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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1984-1985
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1985
Report date:
1985

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
GLP compliance:
no
Limit test:
no

Test material

1
Chemical structure
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:
solid: crystalline
Details on test material:
Fenuron
Chemical name: 1,1-Dimehtyl-3-phenylharnstoff
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source of test material: Received from: VEB Fahlberg-List-Magdeburg

OTHER SPECIFICS: Received on: 1984-01-18
Solubility: 2.9 g/L Water (24°C) in alcohol good soluble
Appearance: colorless and crystalline

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: own breeding
- Weight at study initiation: males 82.0 g; females 75.5 g
- Fasting period before study: - Housing: : Groups of 8 per cage, for urine and faeces production 16 h group housing in modified multi-purpose cages with wire mesh shelves
- Diet (e.g. ad libitum): Standard pellets for rats and mice, formulation R, of VEB KFW Altglienicke ad libitum
- Water (e.g. ad libitum): water ad libitum

ENVIRONMENTAL CONDITIONS
- Air changes (per hr): partial air conditioning
- Photoperiod (hrs dark / hrs light): daylight

IN-LIFE DATES:
Application period: 1984-01-23 to 1984-05-28

Administration / exposure

Route of administration:
oral: gavage
Details on route of administration:
Administration: oral gavage with a rigid pharyngeal probe, 5 days/week
Vehicle:
other: 0.5 M Tragacanth
Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: Suspension in 0.5 M Tragacanth. The application solutions were prepared weekly.

Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
90 days
Frequency of treatment:
daily exposure 5 days/week
Doses / concentrationsopen allclose all
Dose / conc.:
20 mg/kg bw/day (actual dose received)
Remarks:
Group IV
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Remarks:
Group III
Dose / conc.:
500 mg/kg bw/day (actual dose received)
Remarks:
Group II
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
Group I
No. of animals per sex per dose:
24 in the 3 test groups and 32 in the control group
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily check for appearance and general behaviour(visually) and mortality (count)

DETAILED CLINICAL OBSERVATIONS: Not specified

BODY WEIGHT: Yes
- Time schedule for examinations: weekly (weighing)

FOOD CONSUMPTION : weekly (weighing)

HAEMATOLOGY: Yes. Blood collection: Puncture of a retroorbital plexus.
- Time schedule for collection of blood: Week 0, 4, 8 and 18 for Erythrocytes, Hematocrit, Hemoglobin, Mean Corpuscular Hemoglobin Concentration, Leucocytes and Differential blood count; Week 8 and 18 for Hemiglobin (Methemoglobin)
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals: each 8 male and 8 female animals per dose group and 16 male and 16 female animals as controls
- Parameters examined: Erythrocytes, Hematocrit, Hemoglobin, Hemiglobin, Mean Corpuscular Hemoglobin Concentration, Leucocytes and Differential blood count

CLINICAL CHEMISTRY: Yes. Blood collection: Puncture of a retroorbital plexus.
- Time schedule for collection of blood: Week 0, 4, 8 and 18 for Total protein, Albumin, Gamma globulin, Glucose, Aspartate aminotransferase, Alanine aminotransferase, Leucine aminopeptidase, Alkaline phosphatase and Cholinesterase in plasma; Week 4, 8 and 18 for Urea, Creatinine and Cholesterol; Week 18 for electrolyte analyzes Na, K, Ca and Cl and kidney function.
- Animals fasted: Not specified
- How many animals: Animal number for clinical-chemical diagnosis: each 8 male and 8 female animals per dose group and 16 male and 16 female animals as controls
- Parameters examined: Total protein, Albumin, Gamma globulin, Glucose, Aspartate aminotransferase, Alanine aminotransferase, Leucine aminopeptidase, Alkaline phosphatase, Cholinesterase in plasma, Urea, Creatinine, Cholesterol, electrolyte analyzes Na, K, Ca and Cl and kidney function.

URINALYSIS: Yes
- Time schedule for collection: week 8, 18
- Metabolism cages used for collection of urine: Not specified
- Animals fasted:Not specified
- Parameters examined: protein, glucose, pH.

STOOLS Yes
- Time schedule for collection: week 8, 18
- Parameters examined: Blood.

- Time schedule for collection of urine: 16 h-urine in Week 8 and 18
- Metabolism cages used for collection of urine: modified multi-purpose cages with wire mesh shelves
- Animals fasted: Not specified
- Parameters examined: Protein, sugar, pH-value
Kidney function was tested in Week 18.

OTHER: Feces and free blood were tested in Week 8 and 18.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes. End of experiment, all animals that died during the experiment.
Heart, lungs, liver, pancreas; kidneys, bladder, spleen, thymus, gastro-intestinal tract, gonads, uterus, thyroid, adrenal glands, brain, pituitary gland.
The test animals were killed with CO2. The dissection was followed by a macroscopic evaluation of the following organs: heart, lungs, liver, pancreas, kidneys, urinary bladder, spleen, thymus, gastrointestinal tract, gonads, uterus, thyroid gland, adrenals, brain, pituitary gland.

