinsäurepentylester HF is higher than 2000 mg/kg body weight by oral route in the rat.

Executive summary:

The item Nicotinsäurepentylester HF was administered to a group of 6 Sprague Dawley rats (3 males and 3 females) at the single dose of 2000 mg/kg body weight according to the experimental protocol established on the basis of the official method as defined in the O.E.C.D. guideline N° 423 dated March 22nd, 1996 and the test method B.1ter of the Directive N° 96/54/EC dated July 30th, 1996.

No mortality occurred during the study.

No clinical signs related to the administration of the test item were observed.

The body weight evolution of the animals remained normal throughout the study, similar between treated and control animals.

The macroscopical examination of the animals at the end of the study did not reveal treatment-related changes.

In conclusion, the LD50 of the item Nicotinsäurepentylester HF is higher than 2000 mg/kg body weight by oral route in the rat.

According to the criteria for classification, packaging and labelling of dangerous substances and preparations in accordance with the E.E.C. Directives 67/548, 2001/59 and 99/45, the item Nicotinsäurepentylester HF must not be classified.