Registration Dossier

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Some information in this page has been claimed confidential.

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2006
Report Date:
2006

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
2 out of 6 analytical investigation of the dosage formulations were conducted under non-GLP conditions
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Deviations:
yes
Remarks:
2 out of 6 analytical investigation of the dosage formulations were conducted under non-GLP conditions
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female

Administration / exposure

Route of administration:
oral: feed

Results and discussion

Results of examinations

Details on results:
ANALYSIS OF TEST SUBSTANCE IN VEHICLE
Homogeneity and stability of the test compound in the diet were checked prior to study start. These analytical investigation showed the test compound to be homogeneously distributed and stable in the concentration range used beyond the period of use. Analyses during the study verified that the test compound content agreed with the target concentrations and that the test compound was homogeneously distributed in the diet within the defined limits (Table 1)

CLINICAL SIGNS AND MORTALITY
- Loss of hair was observed in control animals (1 male, 3 females). Tilted head was observed in 2 males and 2 females of the 1400 ppm group and in 2 males of the 14000 ppm group. No other clinical signs were observed in any animal.
- Survival was not affected by the treatment with the test compound since all animals survived until scheduled day of sacrifiec

BODY WEIGHT AND WEIGHT GAIN
Body weight development was unaffected in all treated animals (Table 2). The slightly lower body weight in 1400 ppm and 14000 ppm females compared to control is not considered to be adverse (at the end of treatment: 4%, 6%) as there was no dose dependency. A transient body weight reduction from day 29 to 36 and from day 85 to 92, could be observed in all groups (females: delayed body weight gain) and was likely caused by blood and urine sampling, respectively.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
- Food intake per animal and per kg body weight of all treated animals was comparable to the respective controls (Table 3).
- The mean daily test compound intake with the food over 13 weeks, in order of ascending dosages, was 94.0, 276.1, 974.2 mg/kg body weight in males and 135.1, 391.2 and 1480.4 mg/kg body weight in females. The test compound intake was comparable to the theoretical dose interval (Table 3).

WATER CONSUMPTION
Water intake per animal and per kg body weight of all treated animals was unaffected compared to controls (Table 4).

OPHTHALMOSCOPIC EXAMINATION
At study start no ophthalmological findings were seen. The examinations at termination gave no evidence for treatment-related effects. Isolated findings (reduced pupillary reflex, opacity changes of the lens) in all dose groups were regarded as spontaneous and gave no indication of a treatment effect.

HAEMATOLOGY
Hematological investigation revealed no treatment-related changes of parameters of white and red blood count as well as blood coagulation (Table 5 and 6).
The decreased mean erythrocyte count in males (day 92) at 1400 ppm, decreased hematocrit and increased mean corpuscular hemoglobin concentration in males at 1400 and 4200 ppm (day 92) as well as decreased thrombocyte count in males at 14000 ppm on day 36 and 92 (on day 92 also at 4200 ppm), which were statistically significantly different from control values are considered to be of no toxicological relevance, since they did not show a correlation with the dose administered and / or with the time of treatment and the differences from control were low.
In one female (14000 ppm) several parameters of the white blood counts were increased on day 91: leucocytes, neutrophils, lymphocytes, monocytes, eosinophils, and basophils (values out of the 2s range of historical data). The histopathology evidenced an early tumor of the hematopoietic system in this animal. This animal was excluded with regard to the evaluation of these haematological parameters. However, even before excluding, no statistically significantly changes were observed in mean differential blood count

CLINICAL CHEMISTRY
Determination of enzyme activities in peripheral blood showed no toxicologically relevant changes of enzyme activities compared to control values (Tables 7 - 9). Statistically significantly higher activities of glutamate dehydrogenase (GLDH) in males at 1400 ppm were considered as incidental, since no dose response was evident.
Increased cholesterol concentrations were measured in males at 1400 ppm, total protein and albumin concentrations in males at 4200 ppm and creatinine concentrations in females at 14000 ppm (all findings on day 35/36; p<=0.05). Furthermore, reduced cholesterol concentrations (day 35 and 91) and triglyceride concentration (day 35) were seen in 14000 ppm females (each p>0.05). These findings are considered to be of no toxicological relevance since the differences from control were low and/or they did not show a correlation with the dose administered and/or with the time of treatment. The concentration of urea was increased in 4 of 10 females at 14000 ppm on day 91. However, these values were not statistically significant, but exceeded the range of historical data.
Sodium was decreased in 1400 ppm males and above (day 36; 14000 ppm: p>0.05) and increased in 4200 ppm males (day 92), calcium was decreased in 1400 ppm males and above (day 36), inorganic phosphate was increased in 4200 ppm males (day 92), and chloride was increased in 14000 ppm females (day 35; all p<=0.05). These findings are considered to be of no toxicological relevance, since the differences from controls were low and/or did not show a correlation with the dose administered and/or with the time of treatment.

URINALYSIS
Urine volumes and densities as well as excreted amounts of urea and creatinine were comparable in treated animals and controls (Table 10).Excretion of protein and protein/creatinine ratio were increased in females at 4200 ppm (p>0.05). This increase was however due to the values of only one animal of this group. E ven before excluding this animal, no statistically significantly changes were observed for these parameters. Therefore, for these (not dose-dependent) isolated higher parameters are considered toxicologically not relevant.
The semi-quantitatively determined blood, bilirubin, glucose, urobilinogen, and ketone body concentrations and also the pH values were unremarkable in all groups. The sediments showed no abnormalities in males or females


NEUROBEHAVIOUR
- FOB: alopecia was observed in control animals (1 male, 4 females). Furthermore, single animals showed tilted head, but without dose dependency (0, 1400, 4200, 14000 ppm): 0-2-1-1 in males, 0-0-1-0 in females (Table 11). The number of rearing counts was slightly higher compared to controls in 4200 ppm females and 14000 ppm male and female rats.
- Motor Activity Assessment: The activity determination over the entire 60 minute observation period failed to reveal a significant effect on motor (MA) and locomotor activity (LMA). The results of the 10-minute intervals indicate that treated and control groups reacted in a similar way. In particular, there were no significant differences in the first 10-minute intervals which are regarded as best indicator of increases or decreases in activity before the animals habituate to a minimal level of activity (Table 11).

