1,2,3,6-tetrahydrophthalimide

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1991

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Standard test method used (OECD test guidelne) GLP statement

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1991

Report date:

1991

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

1,2,3,6-tetrahydrophthalimide

EC Number:

201-602-8

EC Name:

1,2,3,6-tetrahydrophthalimide

Cas Number:

85-40-5

Molecular formula:

C8H9NO2

IUPAC Name:

2,3,3a,4,7,7a-hexahydro-1H-isoindole-1,3-dione

Details on test material:

- Name of test material (as cited in study report): P2008
- Analytical purity: 97.70%
- Impurities (identity and concentrations): Tetrahydrophthalic anhydride D3 - 0.02%; Tetrahydrophthalic anhydride D4 - 0.05%;
Tetrahydrophthalimide D3 - 1.48%; Tetrahydrophthalimide D4 isomer - 0.75%
- Lot/batch No.: 1801

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Limited, Manston, Kent, England
- Age at study initiation: 6-9 weeks
- Weight at study initiation:
- Fasting period before study: Overnight
- Housing: 5/sex/cage
- Diet (e.g. ad libitum): Conventional laboratory diet (Rat and Mouse No. 1 expanded; Special Diet Services Limited) fed ad libitum except for overnight fast before dosing and approximately 2 hours following dosing
- Water (e.g. ad libitum): Municipal mains water available ad libitum
- Acclimation period: Minimum of 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24
- Humidity (%): 34-84
- Air changes (per hr): Approximately 15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 1991-01-15 To: 1991-02-28

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

arachis oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 500 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg


MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

Doses:

5000 mg/kg

No. of animals per sex per dose:

5 males / 5 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations 30 minutes, 1, 2 and 4 hours after dosing then daily for 14 days. Body weights recorded on day of dosing (Day 0) and at weekly intervals during post-dose observation period (Days 7 and 14)
- Necropsy of survivors performed: yes

Statistics:

None

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

approximate LD50

Effect level:

> 5 000 mg/kg bw

Mortality:

One of 5 males and 1 of 5 females died within 24 hours of dosing (See Table 1 for details)

Clinical signs:

other: Lethargy, hunched posure, ataxia, ptosis, laboured respiration and loss of righting reflex noted following dosing. Surviving animals had generally recovered within 24 hours of dosing (See Table 1 for details)

Gross pathology:

No abnormal findings in surviving animals
Animals that died showed changes to the lungs, liver and kidneys that were possibly agonal in nature.
Haemorrhaging noted in regions of the stomach, small and large intestines noted (See Table 2 for details)

Any other information on results incl. tables

Table 1: Clinical findings / mortality
Dose		Animal	Clinical signs / Mortality
level	Sex	number	Hours					Days
(mg/kg)			0.5	1	2	4		1	2-14
		5-0	0	0	HLPtA	HLPtRlA		X	-
		5-1	0	0	L	L		0	0
	Male	5-2	0	0	L	L		0	0
		5-3	0	0	L	L		0	0
		5-4	0	0	L	L		0	0
5000
		6-0	0	0	LPt	HLPt		H	0
		6-1	0	0	HL	HLPt		0	0
	Female	6-2	0	0	L	0		0	0
		6-3	0	0	0	0		0	0
		6-4	LA	LPtRr	X	-		-	-
Key:	0 : No signs of toxicity
	H : Hunched posture
	L : Lethargy
	A : Ataxia
	Pt : Ptosis
	Rl : Laboured respiration
	Rr : Loss of righting reflex
	X : Animal dead

Table 2: Necropsy findings
Dose level	Sex	Animal	Day of death	Macroscopic observations at necropsy
(mg/kg)	_	_	_	_
		5-0	Died Day 1	Lungs: haemorrhagic
				Liver: dark
				Kidneys: dark
				Stomach: epithelial sloughing from glandular and non-glandular regions
				Small intestine: haemorrhagic
				Large intestine: haemorrhagic
		5-1	Terminal kill	No abnormalities noted
	Male	5-2	Terminal kill	No abnormalities noted
		5-3	Terminal kill	No abnormalities noted
		5-4	Terminal kill	No abnormalities noted
5000
		6-0	Terminal kill	No abnormalities noted
		6-1	Terminal kill	No abnormalities noted
	Female	6-2	Terminal kill	No abnormalities noted
		6-3	Terminal kill	No abnormalities noted
		6-4	Died Day 0	Lungs: abnormally red
				Liver: dark
				Stomach: glandular region haemorrhagic
				Small intestine: haemorrhagic

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU