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Diss Factsheets

Administrative data

Endpoint:
multi-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
July 1980 to June 1982
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2003
Report date:
2003

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The multi-generation study was based on the recommendations published by the FDA:
Modern Trends in Toxicolop-y. Vol. 1, 1968, 75 - 85
Toxicol. appl. Pharmacol., Vol. 16, 1980, 264-369.
In a three-generation test with two litters per generation Triflumuron was administered in the diet to dose groups made of up to 10 male and 20 female rats at concentrations of 0, 20 200 or 2000 ppm. The F0 (parental generation) animals were exposed to Triflumuron for about 70 days before mating. The rats treated in this way were examined in regard to behaviour, body weight development, mortality, fertility, lactation ability, development of young, and also male/female
relation after two matings in each of three successive generations.
Histopathological examinations of main organs and tissues (including reproductive organs) was done on 4-week old pups of the F3 generation.
GLP compliance:
no
Remarks:
The study was performed before GLP principles were in place.

Test material

Constituent 1
Chemical structure
Reference substance name:
2-chloro-N-[[[4-(trifluoromethoxy)phenyl]amino]carbonyl]benzamide
EC Number:
264-980-3
EC Name:
2-chloro-N-[[[4-(trifluoromethoxy)phenyl]amino]carbonyl]benzamide
Cas Number:
64628-44-0
Molecular formula:
C15H10ClF3N2O3
IUPAC Name:
3-(2-chlorobenzoyl)-1-[4-(trifluoromethoxy)phenyl]urea

Test animals

Species:
rat
Strain:
Wistar
Remarks:
SPF rats strain BOR:WISW.
Sex:
male/female
Details on test animals or test system and environmental conditions:
The animals were approximately 5-6 weeks old at start of study, with a mean starting weight of 80 g (males) and 79 g (females). The adaptation period was seven days. Apart from mating, the animals were kept singly in Makrolon cages type II, at a room temperature of approx. 22° C ± 1° C, atmospheric humidity of approx. 60 %, and with a 12-hour light/dark rhythm (artificial lighting from 7 am to 7 pm MET). During the matings and for F1b and F2b pups aged 4-8 weeks, Makrolon cages type III were used, the other conditions remaining the same. Fresh Altromin R and Ssniff R powdered feed (50:50) was provided once a week (the dams during lactation ad libitum) and tap water was available ad libitum.

Administration / exposure

Route of administration:
oral: feed
Details on exposure:
The rats received the test substance in the powdered feed. The test item was mixed in the feed weekly. The rats were treated with active ingredient over the entire study period, including mating,
gestation and lactation.
Details on mating procedure:
The 5-6 weeks old animals used for the study were kept singly for about 70 days (up to sexual maturity), and then mated. During mating two female rats were caged constantly with one male in a Makrolon cage type III. During the three-week mating period the males were interchanged, so that each female was confined with three different males, in each case for longer than the length of one cycle. After the matings the animals were recaged singly in type II cages. Five days after birth the litters were reduced, where necessary to ten animals. The animals with which treatment was to be continued were selected by a random list (except for the F1a generation). The young of the F1a, F2a and F3a generations were reared by the dams up to an age of four weeks, and then sacrificed. Each of the FO, F1b and F2b animals were mated for a second time after a two-week waiting period. After each second mating the pups (F1b and F2b) were kept and reared for four weeks like the pups from the first mating, and then separated from the dams and divided into sexes. After the 8th week groups of ten male and twenty female rats in each of the dose groups were chosen randomly for further matings. After reaching a mean age of approx. 100 days, mating took place as described above. The F0, F1b and F2b generation animals were sacrificed after rearing two sets of pups, approx. 1-3 weeks after weaning.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Before start of study stability and homogeneity in the feed were checked by analysis. During the
study the active ingredient content was checked regularly.
Frequency of treatment:
Continuous exposure via feed.
Details on study schedule:
Approximate length of each study phase:

Pre-treatment of F0 generation rats up to 1st mating: 70 days.

Length of 1st mating of F0 generation 20 days.

Length of gestation 21 Lactation of F1a pups up to 4- weeks with subsequent sacrifice: 28 days.

Waiting period: 14 days.

Length of 2nd mating of F0 generation: 20 days.

Length of gestation: 21 days.

Lactation of F1a pups up to age of approximately 100 days (sacrifice of F0 generation): 100 days.

Length of 1st mating of F1b generation: 20 days.

Length of gestation: 21 days.

Lactation of F2a pups up to 4-weeks with subsequent sacrifice: 28 days.

Waiting period: 14 days.

Length of 2nd mating of F1b generation: 20 days.

Length of gestation: 21 days.

Lactation of F2b pups up to age of approx. 100 days (sacrifice of F1b generation): 100 days.

Length of 1st mating of F2b generation: 20 days.

Length of gestation: 21 days.

Lactation of F3a pups up with subsequent sacrifice: 28 days.

Waiting period: 14 days.

Length of 2nd mating of F2b generation: 20 days.

Length of gestation: 21 days.

Lactation of F3b pups up to age of 4- weeks with subsequent sacrifice: 28 days.
Doses / concentrationsopen allclose all
Dose / conc.:
20 ppm
Remarks:
Low dose group, equivalent to 1.43 mg/kg bw/d in males and 1.50 mg/kg bw/d in females.
Dose / conc.:
200 ppm
Remarks:
Mid dose group, equivalent to 14.25 mg/kg bw/d in males and 15.04 mg/kg bw/d in females.
Dose / conc.:
2 000 ppm
Remarks:
High dose group, equivalent to 142.5 mg/kg bw/d in males and 150.4 mg/kg bw/d in females.
No. of animals per sex per dose:
In each test group there were ten male and twenty female rats.
Control animals:
yes
Details on study design:
Determination of the weights of parents: The rats were weighed before and after mating in a weekly rhythm. F0 animals were weighed weekly during first mating, and every three days during second mating. F1b and F2b rats were weighed every three days during both matings. Females which gained more than 35 g in weight within three weeks after mating were assumed to be pregnant. Parental F0 (indicated as P0 below), First (F1a, F1b) and second (F2a, F2b) generation results are presented.

In regards to pup data, each litter was weighed immediately after birth, on the 5th day after birth, after reduction to ten pups per birth, and after 1, 2, 3 and 4 weeks. On the date of birth the total number of pups born, the number of living and stillborn animals, and the ratio of males to females were also noted. We appraised the pups grossly immediately after birth, to detect malformations. The pups were also inspected during lactation for malformations.

Examinations

Parental animals: Observations and examinations:
Appearance and behaviour was observed.
Postmortem examinations (parental animals):
Gross pathology: The 4-week old pups in the F3b generation and their parents (F2b generation) were anaesthetised with ether, sacrificed by exsanguination and then autopsied.
Postmortem examinations (offspring):
The F2b parents' livers, kidneys, testicles or ovaries were weighed.

The following organs of F3B pups were examined histopathologically: brain, eyes, thyroid, thymus, heart, lung, liver, spleen, pancreas, mesenteric lymph nodes, stomach, small intestine, kidneys, adrenals, urinary bladder, testicles, epididymes, sternum (bone marrow) skeletal musculature en bloc with femur, uterus and ovaries.
The organs examined came from one male and one female pup aged four weeks from each of ten dams per dose group. The animals were selected at random.
Statistics:
The following were calculated: arithmetic group means, standard deviations, upper and lower confidence limits at the confidence level of 1 - alpha = 95 % and 1 - alpha = 99 %. The findings for the test groups were compared with the control by the U significance test after MANN, WHITNEY and WILCOXON on the significance level alpha = 5 % and alpha = 1 %. For the indices (numerically derived) the confidence limits were calculated after CLOPPER and PEARSON on the confidence level 1 - alpha = 95 9 and 1 - alpha = 99 %. The test groups were compared with the control group with the exact Fisher test on the significance level alpha = 5 % and alpha = 1 %. To calculate the means of the pups' weights per dose the mean pup weight of each litter was used.
Reproductive indices:
Fertility index: number pregnant females/number mated females *100.

Gestation index: number females with live litters/number pregnant females*100.

Viability index: Number live pups after 5 days/number pups born*100.

Lactation index: Number live pups after 4 weeks/number live pups after 5 days after reduction to 10 *100.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
The rats in the 20 - 2000 ppm dose groups did not differ in appearance and behaviour from the controls during the study period.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One female in each of the 0, 200 and 2000 ppm groups in the F0 generation died. The death of these
animals was not be attributed to the treatment.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Doses up to 2000 ppm did not result in any significant treatment-related effects on growth either in males or in females (F0 generation).

Reproductive function / performance (P0)

Reproductive performance:
no effects observed
Description (incidence and severity):
The females treated with up to 2000 ppm of the test material did not differ in respect to fertility and gestation indices to any great extent from the control females. The results are attached below in tabular form.
For the F1a and F1b generation, the total pups, numbers of males and females born, and the ratio in percent of males to females for each dose group. It is apparent that in the F1a and F1b generation, up to the dosage of 2000 ppm there were no differences attributable to the treatment in ratios of males to females and in the total number of animals born in comparison to the control.

Effect levels (P0)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
150.4 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
other:
Remarks on result:
other: Exposure based on calculation by estimation
Key result
Dose descriptor:
NOAEL
Effect level:
150.4 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other:
Remarks on result:
other: Exposure based on calculation by estimation
Key result
Dose descriptor:
NOAEL
Effect level:
2 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other:
Remarks on result:
other: Highest dose level tested

Target system / organ toxicity (P0)

Key result
Critical effects observed:
no

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:
no effects observed
Description (incidence and severity):
In appearance and behaviour the rats (P1 and P2) in the 20 to 2000 ppm dose groups did not differ from the controls during the study period.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
For the P1, during 1st and 2nd mating one male died in the 20 ppm dose group. Autopsy of this animal did not detect a substance-related cause of death.
No mortality occurred in the P2- generation.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Treatment with the test item in doses up to and including 2000 ppm did not have any negative effects on the F1b generation's body weight development. Animals in the 200 ppm group (only females significant) were generally heavier than the controls. there were no treatment-related negative effects on body weight development up to 2000 ppm for males and females.

For the P2-generation, there were no treatment-related negative effects on body weight development up to 2000 ppm for males and females.
Description (incidence and severity):
Liver, kidney and testicles or ovaries from all the parent animals in the F2b generation were weighed on autopsy. No differences in weights were noted in males and females up to 2000 ppm which could not be explained by increased body weights, or which were in correlation to dose. The significantly lower relative kidney weights in females in the 2000 ppm group were within the normal range and not considered toxicologically relevant.
Gross pathological findings:
no effects observed
Description (incidence and severity):
All the parents in the F2b generation were sacrificed and examined two weeks after weaning. Gross appraisal of the dissected animals did not provide any indications of substance-specific organ damage.

Reproductive function / performance (P1)

Reproductive performance:
no effects observed
Description (incidence and severity):
P1:
Treatment with doses up to and including 2000 ppm after two matings had no negative influence on fertility and gestation. There were no dose related differences from the control either in total of animals born or in the male/female ratio. There were no significant differences between treated and untreated animals in regard to mean litter size.

P2:
The fertility and gestation indices detailed above do not reveal any treatment-induced effects on fertility and gestation in the dose groups up to 2000 ppm after both matings. The male/female ratio for the treated animals up to 2000 ppm did not differ from that of the controls. In regard to the total number of animals born, no dose correlation was apparent after first mating.
In the 2000 ppm group fewer F3b pups were born. This is considered a random result.

Effect levels (P1)

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
P1 and P2
Effect level:
150.4 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No adverse effects observed
Remarks on result:
other: Exposure based on calculation by estimation
Key result
Dose descriptor:
NOAEL
Effect level:
142.5 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No adverse effects observed
Remarks on result:
other: Exposure based on calculation by estimation
Key result
Dose descriptor:
NOAEL
Effect level:
2 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed up to and including the highest dose level tested
Remarks on result:
other: Highest dose level tested

Target system / organ toxicity (P1)

Key result
Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
mortality observed, non-treatment-related
Description (incidence and severity):
Viability after five days also did not differ in correlation to dose up to 2000 ppm. Any significant
deviations in the 200 ppm dose group (F1a and F1b) are not of toxicological importance.
The lactation index of treated dams up to 2000 ppm after two matings was about the same as that of the control females.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The birth weights of the F1a and F1b pups in the groups up to 2000 ppm did not differ significantly from those of the untreated pups. The results are attached below in tabular form.
The F1a and F1b pups' growth in the treated groups up to 200 ppm was the same as that of the
controls. At 2000 ppm the F1b pups had significantly lower body weights in the 2nd, 3rd and 4th study weeks. As these deviations were only slight, they are not considered the result of a toxic effect on growth.
Gross pathological findings:
no effects observed
Description (incidence and severity):
All the pups were without grossly apparent abnormalities at birth and during lactation.

