Carbamic acid, N-[[5-[[[2-[2-(dimethylamino)ethoxy]ethoxy]carbonyl]amino]-1,3,3-trimethylcyclohexyl]methyl]-, 2-[2-(dimethylamino)ethoxy]ethyl ester

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Part of the SNIF file, which was accepted by the Belgian national authority for NONS.

Data source

Reference

Reference Type:

other company data

Title:

Unnamed

Year:

2002

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: EEC Directive 96/54, B.7

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

441-100-8

EC Name:

-

Cas Number:

351197-46-1

Molecular formula:

Hill formula: C24 H48 N4 O6 CAS formula: C24 H48 O6 N4

IUPAC Name:

2-[2-(dimethylamino)ethoxy]ethyl N-{[1,3,3-trimethyl-5-(9-methyl-2-oxo-3,6-dioxa-1,9-diazadecan-1-yl)cyclohexyl]methyl}carbamate

Test animals

Species:

rat

Strain:

other: Wistar (SPF)

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: bidistilled water

Details on oral exposure:

Method of administration:
gavage

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Test duration: 28 days

Frequency of treatment:

Dosing regime: 7 days/week

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 30, 150, 450 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

Male: 10 animals at 0 mg/kg bw/day
Male: 5 animals at 30 mg/kg bw/day
Male: 5 animals at 150 mg/kg bw/day
Male: 10 animals at 450 mg/kg bw/day
Female: 10 animals at 0 mg/kg bw/day
Female: 5 animals at 30 mg/kg bw/day
Female: 5 animals at 150 mg/kg bw/day
Female: 10 animals at 450 mg/kg bw/day

Control animals:

yes

Results and discussion

Results of examinations

Details on results:

Clinical observations:
MORTALITY / VIABILITY

One male treated with 450 mg/kg/day died at treatment day 23 and one male of the same dose group at day 26. Four females treated with 450 mg/kg/day died on treatment days 5, 10 and 19. The cause of the deaths was not evident at microscopic level. However, a relation to the treatment with the test item cannot be excluded. All other animals survived until scheduled necropsy.


CLINICAL SIGNS

No test item related clinical signs were evident in animals treated with 30 or 150 mg/kg/day. The following signs were observed in animals treated with 450 mg/kg/day. Slight piloerection was seen in two males and three females in treatment week three and in one female in treatment week four. This finidngs may be test item related. Slight ataxia was observed in two males and three females in treatment week three and in one female in treatment week two. Slight tremor was observed in two males and five females in treatment week three and in one female in treatment week two. It could not be excluded that these findings were test item related. Slight spasm was noted in two females in treatment week one. It could not be excluded that this was test item related. Slight sedation was noted in two males and seven females in treatment week three and one female in treatment week two. It could not be excluded that this was test item related. Slight dyspnea was noted in four females in treatment week one. Slight bradypnea was noted in one male in treatment week one. Breathing noise was evident in two males and in four females in treatment week three. It could not be excluded that these findings are due to test item treatment. No other clinical signs were evident in males or females (week 1-3).


FUNCTIONAL OBSERVATIONAL BATTERY

Grip Strength

No test item related changes in fore- or hind limb grip strength were evident in males or females when compared with controls.

Locomotor Activity

Significantly decreased (p<0.01) locomotor activity was observed in males treated with 450 mg/kg/day during the whole observation period of 60 minutes when compared with controls. In females of the same dose group this activity was significantly decreased in the first 30 minutes (p<0.01), and between 45 and 60 minutes (p<0.05) of observation. Between 30 and 45 minutes this decrease was not significant. Significantly decreased locomotor activity was also observed in males treated with 150 mg/kg/day in the first 30 minutes of observation (p<0.01), and between 45 and 60 minutes (p<0.05). Between 30 and 45 minutes this decrease was not significant. These differences in locomotor activity were considered to be test item related.

No further changes in locomotor activity were noted when compared with controls.


