Fenuron

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1989

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Data source

Reference

Reference Type:

publication

Title:

Hygienic significance of pathomorphologic changes of the organs in albino rats in studying the embryotoxic effect of Fenuron

Author:

Talakin Y.N. et al.

Year:

1989

Bibliographic source:

Gigiena i Sanitariya,1989, Issue 9, Sep 1989, p.73-5

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test: in accordance with a complex scheme developed by V.A. Gofmekler et al. described in “Methods of studying long-term effects of chemical air pollution: Experimental and in-situ study of embryotropic effects and influence on the female organism during pregnancy / Gofmekler, V.A., Krasovitskaya, M.M., Sheparev, A.A. et al. Methodological instructions. – Vladivostok, 1978.”
- Short description of test conditions:
4 groups of female albino rats with 15 animals / group were treated with the study preparation administered intragastrically in the doses of 1/5, 1/100, 1/200, and 1/400 LD50 from the 6th to the 15th day of pregnancy. A fith control group was only treated with starch.
- Parameters analysed / observed:
The organs of the pregnant rats and embryos were subject to histological examination.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Fenuron

EC Number:

202-941-4

EC Name:

Fenuron

Cas Number:

101-42-8

Molecular formula:

C9H12N2O

IUPAC Name:

fenuron

Test material form:

not specified

Test animals

Species:

rat

Strain:

other: albino

Sex:

female

Administration / exposure

Route of administration:

oral: gavage

Duration of treatment / exposure:

from the 6th to the 15th day of pregnancy

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

1 500 mg/kg bw/day (actual dose received)

Remarks:

1/5 LD50

Doses / concentrations 2

Dose / conc.:

75 mg/kg bw/day (actual dose received)

Remarks:

1/100 LD50

Doses / concentrations 3

Dose / conc.:

38 mg/kg bw/day (actual dose received)

Remarks:

1/200 LD50

Doses / concentrations 4

Dose / conc.:

20 mg/kg bw/day (actual dose received)

Remarks:

1/400 LD50

No. of animals per sex per dose:

15

Control animals:

yes, sham-exposed

Examinations

Postmortem examinations (parental animals):

The organs of the pregnant rats and embryos were subject to histological examination. The material was preserved in a 10% neutral formalin solution, and paraffin sections of the rat organs and transverse sections of the fetuses were stained with hematoxylin and eosin.
This article presents the results of the histological examination of the ovaries, placenta, brain, oesophagus, stomach, and heart of the pregnant rats which were treated with various doses of fenuron, administered intragastrically, with histotopograms of their fetuses provided as well.

Postmortem examinations (offspring):

The organs of the embryos were subject to histological examination. The material was preserved in a 10% neutral formalin solution, and paraffin transverse sections of the fetuses were stained with hematoxylin and eosin.
This article presents the results of the histological examination of the ovaries, placenta, brain, oesophagus, stomach, and heart of the pregnant rats which were treated with various doses of fenuron, administered intragastrically, with histotopograms of their fetuses provided as well.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

Food efficiency:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

The results of the histological examination of the organs of the rats that received 1/5 LD50 of fenuron (1500 mg/kg) (and of their fetuses) contained pathological changes.
The oesophagus and stomach walls, heart and brain of the rats had signs of hemodynamic abnormalities and dystrophic changes. The vessels of the brain tunics and brain substance were expanded and hyperemic; moderate perivascular edema was detected. The nerve cells of the cortex and the brainstem nuclei were in a swollen state. The mucous membrane of the stomach and oesophagus was edematous and hyperemic. The heart had cloudy swelling and uneven colouring of the myocardiocytes, sudden expansion and hyperemia of the epicardium and myocardium vessels. The cortical layer of the ovaries contained massive yellow bodies, primordial and growing follicles, and numerous atretic bodies. In the placenta, acute vascular hyperemia, single small perivascular hemorrhages, and chorion edema were observed. The layers of decidual cells penetrated deeply into the myometrium with edematous and hyperemic stroma.
With the dose of fenuron reduced to 75 mg/kg (1/100 LD50), the response of the pregnant females to the effect of the toxic agent decreased. The revealed hemodynamic abnormalities in the stomach and oesophagus walls, myocardium, and brain are significantly weaker than in the females that received the preparation in the dose of 1500 mg/kg
The effect of fenuron in the dose of 38 mg/kg (1/200 LD50) on the reproductive function of white female rats was characterized by an increase of the placental-fetal coefficient and changes in hemodynamics in the stomach, oesophagus walls, myocardium, and brain.
When the herbicide was administered in the dose of 20 mg/kg (1/400 LD50), no changes in the organs of the pregnant rats or their fetuses were detected.
Thus, in the examined organs of pregnant rats, circulatory disorders, manifested by vascular expansion and hyperemia, edemas, and sometimes small hemorrhages, prevailed.
The obtained results indicate the effect of fenuron on the blood flow and permeability of the vascular walls.

