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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
July 5, 1988 - January 16, 1990
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Not completely according to the current version of OECD 407. Although no Functional observational battery (FOB) observations, all other parameters are included. The test material was not administered daily, but 5 times per week (Monday-Friday). Not GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report Date:
1990

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Test material form:
other: Aqueous solution

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS (SPF quality)
- Source: Charles River wiga, Sulzfeld
- Age at study initiation: 4 weeks
- Weight at study initiation: 68 - 90 g (male) and 64 - 86 g (female)
- Fasting period before study: Not applicable
- Housing: 2 - 3 rats per Makrolon cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 10 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23 degrees Celsius
- Humidity (%): 51 - 64%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 hrs dark/12 hrs light

IN-LIFE DATES: no data

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
The animals were all dosed with 10 ml/kg bw. Depending on the dose, the concentration of the testmaterial in the dose was either 0, 2.5, 5 or 10%.
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
Not applicable
Duration of treatment / exposure:
28 days
Frequency of treatment:
5 times per week (Monday-Friday)
Doses / concentrationsopen allclose all
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- 100 rats (50 male and 50 female) were used in total.
- 80 rats for the main groups (control and the 3 doses) and 20 rats for the satellite groups
- Post-exposure recovery period in satellite groups: 14 days
- Satellite groups:
1) 0 mg/kg bw/day: 5 male and 5 female rats
2) 1000 mg/kg bw/day: 5 male and 5 female rats
Positive control:
Not applicable

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes, 2 times daily
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes, weekly
HAEMATOLOGY: Yes, at the end of the test period, for main groups only, see below for the examined parameters.
CLINICAL CHEMISTRY: Yes, at the end of the test period, for main groups only, see below for the examined parameters
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, at the end of the test period, for both the 4 main and 2 satellite groups.
HISTOPATHOLOGY: Yes, at the end of the test period, for the entire control group and for the entire group with the highest dose received.
Other examinations:
Food consumption: weekly/group
Water consumption: weekly/group
Opthalmoscopy: at the end of the test period, for the entire control group and for the entire group with the highest dose received.
Statistics:
- t-Test for determination of significant inter-group difference, for body weight and biochemical examinations: L. Sachs, Statistische Auswertungsmethoden, 3. Auflage, S. 11, 212, Springer-Verlag, Berlin, 1971
- t-Test for determination of significant inter-group difference, for biochemical and hematological examinations:
1) C.W. Dunnett, 1955: A Multiple Comparison Procedure for comparing several treatments with a control, Journal of the American Statistical Association, Dec. 1955, Vol. 372, 1096-1121
2) C.W. Dunnett, 1964: New tables for multiple comparisons with a control, Biometrics, 1964, 482-490
- U-test for the determination of significant inter-group difference, for organ weights: L. Sachs, Statistische Auswertungsmethoden, 3. Auflage, S. 172, 230-236, Springer-Verlag, Berlin, 1971

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food efficiency:
not specified
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY: No substance-related observations compared to controls
BODY WEIGHT AND WEIGHT GAIN: No significant substance-related effects compared to controls
FOOD CONSUMPTION: No significant substance-related effects compared to controls
WATER CONSUMPTION: No significant substance-related effects compared to controls
OPHTHALMOSCOPIC EXAMINATION: No significant substance-related effects compared to controls

HAEMATOLOGY: Statistically significant observations:

Females given 250, 500 and 1000 mg/kg bw/day showed a significant increase of thrombocytes of 114, 115 and 116%, respectively. These changes are not considered toxicological relevant, since values were within normal ranges and because of the absence of further changes in haematology. Changes were probably due to incidental low control values.

CLINICAL CHEMISTRY: Statistically significant observations:

Male rats given 250, 500 or 1000 mg/kg bw/day showed a significant decrease in GGT (26, 28 and 17% of controls, respectively).
This finding is not considered toxicological relevant, since it was accompanied by other changes in clinical biochemistry in males (e.g. AP, Bili.) and since a decrease was measured, instead of a more toxicological relevant increase.

Female rats given 500 or 1000 mg/kg bw/day showed a significant decrease in GOT of 85% and 78% of controls, respectively. Since a decrease was measured, this finding is considered not toxicological relevant; further more, since no histopathological changes in liver were observed.

URINALYSIS: Not examined
NEUROBEHAVIOUR: Not examined

ORGAN WEIGHTS: Statistically significant observations:

In females, at 250, 500 and 1000 mg/kg bw/day, a significant increase in absolute liver weight was noted (110, 121 and 121% of controls, respectively). Relative liver weights were also significant increased in all dose groups (104, 109 and 112% of controls, respectively). Although no histopathological changes were noted in liver, an increase in liverweight of >10% in absence of further changes in a sub-acute toxicity study, should be considered toxicological relevant (Reference: TNO report V2524, 2000).

GROSS PATHOLOGY: No significant substance-related observations
HISTOPATHOLOGY: NON-NEOPLASTIC: No significant substance-related observations
HISTORICAL CONTROL DATA (if applicable): No data

Effect levels

open allclose all
Key result
Dose descriptor:
LOAEL
Effect level:
500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
organ weights and organ / body weight ratios
Key result
Dose descriptor:
LOAEL
Effect level:
185 mg/kg bw/day (actual dose received)
Based on:
other: solid content of test material
Sex:
female
Basis for effect level:
other: The solid content of the testmaterial is 37%. The LOAEL based on the testmaterial is 500 mg/kg bw/day. Calculation: 500 x 0.37 = 185 mg/kg bw/day (LOAEL based on the solid content of the substance)
Key result
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
organ weights and organ / body weight ratios
Key result
Dose descriptor:
NOAEL
Effect level:
92.5 mg/kg bw/day (actual dose received)
Based on:
other: solid content of test material
Sex:
female
Basis for effect level:
other: The solid content of the testmaterial is 37%. The NOAEL based on the testmaterial is 250 mg/kg bw/day. Calculation: 250 x 0.37 = 92.5 mg/kg bw/day (NOAEL based on the solid content of the substance)

Target system / organ toxicity

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
500 mg/kg bw/day (actual dose received)
System:
hepatobiliary
Organ:
liver
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified

Applicant's summary and conclusion

Conclusions:
A 28 days repeated dose oral toxicity study was conducted with Dehyton G (an aqueous solution of Amphoacetates (C8-C18) similar to OECD 407. Based on a dose-dependent effect on liver weight in females the NOAEL for the testmaterial was determined to 250 mg/kg bw/day, resulting in a NOAEL for the substance of 92.5 mg/kg bw/day.
Executive summary:

A 28 days repeated dose oral toxicity study was conducted with an aqueous solution of a related member of the chemical category (Amphoacetates C8-C18) similar to OECD 407. The aqueous solution was administered 5 times per week (Monday-Friday) in doses of 0, 250, 500 and 1000 mg/kg bw. In females, at 250, 500 and 1000 mg/kg bw/day, a significant increase in absolute liver weight was noted (110, 121 and 121% of controls, respectively). Relative liver weights were also significant increased in all dose groups (104, 109 and 112% of controls, respectively). Although no histopathological changes were noted in liver, the NOAEL was established to be 250 mg/kg bw/day based on a dose-dependent effect on liver weight, resulting in a NOAEL for the substance of 92.5 mg/kg bw/day.