Registration Dossier

Toxicological information

Toxicity to reproduction

Currently viewing:

Administrative data

toxicity to reproduction
other: combined chronic toxicity carinogenicity study with gross pathology and histopathology of gonades etc.
Type of information:
experimental study
Adequacy of study:
key study
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: combined chronic toxicity and carcinogenicity study with gross pathology and histopathology data from ovaries/testes and prostate/uterus of control and treated animals (highest dose group)
Reason / purpose:
reference to same study

Data source

Reference Type:
study report

Materials and methods

Principles of method if other than guideline:
other: combined chronic toxicity and carcinogenicity study with gross pathology and histopathology data from ovaries/testes and prostate/uterus of control and treated animals (highest dose group)
GLP compliance:
Limit test:

Test material

Details on test material:
Santocure MOR, Lot no. 790114/LLN/AS, 810323/LLN/AS, 810323/LLN/AS, purity: 97 %

Test animals


Administration / exposure

Route of administration:
oral: feed
other: MBS contained in the diet
Details on mating procedure:
no data
Analytical verification of doses or concentrations:
Duration of treatment / exposure:
113 weeks (satellite group 53 weeks)
Frequency of treatment:
Details on study schedule:
other: chronic toxicity study
Doses / concentrations
Doses / Concentrations:
0, 5, 50, 400 mg/kg bw/d

No. of animals per sex per dose:
50 per dose and sex (satellite group 10 per dose and sex)
Control animals:
yes, plain diet

Results and discussion

Results: P0 (first parental animals)

Effect levels (P0)

Dose descriptor:
Effect level:
400 mg/kg bw/day
Basis for effect level:
other: No adverse effects on reproductive organs

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Dietary analysis:

Homogeneity ± 7 % was regared as acceptable, investigation of formulation stability under laboratory conditions showed a small but acceptable decrease in concentration over a 28 day period.

Analysis of the formulations before the feeding phase showed satisfactory homogeneity and stability under suitable conditions of use. anaylsis of formulations during the feeding phase showed a satisfactory agreement between the nominal and actual concentrations of Santocure MOR.

General observations and mortality:

The physical condition of the treated rats did not differ from controls. Changes which were seen were those commonly seen in ageing CD rats. In the period between weeks 58 and 85 the male medium and high dose groups experienced a greater mortality rate than did the control group. There was also strong evidence of a trend with dose (p<0.01). Significant excess mortality was seen in the mid and high dose group (p<0.01). The differences then declined and at termination there was no effidence of a treatmant-related trend in mortality. In the latter part of the study the female medium and high dose group mortality rate was lower than that of the control group.

Body weight gain

High dose group males gained less weight than controls from the very early part of the study so that at termination there was a difference between the groups of about 22 %. A simular less pronounced trend was seen in the male medium dose group, a difference from the control group of about 7 % being seen at termination. This trend was also seen in treated females. At termination high dose group females weighed about 28 % less than controls and medium dose group about 10 % less. There was also a small differences (about 5 %) between low dose females and controls, but this did not begin to develop until week 65.

Male and females rats given the high and medium doses gained less weight than controls throughout study.

(Study termination body weights conpared to control, males: 100 %, 98 %, 93% and 78 at 0, 5, 50, 400 mg/kg bw/d; females: 100 %, 95%, 90 % and 72 % at 0, 5, 50 and 400 mg/kg bw/d)

Food consumption:

The reduced weight gain was associated with slight reductions in food consumption. High dose males ate slightly less than controls. This pattern was also evident in female of the mid and high dose groups. The differences were of the order of 5%. Low and mid dose group males and low dose females had similar food consumption patterns to the controls.

Test article intake:

The overall mean test article intakes, unadjusted for the formulation analysis, were in very good agreement with the nominal values. The analysis of diet bin residues suggested that the actual doses were slightly below the nominal concentrations, perhaps up to 10 % lower.

Gross pathology:

Palpable subcutaneous masses were identified in a proportion of the animals in all groups in the course of the study. The masses were of the type commonly seen in the CD rat and were most frequently seen in the axillae and mammary glands. The time to first mass was not affected by treatment. Male groups 3 (mid dose) and 4 (high dose) showed a statistically significant increase in palpable masses, whereas the corresponding female groups showed a reduced incidence. The microscopic pathology data did not indicate this to be an oncogenic response.


No changes were seen in haematological parameters to suggest an effect of treatment with the test article.

Clinical biochemistry:

Considerable variation within groups was seen in some parameters, notably some plasma enzyme activities and bilirubin concentrations. The male and female high dose animals did, however, trend to have lower plasma LDH activities than controls. No statistically significant differences were seen between control and test groups.

(No test substance-related biologically relevant effects on GOT values during the study)

Urine analysis

Male rats given high dose Santocure MOR tended to have more urinary reducing substances than controls. The differences were, however, small and did not appear to be due to glycosuria. Microscopic examination of urinary deposits showed no trends to suggest an effect of treatment.

Organ weights:

Interim kill (week 54)

The absolute kidney weight of group 4 (high dose) males was statistically significant greater than that of the control group. The relative (organ to body weight) weights of the livers and kidneys of group 4 males (high dose group), the relative kidney weight of group 3 females (mid dose group) and the relative heart weight of the group 4 females (high dose group) exceeded the control values to a statistically significant excent.

Terminal kill:

The relative brain,liver, heart, gonad (males only), adrenal (females only), kidney, spleen (females only) and lung weights of group 4 animals (high dose group) were greater than control values. The intergroup variation was, however, considerable, although in some instances the differences were statistically significant.

Slight changes were seen in the absolute and relative weights of certain organs at necropsy. The changes in the kidney and liver weights suggest a slight response to treatment. The changes in the weights of other organs are considered to be a secondary effect of treatment, refecting the interference with the normal growth pattern.

Gross and microscopic pathology

Interim kill:

No consistent pattern of changes was seen to suggest a response to treatment.

Terminal kill:

There was no differences in the total incidence of morbidity or mortality from all causes between control groups and highest dose group animals. In females most of the preterminal morbidity and mortality was associated with neoplasia, a less clear pattern being seen in males. The total incidence of neoplastic cause of demise in high dose group males was slightly higher than in controls; wheras the reverse occured in females. This was due mainly to losses due to mammary neoplasia in control group females.

A variety of non-neoplastic conditions was found in both sexes. These did not, however, appear to be influenced, in terms of incidence or severity, by treatment.

There was no apparent difference between control and high dose group in the incidence of tumor-bearing animals or in the incidence of animals with tumors of single or multiple organ sites.

Histopathology: Reproductive organs

Histopathology from all control animals and all animals from the highest dose group (400 mg/kg bw and day) was performed. The reproductive organs (ovaries, testes, prostate, and uterus) were evaluated. No adverse effects of the test substance MBS on these organs was indicated in treated animals (400 mg/kg bw and day). However, a significant increase in relative gonad weights (146 %, p< 0.01) was indicatives for males of the highest dose group, but this change was considered to be a secondary effect.

Therefore, for MBS the NOAEL (400 mg/kg bw and day) from the chronic toxicity study (Monsanto Co. 1982) could be used for DNEL derivation.

Applicant's summary and conclusion