FOOD CONSUMPTION

No changes in mean daily or relative food consumption were observed in males or females after four or six weeks when compared with control animals.


BODY WEIGHT

Significantly decreased (p<0.05) mean body weight was noted in males treated with 450 mg/kg/day in treatment week four when compared with the controls. Significantly decreased (p<0.05) mean body weight gain was observed in males treated with 450 mg/kg/day in treatment weeks three and four when compared with the controls. Significantly (p<0.01) decreased mean body weight gain was noted in females treated with 450 mg/kg/day on days 22 (week four) and 28 (week four) and in females treated with 150 mg/kg/day on day 28 (week four). Significantly decreased (p<0.05) mean body weight gain was noted in females treated with 450 mg/kg/day within week two of the recovery period when compared with controls. These effects were considered to be test item related. No other significant changes were observed in males or females after four or six weeks.

Laboratory findings:
Hematology

Significantly decreased relative and absolute reticulocytes were noted in males treated with 450 mg/kg/day after four weeks when compared with controls. A dose response relationship could be observed within the absolute values. The decrease was also observed in females of this dose group but without statistical significance after four or six weeks when compared with controls. It can not be excluded that this effect is test item related. No other test item related changes in parameters of hematology were seen in test item treated animals after four or six weeks when compared with controls.


Clinical Biochemistry

Significantly increased activity of Aspartate aminotransferase was measured in males treated with 150 and 450 mg/kg/day after four and six weeks when compared with controls. This increase was also observed in females but was only significant at 450 mg/kg/day. Due to this and due to dose response relationship the increase was considered to be test item related.

The activity of Lactate dehydrogenase was significantly increased in males treated with 150 or 450 mg/kg/day after four weeks when compared with controls. This was considered to be test item related because it was also seen in males treated with 450 mg/kg/day after six weeks and in females treated with 450 mg/kg/day after four weeks when compared with controls.


Urinalysis

No test item related changes in parameters of urinalysis were evident in males or females after four or six weeks when compared with control animals

Effects in organs:
ORGAN WEIGHTS

No changes in mean organ weights, organ to body- or organ to brain weight ratios were noted in test item treated males after four weeks when compared with controls.

Significantly increased (p<0.01) mean liver to body weight ratios were noted in females treated with 150 or 450 mg/kg/day after four weeks when compared with controls. This was considered to be test item related because a dose response relationship was observed.

No test item related changes in mean organ weights, organ to body- or organ to brain weight ratios were noted in males and females treated with 450 mg/kg/day after six weeks when compared with controls.


MACROSCOPIC / MICROSCOPIC FINDINGS

A number of gross findings distinguished some treated decedents from rats at terminal sacrifice:

Lung, pancreas, mandibular lymph node, salivary glands:
Reddish to dark red discoloration in a few males of group 04 and dark red discoloration of lung in 1 female of group 04; Lung, stomach, thymus, ovaries: Dark red foci in a few males or females of group 04;

Intestinal tract: Distended with gas in 1 female of group 04

A number of findings were noted at the end of the treatment period. From these findings, the following ones distinguished decedent rats from rats at terminal sacrifice (K0):

Lung, adrenal glands, stomach, liver, kidneys, thymus, mesenteric and mandibular lymph nodes, ovaries, brain, pancreas, salivary glands:
A congestion was present in some males and/or females of group 04.

Lung, thymus:
A hemorrhage occurred each in 1 high-dose female.

Lung:
An alveolar edema was noted in 1 high-dose female.

All other findings noted in this study at the end of treatment (K0) were considered to be incidental findings commonly occurring in rats of this strain and age.

None of the microscopic findings present after an additional recovery period (R1) were considered to distinguish treated group 04 rats from the control rats.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

150 mg/kg bw/day (nominal)

Basis for effect level:

other: original NCD unit is mg/kg/day.

2

Dose descriptor:

NOEL

Effect level:

30 mg/kg bw/day (nominal)

Basis for effect level:

other: original NCD unit is mg/kg/day.

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Classified as: Not classified