HISTOPATHOLOGY: Yes. End of experiment on 8 males & 8 females/group.
Brain, thyroid, adrenals, heart, spleen, thymus, trachea, lungs, esophagus, stomach, duodenum, liver, pancreas, kidneys, testicles, ovaries, lymph nodes, bone marrow.
Formalin fixation, paraffin embedding, hematoxylin-eosin staining of all tissue samples, additional fat staining of liver, kidney, adrenals, brain.
For histological evaluation, the following organs or parts were taken: brain, thyroid, adrenals, heart, spleen, thymus, lungs, trachea, esophagus, stomach, intestine, liver, pancreas, kidneys, testicles, ovaries, lymph nodes and bone marrow.
The organs were fixed in 4% formalin. The sections were stained with hemalaun-eosin.
The liver, kidney, adrenal gland and brain underwent additional Sudan III-stained sections for fat staining.
Haemosiderin-stained sections were also prepared from spleen and liver.

ORGAN WEIGHTS: End of experiment. Heart, liver, kidneys, spleen, thymus, adrenal glands, brain, gonads, thyroid.
After determining the absolute organ weights of the heart, liver, kidneys, adrenals, spleen, thymus, brain, gonads, thyroid, the relative organ weights were calculated.
Statistics:
The student t-test was used for the statistical processing of the measured data. The calculation as well as the printing of the tables was carried out by means of the small calculator C 8205 according to a specially developed program.
The tables are written according to the following scheme
n x
s
p
n= number of animals examined
x= mean value of the measured data
s= scattering of the individual measured data
p= probability of error

The data for the control group are always entered in the first row of the tables, so that the values for the error probability p are omitted here.
The printed numerical value for p is to be understood as the upper limit value. If no statistically significant differences to the control group were calculated (significance limit p > 5%), the symbol – is used.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
In the first weeks of the trial a mild diarrhea was observed in all groups. In the further course of the experiment, the general condition of the test animals of the experimental and control groups was undisturbed, with the exception of high dose female 1, high dose female 19 and control male 29 in which abscess formation was observed in the neck area and low dose female 6 in which otitis media was present.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
In total, 8 deaths were recorded that were not directly related to Fenuron administration
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Doses of 100 and 20 mg/kg bw resulted in no adverse effect on body weight gain. At the highest dose (500 mg/kg bw), slight reduction in body weight gain was observed in both sexes.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Food intake was slightly increased in both sexes in the highest dose group
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
The deviations of the red blood cell picture, such as the decrease in the erythrocyte count, hemoglobin and increase in hemiglobin in the highest and partly in the intermediate dose group, are the result of the administration of the substance. These findings are expected values for compounds of this substance class. The changes in the white blood picture cannot be interpreted as a substance-related effect, a reference to intercurrent infectious events is likely, with the exception of interim lymphocyte decrease.
A correlation to the thymus decrease observed in the highest dose is conceivable.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
The results of clinical chemistry studies, such as increases in alanine aminotransferase activity in the highest and intermediate dose groups, indicate an influence on liver function.
Urinalysis findings:
no effects observed
Description (incidence and severity):
Examinations of the urine after 8 and 18 weeks showed no differences and deviations from the normal findings between male and female control and experimental animals.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
The absolute organ weights of the thymus, the brain and the testes were reduced in the highest dose males, while those of the adrenal glands were elevated.
In the females, an increase in absolute liver weights and a decrease in thymus weights were observed at the highest dose. In the intermediate dose, there was also a decrease in spleen weight
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Abscess formation in the neck area was observed in the following animals: Group II female 6, female 7 and female 1 who died. The group IV female 5 was killed as a result of otitis media. Group II male 18 died due to incorrect application. The remaining dead animals could no longer be judged due to cannibalism or autolysis. The animals of the control and experimental group IV killed at the end of the experiment were pathologically-anatomically without any special findings. At the highest and intermediate dose liver swelling was observed in both sexes.
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
The patho-histological studies in the heart, trachea, lung, pancreas, kidney, thymus, spleen, lymph nodes, bone marrow, esophagus, stomach, duodenum, colon, gonads, adrenal glands and brain by means of hemalaun-eosin, Sudan III and hemosiderin staining showed that Fenuron at the tested doses of 500, 100 and 20 mg/kg bw did not lead to any morphologically detectable tissue changes that could be interpreted as an expression of a substance related effect.
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
The feces had the typical form, consistency and color at all examination time points in control and experimental animals. Occult blood was not detected by benzidine sample.
Details on results:
-General development
Administration of Fenuron in a 90-day test on growing Wistar rats/Bop with five oral doses per week at doses of 100 and 20 mg/kg bw resulted in no adverse effect on body weight gain. Food intake was slightly increased in both sexes in the highest dose group.
In the first weeks of the trial a mild diarrhea was observed in all groups. In the further course of the experiment, the general condition of the test animals of the experimental and control groups was undisturbed, with the exception of Group II female 1, Group II female 19 and Group I male 29 in which abscess formation was observed in the neck area and Group IV female 6 in which otitis media was present. In total, 8 deaths were recorded that were not directly related to Fenuron administration.

