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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Remarks:
combined repeated dose and carcinogenicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comprehensive 2 years feeding study conducted according to GLP
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report Date:
1992

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
not applicable
Remarks:
; althought no guideline was folled this is a comprehensive study conducted similar to actual guidleine
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Test substance: Flectol Pastilles; purity: 100% product

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
2 years
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
50, 250, 1000 ppm; approx. 2.3, 11.8 and 48 mg/kg bw (males); approx. 3.1, 15.3 and 63 mg/kg bw (females)
Basis:

No. of animals per sex per dose:
60/sex/dose
Control animals:
yes, concurrent no treatment
Details on study design:
Post-exposure period: no

Results and discussion

Effect levels

Dose descriptor:
NOAEL
Effect level:
ca. 11.8 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: target organs: liver and adrenals

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Analytical verification of stability of the test material, homogeneity and concentration of test material in the diet with satisfactory results.

Compared with their respective controls, survival at the end of the study was greater at the high level in both males (61 ves 40%) and females (59 vs 48%). These results are not indicative of toxicity.

Clinical signs: no compound related findings.

Body weight: significant lower weight was observed for high dose females from week 11 to week 77; no effect in males.

Food consumption: no consistent effect except a statistically significant decrease was observed during the first week of the study.

Ophthalmic examinations: no abnormalities

Clinical pathology:there were no abnormalities in urinanalysis parameters which were attributed to the test material.

Gross pathology: absolute liver weight were increased in high dose males and females; liver weight relative to brain weight was increased in mid dose females; there were no other organ weights attributed to administration of the test material.There were no gross necropsy alterations attributed to administration of the test material.

Microscopic pathology:

The following oservations were reported; statistically significant observations are indicated by an asterics(*)

:

Organ sex control low mid and high dose group

Adrenal

Cystic degen. cortex M 2/60 4/60 4/60 9/60*

Sinusoidalectasia/cyst M 0/60 3/60 3/60 6/60*

Hyperblasis medulla M 12/60 11/60 22/60* 19/60

Liver:

Bile duct prolif. cholangiofibros. M 31/60 33/60 30/60 43/60*

Fucus of celular alteration M 17/60 12/60 22/60 30/60*

Hepathocell. hypert.

centriiobular M 1/60 0/60 0/60 13/60*

F 0/60 0/59 0/59 11/60*

Hepathocell. vacuol. centriiobular F 1/60 3/59 2/59 16/60*

Sinus dilatation F 2/60 3/59 10/59* 17/60*

Thyroid:

Follicular Adenoma/

cystadenoma M 5/60 2/60 4/60 10/60 (not statistically significant)

F 1/60 3/58 0/60 9/59*

Follicular

hyperblasia M 1/60 2/60 2/60 5/60 (no statistics done)

Additional lesions observed were considered to occur spontaneously and, due to the lack of a dose response relationship and/or lack of consistency in the incidences across the various death categories in this study, were not considered related to administration of thetest material.

Cellular proliferation assay:

The mean positive hepathic nuclei/microscopic field was slightly, but statistically significantly, increased in the high dosefemales after 4 days of exposure. The toxicological significanc, if any, of this difference is not known. There were no significant differences in females at one or six months nor there were any differences in males at any time interval.

Applicant's summary and conclusion

Executive summary:

The following effects were considered to be test materia related: effects on body weight of females in the high dose group; histopathologic effects on adrenals in the high dose males; effects on liver weight and liver histopathology in the high dose males and in the mid and high dose females.

The increased incidence of thyroid follicular adenoma/cystadenomas in the high level males and females was considered to have resulted from compound administration, but may have resulted from compensatory mechanisms as a result of the hepathic changes; see discussion of this study in chapter 7.7 carcinogenicity.

The NOAEL for systemic toxicity was considered to be 250 ppm in males and 50 ppm in females.