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
2 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed
Remarks on result:
other: Highest dose level tested

Target system / organ toxicity (F1)

Key result
Critical effects observed:
no

Results: F2 generation

General toxicity (F2)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Description (incidence and severity):
No deaths occurred. In addition, compilation of the viability indices of the F3a and F3b pups did not reveal any dose correlation.
For the F3-generation, the female rats' lactation performances after the first mating up to 2000 ppm did not differ to any great extent from that of the controls. After the second mating there was a significant reduction in lactation index in the 20 ppm group. This figure is to be considered random and toxicologically insignificant, as better lactation indices were noted at 200 and 2000 ppm.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Administration of up to a dosage of 2000 ppm did not produce any significant and dose-related effects on the birth weights of F2a and F2b pups. The results are attached below in tabular form.

The F3a rats' body weights in the 20 to 2000 ppm dose groups were slightly but significantly lower than those of the controls, and this may be explained by the relatively high birth weight in the control group, so that the finding should not be attributed to the treatment. This is confirmed by the fact that birth weights corresponding to those of the controls were recorded after the second mating up to and including 2000 ppm.
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Description (incidence and severity):
No deformed pups were noted in the F2 and F3 generations, either immediately after birth or during the lactation period.

The pathological anatomical examination of F3 pups did not reveal any alterations attributable to dosage with the test item.
Histopathological findings:
no effects observed
Description (incidence and severity):
No indications of organ alterations were noted in any of the animals examined (F3-generation).
Other effects:
no effects observed

Effect levels (F2)

Key result
Dose descriptor:
NOAEL
Generation:
other: F2 and F3
Effect level:
2 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects observed
Remarks on result:
other: Highest dose level tested

Target system / organ toxicity (F2)

Key result
Critical effects observed:
no

Overall reproductive toxicity

Key result
Reproductive effects observed:
no
Treatment related:
no

Applicant's summary and conclusion

Conclusions:
A 3-generation study (two litters per generation) was performed using dietary concentrations of 20, 200 and 2000 ppm. Based on the results of this study a NOAEL for reproduction of 2000 ppm (corresponding to 142.5 and 150.4 mg/kg bw/d in males and females, respectively) is established.
Executive summary:

Triflumuron was examined in a multigeneration study in rats for its potential effect on reproduction. Triflumuron was administered to male and female rats at dietary concentrations of 0 (controls), 20, 200 and 2000 ppm. The rats treated in this way were examined in regard to behaviour, body weight development, mortality, fertility, lactation ability, development of young, and also sex ratio after two matings in each of three successive generations.
Behaviour, mortality, body weight development in parent and young animals were not negatively affected by administration of Triflumuron up to 2000 ppm. In regard to fertility, viability, lactation, litter size and birth weight no dose-related  differences between treated and untreated animals were recorded up to the dosage of 2000 ppm. In the dose groups up to and including 2000 ppm no malformations were noted in the young. The sex ratio did not show substance-specific abnormalities in any generation up to 2000 ppm. Autopsies on parents which died and were sacrificed provided no indications of treatment-related alterations. Gross and microscopic appraisal of the F3b young provided no indications of organ damage up to 2000 ppm. Triflumuron was tolerated under the conditions described in the multigeneration study, in concentrations up to 2000 ppm in the feed, without damage to reproduction. Food consumption was not measured in this study. For estimation of the compound intake at the NOAEL of 2000 ppm, the lowest food intake values out of four reference studies were taken into account. The NOAEL for reproduction was therefore established retrospectively at 142.5 and 150.4 mg/kg bw/d for males and females, respectively.