-Haematology
A dose-independent decrease of erythrocyte counts was observed in the male animals after the 4th trial week in the highest dose group and in the female animals in all tested dose groups.
In addition, there was an increase in hemoglobin in these groups due to a relatively low hemoglobin content in the control group for this age (Table 6).
After eight weeks of testing, a dose-independent decrease in the number of erythrocytes combined with a decrease in hemoglobin was observed in the males of all experimental groups.
At the highest dose, hemoglobin decrease correlated with increase in hemoglobin.
At the end of the experiment, in both sexes at the highest dose, a decrease in the number of erythrocytes was registered. In the male animals, the hemiglobin content was also increased.
After four weeks of dosing an increase in neutrophils with segmented nuclei and large lymphocytes respectively a decrease in small lymphocytes was observed in the male animals of the highest and middle dose groups. In addition, there was an increase in the leukocyte count in the middle dose males.
At this time point, increased leukocyte counts were seen in all females, an increase in segmented neutrophils and a decrease in small lymphocytes at the highest dose, and an increase in large lymphocytes in the highest and intermediate doses.
After 8 weeks of experiment, the band neutrophils were increased in the males of the highest and intermediate dose groups, and in the lowest dose group neutrophils with segmented nuclei were reduced respectively the small lymphocytes increased.
In the females of all groups increased leucocyte counts were observed and in the highest dose group an increase in band neutrophils.
At the end of the experiment, an increase in neutrophils with segmented nuclei was observed in the males of the highest and medium dose groups. In the females, increased leukocyte counts were observed in the highest dose group.

-Clinical biochemistry
The total protein and albumin content was within the physiological range of the rat strain used.
The gamma-globulin content was increased in the lowest dose male animals after 8 weeks of trial and in the middle dose females. At the end of the experiment, an increase was registered in the intermediate dose males (Table 19). An increase in cholesterol levels was observed at the highest dose in both sexes after 4, 8 and 18 weeks of trial.
A decrease in the glucose content was present in the male animals after 4 weeks of study in all experimental groups, after 8 weeks of testing in the female animals of the highest dose group and at the end of the experiment in the male high and intermediate dose groups in the highest dose females.
The demonstrated differences in urea and creatinine levels of blood plasma at the single blood samplings are not targeted and do not indicate a dose response. The latter also applies to the detected deviations of aspartate aminotransferase activity in the blood plasma.
In contrast, the results of determination of alanine aminotransferase, leucine aminopeptidase, cholinesterase and alkaline phosphatase activity are dose-related. Thus, an increase in the activity of the alanine aminotransferase was found after 4, 8 and 18 weeks of dosing in both sexes in the highest and partly in the middle dose groups. A similar tendency was found in the results of leucine aminopeptidase activity determination. A decrease in cholinesterase activity was observed in the females of the highest and partly in the middle dose group at 4, 8 and 18 weeks of trial. Also at the end of the experiment an increase in the activity of alkaline phosphatase was observed in both sexes at the highest dose. The electrolyte determination at the end of the experiment showed an increase in Calcium ions in the females of all doses.

-Faeces and urine tests
Examinations of the urine after 8 and 18 weeks showed no differences and deviations from the normal findings between male and female control and experimental animals.
The feces had the typical form, consistency and color at all examination time points in control and experimental animals. Occult blood was not detected by benzidine sample.

-Pathological-anatomical and histological findings
Macroscopic findings
Abscess formation in the neck area was observed in the following animals: Group II female 6, female 7 and female 1 who died. The group IV female 5 was killed as a result of otitis media. Group II male 18 died due to incorrect application. The remaining dead animals could no longer be judged due to cannibalism or autolysis. The animals of the control and experimental group IV killed at the end of the experiment were pathologically-anatomically without any special findings. At the highest and intermediate dose liver swelling was observed in both sexes.

Organ weights
The absolute organ weights of the thymus, the brain and the testes were reduced in the highest dose males, while those of the adrenal glands were elevated.
In the females, an increase in absolute liver weights and a decrease in thymus weights were observed at the highest dose. In the intermediate dose, there was also a decrease in spleen weight.
When assessing the relative organ weights, the thymus and adrenal findings were confirmed in the males. In the highest and intermediate dose, liver weight increase was also found. In the female animals the liver and thymus findings were confirmed.