BIOCHEMICAL LIVER PARAMETERS
The investigation in liver tissue showed slightly increased activities of p-Nitroanisole-O-Demethylase in males at 1400 ppm and above (p<= 0.01; Table 12). Because a clear dose response was missing and all individual data of dosed animals were within the range of historical data and furthermore, in 1 of the 10 control animals the individual value was below this range, these findings were considered to be incidental and rather related to low control values. The slightly decreased activity of aminopyrine-N-Demethylase (N-DEM) in males at 1400 ppm (p<=0.05) was considered to be of no toxicological relevance since dose correlation was absent.

IMMUNOTOXICITY
- Cell count: The immunotoxicological examinations of the main group animals at the end of the study period revealed no evidence of treatment-related effects (Table 13). Regarding splenic cell counts there were no compound induced effects in both sexes up to 14000 ppm.
- FACS scan analysis: statistically significant decreases of total CD4 cells starting at 4200 ppm and CD45 positive cells at the lower doses 1400 and 4200 ppm were found in males. While CD45 low positive cells were slightly increased at 4200 ppm and above, CD45 high cells were statistically significant reduced in all test item treated groups. These statistically significant changes in males were within the normal range of variance for these parameter, and are thus of no biological relevance. In females only one single statistically significant increase was detected for CD45 low positive cells at
14000 ppm. This increase is within the range of normal variance of this parameter, and is thus of no biological relevance.
- Antibody titer: There was a statistically significant decrease for the antibody titer of IgA in males at 4200 ppm and above (Table 14). These changes were not dose dependent, not corroborated in the other gender (female), and within the range of normal variance for this parameter. Therefore, this change should not be judged as an adverse effect. The females showed no statistically significant changes in any titer of total Ig.
- Plaque forming cell assay: the immunotoxicological examinations of the Plaque Forming Cell Assay revealed no evidence of treatment-related effects although male rats showed a statistically significant decrease of the splenic cell counts at 4200 ppm (Table 15). This has to be seen as an isolated finding which is not corroborated by a finding in the other gender or after a 90 day treatment period. Furthermore, this decrease was within the normal range of variance for this parameter. Regarding splenic cell counts female rats showed no substance induced effects up to and including 14000 ppm.


ORGAN WEIGHTS
The determination of the weights of the organs gave no evidence for treatment-related effects (Table 16).

GROSS PATHOLOGY
Necropsy revealed no evidence of any treatment related gross lesion.

HISTOPATHOLOGY: NON-NEOPLASTIC
The histopathological evaluation revealed no treatment-related findings. All observations occurred at a comparable frequency and severity grade among control and dosed animals.

HISTOPATHOLOGY: NEOPLASTIC
An early tumor of the hematopoietic system (granulocytic leukemia) in one high dose female was found which showed increased numbers of leucocytes. Since none of the clinical chemical or hematological parameters in the remaining animals gave any indication for a compound-related effect, the occurrence of this tumor is considered as an incidental event. No other neoplastic findings were noted.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
>= 14 000 ppm
Sex:
male/female
Basis for effect level:
other: Overall effects: no adverse treatment-related effects were noted. Original nominal value according to the test substance lanthanumcarbonate-octahydrate.
Dose descriptor:
NOAEL
Effect level:
>= 974 mg/kg bw/day (actual dose received)
Sex:
male
Basis for effect level:
other: Overall effects: no adverse treatment-related effects were noted. Original value (mean daily intake) according to the test substance lanthanumcarbonate-octahydrate.
Dose descriptor:
NOAEL
Effect level:
>= 1 480 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: Overall effects: no adverse treatment-related effects were noted. Original value (mean daily intake) according to the test substance lanthanumcarbonate-octahydrate.
Dose descriptor:
NOAEL
Effect level:
>= 6 440 ppm
Based on:
element
Sex:
male/female
Basis for effect level:
other: Overall effects: no adverse treatment-related effects were noted. Recalculated value for La
Dose descriptor:
NOAEL
Effect level:
>= 448 mg/kg bw/day (actual dose received)
Based on:
element
Sex:
male
Basis for effect level:
other: Overall effects: no adverse treatment-related effects were noted. Recalculated value for La
Dose descriptor:
NOAEL
Effect level:
>= 681
Based on:
element
Sex:
female
Basis for effect level:
other: Overall effects: no adverse treatment-related effects were noted. Recalculated value for La
Dose descriptor:
NOAEL
Effect level:
>= 7 553 ppm
Based on:
other: La2O3
Sex:
male/female
Basis for effect level:
other: Overall effects: no adverse treatment-related effects were noted. Recalculated value for La2O3
Dose descriptor:
NOAEL
Effect level:
>= 525 mg/kg bw/day (actual dose received)
Based on:
other: La2O3
Sex:
male
Basis for effect level:
other: Overall effects: no adverse treatment-related effects were noted. Recalculated value for La2O3
Dose descriptor:
NOAEL
Effect level:
>= 799 mg/kg bw/day (actual dose received)
Based on:
other: La2O3
Sex:
female
Basis for effect level:
other: Overall effects: no adverse treatment-related effects were noted. Recalculated value for La2O3

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

For result tables 1 - 16 see attached document.

Applicant's summary and conclusion