Histopathological findings: neoplastic:

not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not examined

Reproductive performance:

effects observed, treatment-related

Description (incidence and severity):

At the dose level of 1500 mg/kg bw, the cortical layer of the ovaries contained massive yellow bodies, primordial and growing follicles, and numerous atretic bodies. In the placenta, acute vascular hyperemia, single small perivascular hemorrhages, and chorion edema were observed. The layers of decidual cells penetrated deeply into the myometrium with edematous and hyperemic stroma.
With the dose of fenuron reduced to 75 mg/kg (1/100 LD50), the response of the pregnant females to the effect of the toxic agent decreased.
The effect of fenuron in the dose of 38 mg/kg (1/200 LD50) on the reproductive function of white female rats was characterized by an increase of the placental-fetal coefficient and changes in hemodynamics in the stomach, oesophagus walls, myocardium, and brain.
When dosed at 20 mg/kg (1/400 LD50), no changes in the organs of the pregnant rats or their fetuses were detected.

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

20 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

histopathology: non-neoplastic

Target system / organ toxicity (P0)

Critical effects observed:

yes

Lowest effective dose / conc.:

38 mg/kg bw/day (actual dose received)

System:

cardiovascular

Treatment related:

yes

Dose response relationship:

yes

Results: F1 generation

General toxicity (F1)

Clinical signs:

not specified

Mortality / viability:

not specified

Body weight and weight changes:

not specified

Food efficiency:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings:

effects observed, treatment-related

Description (incidence and severity):

The results of the histological examination of the organs of the rats that received 1/5 LD50 of fenuron (1500 mg/kg) (and of their fetuses) contained pathological changes.
The oesophagus and stomach walls, heart and brain of the rats had signs of hemodynamic abnormalities and dystrophic changes. The vessels of the brain tunics and brain substance were expanded and hyperemic; moderate perivascular edema was detected. The nerve cells of the cortex and the brainstem nuclei were in a swollen state. The mucous membrane of the stomach and oesophagus was edematous and hyperemic. The heart had cloudy swelling and uneven colouring of the myocardiocytes, sudden expansion and hyperemia of the epicardium and myocardium vessels. The cortical layer of the ovaries contained massive yellow bodies, primordial and growing follicles, and numerous atretic bodies. In the placenta, acute vascular hyperemia, single small perivascular hemorrhages, and chorion edema were observed. The layers of decidual cells penetrated deeply into the myometrium with edematous and hyperemic stroma.
With the dose of fenuron reduced to 75 mg/kg (1/100 LD50), the response of the pregnant females to the effect of the toxic agent decreased. The revealed hemodynamic abnormalities in the stomach and oesophagus walls, myocardium, and brain are significantly weaker than in the females that received the preparation in the dose of 1500 mg/kg
The effect of fenuron in the dose of 38 mg/kg (1/200 LD50) on the reproductive function of white female rats was characterized by an increase of the placental-fetal coefficient and changes in hemodynamics in the stomach, oesophagus walls, myocardium, and brain.
When the herbicide was administered in the dose of 20 mg/kg (1/400 LD50), no changes in the organs of the pregnant rats or their fetuses were detected.
Thus, in the examined organs of pregnant rats, circulatory disorders, manifested by vascular expansion and hyperemia, edemas, and sometimes small hemorrhages, prevailed.
The obtained results indicate the effect of fenuron on the blood flow and permeability of the vascular walls.

Developmental neurotoxicity (F1)

Behaviour (functional findings):

not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:

not specified

Details on results (F1)

At the dose level of 1500 mg/kg bw, the cortical layer of the ovaries contained massive yellow bodies, primordial and growing follicles, and numerous atretic bodies. In the placenta, acute vascular hyperemia, single small perivascular hemorrhages, and chorion edema were observed. The layers of decidual cells penetrated deeply into the myometrium with edematous and hyperemic stroma.
With the dose of fenuron reduced to 75 mg/kg (1/100 LD50), the response of the pregnant females to the effect of the toxic agent decreased.
The effect of fenuron in the dose of 38 mg/kg (1/200 LD50) on the reproductive function of white female rats was characterized by an increase of the placental-fetal coefficient and changes in hemodynamics in the stomach, oesophagus walls, myocardium, and brain.
When dosed at 20 mg/kg (1/400 LD50), no changes in the organs of the pregnant rats or their fetuses were detected.

