2,2,4,4-tetramethyl-7-oxa-3,20-diazadispiro[5.1.11.2]henicosan-21-one hydrochloride

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2008-06-04 till 2008-06-27

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: guideline-conform study under GLP without deviations

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2008

Report date:

2008

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:

2,2,4,4-tetramethyl-7-oxa-3,20-diazadispiro[5.1.11.2]henicosan-21-one hydrochloride

EC Number:

277-620-5

EC Name:

2,2,4,4-tetramethyl-7-oxa-3,20-diazadispiro[5.1.11.2]henicosan-21-one hydrochloride

Cas Number:

73833-37-1

Molecular formula:

C22H40N2O2.xClH

IUPAC Name:

2,2,4,4-tetramethyl-7-oxa-3,20-diazadispiro[5.1.11.2]henicosan-21-one hydrochloride

Details on test material:

- Name of test material (as cited in study report): 2,2,4,4-tetramethyl-7-oxa-3,20-diazadispiro[5.1.11.2]henicosan-21-one hydrochloride
- Physical state: solid, white
- Analytical purity: => 99%
- Lot/batch No.: DEF2036584
- Expiration date of the lot/batch: 2018-05-08
- Stability under test conditions: stable
- Storage condition of test material: At room temperature (range of 20 ± 5 °C), light protected.

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: RCC Ltd
- Age at study initiation: 11 weeks
- Weight at study initiation: 172.8 g to 193.8 g
- Fasting period before study: fasted for approximately 17 to 18 hours (access to water was permitted). Food was provided again approximately 3
hours after dosing.
- Housing: In groups of three in Makrolon type-4 cages with wire mesh tops and standard softwood bedding
- Diet (e.g. ad libitum): Pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, at libidum
- Water (e.g. ad libitum): Community tap water from Füllinsdorf ad libitum.
- Acclimation period:
04-JUN-2008 to 10-JUN-2008 (females, 2000 mg/kg)
06-JUN-2008 to 12-JUN-2008 (females, 2000 mg/kg)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 30-70 %
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 0.2 g substance/mL vehicle
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: PEG 300 was found to be a suitable vehicle.
- Lot/batch no. (if required): 1310049


MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw


DOSAGE PREPARATION (if unusual): prior to dosing


CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: no justification (no datat available)

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

3 females at 2000 mg/kg bw
3 females at 2000 mg/kg bw

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality / Viability: Daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after
administration on test day 1 and twice daily during days 2-15.
Body Weights On test days 1, 8 and 15.
Clinical Signs: Daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on
test day 1. Once daily during days 2-15.

- Necropsy of survivors performed: yes

Statistics:

No statistical analysis was used.

Results and discussion

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

No deaths occurred during the study.

Clinical signs:

other: On test day 6, the three females of the first group were found with delayed clinical signs, such as slight sedation which persisted up to test day 14. A slighty ruffled fur was noted in the three females 6 or 7 days post treatment and persisted up to tes

Gross pathology:

One female was found with an enlarged uterus with gray-white contents and another female was found with a light-brown discolorated liver at
necropsy. Otherwise, no macroscopic findings were recorded at necropsy.

Other findings:

Histopathology: A minimal focal acute inflammation was recorded in the submucosa of the glandular stomach of one female of group 2. Based on its severity and distribution and on the absence of any other degenerative changes, this lesion was considered to be most likely incidental.

Any other information on results incl. tables

Table 1: Animal assignment

Dose (mg/kg bw)	Males	Females	Combined
2000	-	3	-
2000	-	3	-

Table 2: Number of animals dead [and with evident toxicity] [and time range within which mortality occurred]

 

Dose (mg/kg bw)	Mortality (# dead/total)			Time range of deaths (hours)	Number with evident toxicity (#/total)
	Male	Female	Combined		Male	Female	Combined
2000	-	0	-	-	-	0	-
2000	-	0	-	-	-	0

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

67/548/EEC: no classification warranted
1272/2008/EC: no classification warranted

Executive summary:

The acute toxicity by oral application (gavage) was investigated according to OECD guideline 423 .

Two groups, each of three female HanRcc:WIST (SPF) rats, were treated with 2,2,4,4-tetramethyl-7-oxa-3,20-diazadispiro[5.1.11.2]henicosan-21-one hydrochloride by oral gavage administration at a dosage of 2000 mg/kg body weight. The test item was diluted in vehicle (PEG 300) at a concentration of 0.2 g/mL and administered at a dosing volume of 10 mL/kg.

All animals survived until the end of the study period. Some clinical signs were recorded in both groups.

One female was found with an enlarged uterus with gray-white contents and another female was found with a light-brown discolorated liver at necropsy. Otherwise, no macroscopic findings were recorded at necropsy.