-Histopathology
Heart
Myocardium as well as endocardium and epicardium were free from inflammatory or degenerative changes.

Respiratory system
-Trachea
In the mucosa lympho-monocytic cell reactions of different strengths were seen, in particular the glandular bodies were affected. The preference of a sex or a test group was not recognizable.

-Lungs
There were cell reactions in the peribronchial area, from lymphatic hyperplasia to pronounced peribronchitis with local foam cell formation in the alveoli. In one case purulent bronchopneumonia was detectable. The cell reactions were again evenly distributed among the experimental groups and sexes.

Liver
At the organ sections no inflammatory or degenerative changes could be found. There was no lipid storage. Hemosiderin deposition was not apparent.

Pancreas
No pathologic changes were seen.

Kidneys
In none of the investigated organ sections inflammatory or degenerative tissue changes could be found. Lipid storage was undetectable.

Lymphatic organs
-Thymus
Medulla and cortex area were free of pathological changes. In the present organ sections, the experimental groups had no discernable differences in the distribution of medulla and cortex parts compared to the control group. Hemosiderin deposition was not found.

-Spleen
No pathological tissue reactions could be detected. Differences in the hemosiderin content between dose groups could not be clearly established.

-Lymph nodes
Medulla, cortex and sensory area showed no pathological changes.

Bone marrow
The assessed tissue sections showed no differences in tissue structure, disturbances of the hemopoiesis were not recognizable.

Gastrointestinal tract
-Esophagus
The organ showed a normal structure, there were no inflammatory or degenerative changes.

-Stomach
The organ sections allowed an evaluation of the forestomach and the glandular stomach. No pathological changes could be found.

Duodenum
Serosa, muscularis and mucosa showed no pathological changes.

Colon
No pathological changes were seen.

Gonads
-Ovaries
The tissue sections showed all stages of the ovarian cycle. Obvious functional disorders or pathological tissue processes were not detected.

-Testes
A disturbance of spermiogenesis could not be found, degenerative or inflammatory reactions were not present.

Endocrine organs
-Adrenal glands
Medulla and cortex had no degenerative or inflammatory reactions. The part of individual adrenal cortex fluctuations, may be due to the section or due to individually different reaction conditions. There were no group-dependent differences in lipid storage.

-Thyroid
Indications of an activation of the organ or differences in functional status between the dose groups could not be found on the evaluated organ sections.

Brain
The cerebrum, cornu ammonis, thalamus, pons, cerebellum and medulla oblongata as well as leptomeninx and ependyma were examined by means of several sections (HE and Sudan III staining). No pathological changes were found.

In summary, Fenuron in the tested doses did not lead to any morphologically detectable tissue changes that could be interpreted as an expression of a substance effect in heart, trachea, lung, liver, pancreas, kidney, thymus, spleen, lymph nodes, bone marrow, esophagus, stomach, duodenum, colon, gonads, adrenal glands and brain examined by means of hemalaun, eosin, Sudan III and hemosiderin staining.

Effect levels

Key result
Dose descriptor:
NOEL
Effect level:
20 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical biochemistry
food consumption and compound intake

Target system / organ toxicity

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
100 mg/kg bw/day (actual dose received)
System:
hepatobiliary
Organ:
liver
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes

Applicant's summary and conclusion

Conclusions:
male/female NOEL= 20 mg/kg bw/day
Executive summary:

Administration of Fenuron in the 90-day test on growing Wistar rats with five oral doses per week at doses of 100 and 20 mg/kg bw did not lead to any adverse effects on body weight gain. At the highest dose (500 mg/kg bw), slight reduction in body weight gain was observed in both sexes.The food intake was slightly increased in this dose group.

The general condition of the experimental and control animals was undisturbed during the experiment, except for high dose female 1, high dose female 19 and control male 29, in which abscess formation was observed in the neck area and low dose female 6, in which otitis media was present. In total, 8 deaths were recorded, which were not directly related to the substance application.
Most striking hematological findings were a decrease in the erythrocyte count and hemoglobin and an increase in hemiglobin in the highest and partly in the intermediate dose group.

The clinical-chemical findings were also limited to the highest and intermediate dose groups. They consisted in an increase in the activity of alkaline phosphatase, alanine aminotransferase, leucine aminopeptidase and a decrease in cholinesterase activity. In addition, an increase in the level of cholesterol and decrease in the level of glucose were observed.

In the determination of the absolute and relative organ weights especially an increase of the liver weight in the highest and middle dosage and a decrease of the thymus weight in the highest dose group was noticeable. No histopathological findings were observed in any organs at the various doses.

For Fenuron, a NOEL of 20 mg/kg bw was determined under the given experimental conditions.