Isonicotinaldehyde

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

25 May - 23 June 1983

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP -guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1983

Report date:

1983

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Isonicotinaldehyde

EC Number:

212-832-3

EC Name:

Isonicotinaldehyde

Cas Number:

872-85-5

Molecular formula:

C6H5NO

IUPAC Name:

pyridine-4-carbaldehyde

Test material form:

other: liquid

Details on test material:

- Name of test material (as cited in study report) : Pyridin-4-aldehyd
- Physical state : liquid
- Analytical purity :minimum 85% (GC)
- Lot/batch No. : 05394

Test animals

Species:

rat

Strain:

other: outbred WISTARSTOCK kfm. WIST (SPF Han.)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Kleintierfarm Madoerin AG , 4414 Fuellinsdorf , Switzerland
- Age at study initiation: 7 - 11 weeks
- Weight at study initiation: males : 185-224 g , females : 164-182 g
- Fasting period before study: 12-18 hours (overnight) before treatment , approximately 1 hour after treatment
- Housing: animals were caged in groups of five in Macrolon cages type 3 with wire mesh lids and standardized granulated soft wood bedding
- Diet (e.g. ad libitum): pelleted standard Kliba 343 , Batch 74/83 and 77/83 rat maintenance diet, ad libitum
- Water (e.g. ad libitum): tap water , ad libitum
- Acclimation period: 1 week under test conditions

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 55 +/- 10
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

2% solution of CMC in distilled water

Details on oral exposure:

VEHICLE
- Concentration in vehicle : no data
A dilution (w/w) of the test article was prepared using a homogenizer . A magnetic stirrer was used to maintain homogeneity during treatment .

- Amount of vehicle (if gavage):
Volume/kg body weight :
10 ml at 1000 mg/kg
10 ml at 3000 mg/kg
5 ml at 5000 mg/kg
The rats of the 5000 mg/kg group were treated with the undiluted test article .

Doses:

- 1000 mg/kg bw
- 3000 mg/kg bw
- 5000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality : Five times during the first day , daily thereafter
Body weight : Body weights were recorded on the day of administration and days 8 and 15 of the test
Symptoms : Five times at day 1 , daily thereafter for the nature , onset , severity and duration of all gross or visible toxic or pharmacologic effects or time of death
- Necropsy of survivors performed:
yes , all test animals were subjected to a complete gross necropsy . All animals surviving to termination were killed by exsanguination after pentobarbital anestesia . All organ abnormalities were recorded .

- Other examinations performed : The animals were checked daily for the symptoms listed below .
General behaviour : aggressive,crying,restlessness/excitement,nervousness,fear,sedation,somnolence,sleep,coma
Respiration : apnea,dyspnea
Eye : chromodacryorrhea,exophthalmos,miosis,mydriasis,whitish discharge,lid adhesion
Nose : rhinorrhea,epistaxis
Motility : akinesia,ataxia,drooped head,hyperkinesia,hypokinesia,paralysis flaccid,paralysis spatic,paddling movements,stiff movements,rolling movements,hunched posture
Body position : ventral body position,latero-abdominal position,curved body position
Skin : erythema,edema,necrosis
Motor susceptibility : spasms,tonic muscle spasms,clonic muscle spasms,opisthotonus,saltatory spasms,trismus,retching,"Straub" phenomenon,tremor,muscle -twitching
Various : loss of weight,emaciation,negative corneal reflex,diarrhea,ruffled fur,necrosis of tissue of application area,salivation,pallor,cyanosis

Statistics:

The LOGIT Model (COX , Analysis of Binary Data , London 1977) was applied to estimate the LD50 value . Additionally , the 90 , 95 and 99% confidence intervals for the LD50 for each sex and the slope of the concentration response line was estimated .

Results and discussion

Effect levels

Effect levels 1

Sex:

male

Dose descriptor:

LD50

Effect level:

2 442 mg/kg bw

Based on:

test mat.

95% CL:

>= 1 319 - <= 4 069

Effect levels 2

Sex:

female

Dose descriptor:

LD50

Effect level:

2 167 mg/kg bw

Based on:

test mat.

95% CL:

>= 1 091 - <= 3 360

Effect levels 3

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2 355 mg/kg bw

Based on:

test mat.

95% CL:

>= 1 660 - <= 3 093

Mortality:

For detailed results see Tables 7 at "any other information on results incl. tables"

Clinical signs:

other: For detailed results see Tables 1 - 6 at "any other information on results incl. tables"

Gross pathology:

Necropsy :
In three male and four female rats of the 3000 mg/kg group , which died at day two of test , dark-red , mottled , liver , lungs and kidneys as well as suspecious corrosion of stomach was observed . In one male rat of the same group , killed at termination , mottled lung was seen .
Five male and five female rats of the 5000 mg/kg group , showed suspecious corrosion of stomach and duodenum , filled with reddish contents .
For detailed description of the findings see at "any other information on results incl. tables"

Any other information on results incl. tables

Signs and symptoms

Table 1 : Dose 1000 mg/kg

Males No. 1 -5
Test day			1		2	3	4	5	6	7	8	9	10	11	12	13	14	15
hrs. after start exp.	1	2	3	5	24
crying	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
restlessness	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
dyspnea	1	1	1	2	1	1	0	0	0	0	0	0	0	0	0	0	0	0
curved body position	0	0	1	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
ruffled fur	1	1	1	1	1	1	0	0	0	0	0	0	0	0	0	0	0	0
hyperaemia	1	1	1	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0

Table 2 : Dose 1000 mg/kg

Females No. 26 -30
Test day			1		2	3	4	5	6	7	8	9	10	11	12	13	14	15
hrs. after start exp.	1	2	3	5	24
crying	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
restlessness	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
dyspnea	1	1	1	1	1	1	0	0	0	0	0	0	0	0	0	0	0	0
curved body position	0	0	1	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
ruffled fur	1	1	1	1	1	1	0	0	0	0	0	0	0	0	0	0	0	0
hyperaemia	1	1	1	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0

Table 3 : Dose 3000 mg/kg

Males No. 11 - 15
Test day			1		2	3	4	5	6	7	8	9	10	11	12	13	14	15
hrs. after start exp.	1	2	3	5*	24
sedation	1	1	1		0	0	0	0	0	0	0	0	0	0	0	0	0	0
dyspnea	1	1	2		1	1	1	1	0	0	0	0	0	0	0	0	0	0
curved body position	1	1	1		1	1	0	0	0	0	0	0	0	0	0	0	0	0
ruffled fur	2	2	3		1	1	1	0	0	0	0	0	0	0	0	0	0	0

* Due to technical reasons no observation posible

Table 4 : Dose 3000 mg/kg

Females No. 36 -40
Test day			1		2	3	4	5	6	7	8	9	10	11	12	13	14	15
hrs. after start exp.	1	2	3	5*	24
sedation	1	1	1		1	1	0	0	0	0	0	0	0	0	0	0	0	0
dyspnea	1	1	2		1	1	1	1	0	0	0	0	0	0	0	0	0	0
ataxia	0	0	0		1	1	0	0	0	0	0	0	0	0	0	0	0	0
ventral body position	0	1	1		0	0	0	0	0	0	0	0	0	0	0	0	0	0
latero-abdominal position	0	0	1		0	0	0	0	0	0	0	0	0	0	0	0	0	0
curved body position	1	1	1		1	1	0	0	0	0	0	0	0	0	0	0	0	0
ruffled fur	2	2	3		3	2	1	0	0	0	0	0	0	0	0	0	0	0

* Due to technical reasons no observation posible

Table 5 : Dose 5000 mg/kg

Males No. 6 - 10
Test day			1		2	3	4	5	6	7	8	9	10	11	12	13	14	15
hrs. after start exp.	1	2	3	5	24
aggressive	1	0	0	0
restlessness	1	0	0	0
sedation	0	1	2	2
dyspnea	1	2	2	2
ventral body position	1	2	2	2
curved body position	1	0	0	0	DEAD
spasms	1	0	0	0
ruffled fur	2	2	2	2
cyanosis	1	1	1	1

Table 6 : Dose 5000 mg/kg

Females No. 31 - 35
Test day			1		2	3	4	5	6	7	8	9	10	11	12	13	14	15
hrs. after start exp.	1	2	3	5	24
aggressive	1	0	0	0
restlessness	1	0	0	0
sedation	0	1	2	2
dyspnea	1	2	2	2
ventral body position	1	2	2	2
curved body position	1	0	0	0	DEAD
spasms	1	0	0	0
ruffled fur	2	2	2	2
cyanosis	1	1	1	1