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

20 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

histopathology: non-neoplastic

Target system / organ toxicity (F1)

Critical effects observed:

yes

Lowest effective dose / conc.:

38 mg/kg bw/day (actual dose received)

System:

cardiovascular

Treatment related:

yes

Dose response relationship:

yes

Overall reproductive toxicity

Reproductive effects observed:

yes

Lowest effective dose / conc.:

38 mg/kg bw/day

Treatment related:

yes

Relation to other toxic effects:

reproductive effects as a secondary non-specific consequence of other toxic effects

Dose response relationship:

yes

Relevant for humans:

not specified

Applicant's summary and conclusion

Conclusions:

The effect of fenuron in the dose of 38 mg/kg (1/200 LD50) on the reproductive function of white female rats was characterized by an increase of the placental-fetal coefficient and changes in hemodynamics in the stomach, oesophagus walls, myocardium, and brain.
When the herbicide was administered in the dose of 20 mg/kg (1/400 LD50), no changes in the organs of the pregnant rats or their fetuses were detected.

Executive summary:

The studies were carried out in in 4 groups of female white rats with 15 animals in each group. The fifth group served as a control group. The tested animals were treated with the study preparation administered intragastrically in the doses of 1/5, 1/100, 1/300200, and 1/400 LD50 from the 6th to the 15th day of pregnancy. The control group was only treated with starch.

The organs of the pregnant rats and embryos were subject to histological examination. The material was preserved in a 10% neutral formalin solution, and paraffin sections of the rat organs and transverse sections of the fetuses were stained with hematoxylin and eosin.

This article presents the results of the histological examination of the ovaries, placenta, brain, oesophagus, stomach, and heart of the pregnant rats which were treated with various doses of fenuron, administered intragastrically, with histotopograms of their fetuses provided as well.

The results of the histological examination of the organs of the rats that received 1/5 LD50 of fenuron (1500 mg/kg) and of their fetuses contained pathological changes.

The oesophagus and stomach walls, heart and brain of the rats had signs of hemodynamic abnormalities and dystrophic changes. The vessels of the brain tunics and brain substance were expanded and hyperemic; moderate perivascular edema was detected. The nerve cells of the cortex and the brainstem nuclei were in a swollen state. The mucous membrane of the stomach and oesophagus was edematous and hyperemic. The heart had cloudy swelling and uneven colouring of the myocardiocytes, sudden expansion and hyperemia of the epicardium and myocardium vessels. The cortical layer of the ovaries contained massive yellow bodies, primordial and growing follicles, and numerous atretic bodies. In the placenta, acute vascular hyperemia, single small perivascular hemorrhages, and chorion edema were observed. The layers of decidual cells penetrated deeply into the myometrium with edematous and hyperemic stroma.

With the dose of fenuron reduced to 75 mg/kg (1/100 LD50), the response of the pregnant females to the effect of the toxic agent decreased. The revealed hemodynamic abnormalities in the stomach and oesophagus walls, myocardium, and brain are significantly weaker than in the females that received the preparation in the dose of 1500 mg/kg

The effect of fenuron in the dose of 38 mg/kg (1/200 LD50) on the reproductive function of white female rats was characterized by an increase of the placental-fetal coefficient and changes in hemodynamics in the stomach, oesophagus walls, myocardium, and brain.

When the herbicide was administered in the dose of 20 mg/kg (1/400 LD50), no changes in the organs of the pregnant rats or their fetuses were detected.

Thus, in the examined organs of pregnant rats, circulatory disorders, manifested by vascular expansion and hyperemia, edemas, and sometimes small hemorrhages, prevailed. In the fetuses, these changes were more significant – the edemas were diffuse, and the hemorrhages were abundant. The obtained results indicate the effect of fenuron on the blood flow and permeability of the vascular walls, which was more pronounced in the fetuses.

In the course of examination of the histotopograms of fetuses obtained from these females, the following changes were established: edema of the fibrous connective tissue of the mediastinum and subcutaneous tissue, organ stroma, and acute hyperemia of the vessels of the brain, body, and all the internal organs; extensive hemorrhages in the liver tissue, mediastinum, spinal cord membranes, pleural and abdominal cavities, subcutaneous tissue, back muscles, as well as a developmental lag in one of the paired organs (cerebral hemispheres, eyes, kidneys).

The organs and tissues of the fetuses obtained from the white female rats, the pregnancies of which occurred against the background of intragastric administration of fenuron in the dose of 75 mg/kg (1/100 LD50), were characterized by edema, vascular hyperemia, and multiple extensive hemorrhages in the liver, spinal cord membranes, pleural cavity, and subcutaneous fatty tissue.

When the herbicide was administered in the dose of 20 mg/kg (1/400 LD50), no changes in the organs of the pregnant rats or their fetuses were detected.

Thus, in the examined organs of pregnant rats, circulatory disorders, manifested by vascular expansion and hyperemia, edemas, and sometimes small hemorrhages, prevailed. In the fetuses, these changes were more significant – the edemas were diffuse, and the hemorrhages were abundant. The obtained results indicate the effect of fenuron on the blood flow and permeability of the vascular walls, which was more pronounced in the fetuses.

When administered in the doses of 1500 and 75 mg/kg, fenuron had significant embryotoxic and teratogenic effects. In the dose of 38 mg/kg, the changes caused by the preparation were less pronounced.