Key : 0=none , 1=slight , 2=moderate , 3=severe

Table 7 : Mortality

		Time of death
Test day		1				2	3	4	5	6	7	8	9	10	11	12	13	14	15
hrs. after start exp.		1	2	3	5	24
Dose (mg/kg)	Number of dead animals
Males
1000	0	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-
3000	3	-	-	-	-	3	-	-	-	-	-	-	-	-	-	-	-	-	-
5000	5	-	2	-	2	1	-	-	-	-	-	-	-	-	-	-	-	-	-
Females
1000	0	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-
3000	4	-	-	-	-	4	-	-	-	-	-	-	-	-	-	-	-	-	-
5000	5	1	1	-	2	1	-	-	-	-	-	-	-	-	-	-	-	-	-

Detailed description of necropsy :

1000 mg/kg (killed at termination)

males , No. 1 - 5 :

No pathologic changes

females , No. 26 - 30 :

No pathologic changes

3000 mg/kg

male , No. 11 - 13 : dead day 2

Liver : mottled , dark red

Lung : mottled , dark-red

Stomach : suspecious of corrosion , severe

females No. 36, 38 -40 :

Liver : mottled , dark-red (No. 36, 38 -40)

Kidneys : mottled , dark-red (No. 39)

Lung : mottled , dark-red (No. 38, 40)

Stomach : suspecious of corrosion , slight

male No. 14 : killed at termination , No pathologic changes

male No. 15 : killed at termination , Lung : mottled

female No. 37 : killed at termination , No pathologic changes

5000 mg/kg (dead day 1)

males No. 6 -10 :

Stomach : suspecious of corrosion

Duodenum : severe ; contents reddish

females No. 31 -35 :

Stomach : suspecious of corrosion

Duodenum : severe ; contents reddish

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 OECD TG401 without deviations and therefore considered to be of the highest quality (reliability Klimisch 1). The validity criteria of the test system are fulfilled. The test material did induce mortality and treatment-related clinical signs in the dose group of 5000 mg/kg bw (100 % mortality) and in dose group 3000 mg/kg bw (70 % mortality). In the dose group 1000 mg/kg bw treatment-related clinical signs were observed too (0% mortality). The LD50 was identified to be 2355 mg/kg bw for rats of both sexes with a 95% confidence interval of 1660 – 3093 mg/kg bw.

Executive summary:

The acute oral toxicity of the test material was investigated in rats of both sexes. The test was conducted according to OECD TG401. As doses 1000, 3000 and 5000 mg/kg bw of the test substance were administered via gavage to the rats. Observations were made for a period of 14 days.

The following symptoms were observed :

- 1000 mg/kg bw : crying, restlessness, dyspnea, curved body position, ruffled fur, hyperaemia

- 3000 mg/kg bw : sedation, dyspnea, curved body position, ruffled fur

- 5000 mg/kg bw : aggressive, restlessness, sedation, dyspnea, ventral- and curved body position, spasms, ruffled fur

The above symptoms increased in intensity with higher dose levels.

All animals in the highest dose group died within 24 hours. In the 3000 mg/kg bw dose group 7 animals died within 24 hours. No animals died in the lowest dose group. The gross pathology performed after sacrifice reveals the following findings :

1000 mg/kg (killed at termination)

males , No. 1 - 5 :

No pathologic changes

females , No. 26 - 30 :

No pathologic changes

3000 mg/kg

male , No. 11 - 13 : dead day 2

Liver : mottled , dark red

Lung : mottled , dark-red

Stomach : suspecious of corrosion , severe

females No. 36, 38 -40 :

Liver : mottled , dark-red (No. 36, 38 -40)

Kidneys : mottled , dark-red (No. 39)

Lung : mottled , dark-red (No. 38, 40)

Stomach : suspecious of corrosion , slight

male No. 14 : killed at termination, No pathologic changes

male No. 15 : killed at termination, Lung : mottled

female No. 37 : killed at termination, No pathologic changes

5000 mg/kg (dead day 1)

males No. 6 -10 :

Stomach : suspecious of corrosion

Duodenum : severe ; contents reddish

females No. 31 -35 :

Stomach : suspecious of corrosion

Duodenum : severe ; contents reddish

 

An oral LD50 was identified to be 2355 mg/kg bw for rats of both sexes with a 95% confidence interval of 1660 – 3093 mg/kg bw.

LD50 (males) : 2442 mg/kg bw with a 95% Confidence interval of 1319 - 4069 mg/kg bw

LD50 (females) : 2167 mg/kg bw with a 95% Confidence interval of 1091 - 3360 mg/kg bw