Registration Dossier
Registration Dossier
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EC number: 617-441-5 | CAS number: 83121-18-0
Toxicological information
Toxicity to reproduction
Administrative data
- Endpoint:
- two-generation reproductive toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1984-07-18 to 1985-03-08
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
Data source
Referenceopen allclose all
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 989
- Report date:
- 1989
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 989
- Report date:
- 1989
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 83-4 (Reproduction and Fertility Effects)
- Version / remarks:
- November 1982
- Deviations:
- no
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- 1-(3,5-dichloro-2,4-difluorophenyl)-3-(2,6-difluorobenzoyl)urea
- EC Number:
- 617-441-5
- Cas Number:
- 83121-18-0
- Molecular formula:
- C14 H6 Cl2 F4 N2 O2
- IUPAC Name:
- 1-(3,5-dichloro-2,4-difluorophenyl)-3-(2,6-difluorobenzoyl)urea
- Test material form:
- solid: crystalline
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Wiga GmbH, Sulzfeld, Germany
- Age at study initiation: (P) 6-7 wks; (F1) 6 wks
- Weight at study initiation: (P) Males:165-225 g; Females: 140-180 g; (F1) Males: 160-200 g; Females: 120-160 g
- Fasting period before study: no
- Housing: were individually housed in solid floor macrolone cages of type II with stainless steel lids during premating and mating period, P females and F1 dams with litters were housed in solid floor macrolone cages of type II with stainless steel lids
- Diet: ad libitum, powdered diet (Ssniff R 10, Spezialfutter GmbH, Soest, Germany)
- Water: ad libitum, tap water
- Acclimation period: at least 14 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25
- Humidity (%): 25- 66
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- DIET PREPARATION
- Mixing appropriate amounts with (Type of food): separate batches of diet mix (maximally 50 kg) were prepared for each treatment group by Ssniff Spezialfutter GmbH, Germany; the weighted amount of test item was mixed with the final weight of the powdered diet in two steps (5 kg premixture, 50 kg final mixture) - Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: maximal 14 days
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): single - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The concentration of test substance in each formulated diet was analysed by the sponsor.
Analysis was conducted via an established HPLC method. Recovery experiments carried out routinely throughout the course of the feeding study series gave recovery values of 92 to 96 % (20, 100 and 500 ppm applied). - Duration of treatment / exposure:
- After a premating maturation period (10 weeks P animals and approximately 12 weeks F1 animals) the parental animals in each generation were mated and the females were allowed to rear their offspring to weaning. P males from initiation of the study (five weeks old animals) until the end of the mating period and to the P females from initiation of the study until all the F1 offspring are weaned. The F1 males were dosed continuously from weaning until the end of the mating period and the F1 females were dosed continuously from weaning until all the F2 offspring are weaned.
- Frequency of treatment:
- continuously
- Details on study schedule:
- - Selection of parents from F1 generation when pups were 21 days of age.
- Age at mating of the mated animals in the study: ten weeks (P) and twelve weeks (F1)
Doses / concentrationsopen allclose all
- Dose / conc.:
- 20 ppm
- Dose / conc.:
- 100 ppm
- Dose / conc.:
- 500 ppm
- No. of animals per sex per dose:
- 25
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: Dosage selection based on previous study results.
- Rationale for animal assignment:
Selection of weaned F1 pups to form F1 generation was made as follows: after all the F1 pups were weaned, one to two male and one to two female pups were selected from each litter – a minimum of 25 males and females per group- using a system of randomly drawn cards. - Positive control:
- no
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once daily for signs of ill-health or overt signs of toxicity
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations: The body weight of the parental animals was recorded at weekly intervals during the premating period. Inseminated parental P and F1 females were weighed on days 0, 6, 15 and 20 of gestation and parental lactating females weighed on days 1, 4, 7, 14, and 21 of lactation.
FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
-The amount of food consumed by the parental animals in each generation was recorded three times each week. Food consumption was calculated as mean daily food intake.
WATER CONSUMPTION AND COMPOUND INTAKE: No - Oestrous cyclicity (parental animals):
- not examined
- Sperm parameters (parental animals):
- Parameters examined in P male parental generations: histopathological examination of testes, epididymides, seminal vesicles, prostate
- Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 10 pups/litter (5/sex/litter as nearly as possible)
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, physical develepment (pinna unfolding, generalized hair growth, tooth eruption, eye opening)
After weaning two males and two females per litter, where possible, were randomly selected for examination of pupillary reflex and startle response and between days 35 and 40 post partum for learning ability using a water maze. One male and one female per litter (a minimum of 25 males and females per group) were selected after weaning to produce the F2a generation.
GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was not determined for pups born or found dead
ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY: yes, maze test
ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY: no - Postmortem examinations (parental animals):
- SACRIFICE
Animals scheduled for gross necropsy were weighed.
All animals were examined externally and a macroscopic examination carried out of all tissues and organs in situ. The cut surfaces of major organs were examined.
In addition, the following organs were removed: epididymis, testes, seminal vesicles, prostate, ovaries, uterus, cervix, and vagina. Testes were fixed in Bouin's fluid and all other tissues 10 % neutral buffered formalin. Following fixation, sections of all tissues from the control and high dose group were prepared in paraffin wax, stained, and subsequently evaluated.
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera
HISTOPATHOLOGY
The following organs were examined: epididymis, testes, seminal vesicles, prostate, ovaries, uterus, cervix, and vagina. - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at 21 days of age.
- These animals were subjected to postmortem examinations (macroscopic examination)
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera. - Statistics:
- For body weight, body weight gain, food consumption, and litter weight, the Analysis of Variance was performed with one factor, followed by the Student-Newman-Keuls test for multiple group comparisons. For duration of gestation, mean pup weights, number of pups found alive, number of pups found dead, number of pups (days 4, 7, 14, and 21 postpartum), live birth Index, viability indices, weaning Index, pinna unfolding, hair growth, incisor eruption, and eye opening, the Analysis of Variance was performed with one factor - based on taking the ranks of the variables - and followed by the Student-Newman-Keuls test for multiple group comparisons. Results of the ANOVA and all significances found (at least p smaller than 0,05) are presented.
- Reproductive indices:
- see table 1
- Offspring viability indices:
- see table 2
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No abnormalities of clinical condition were observed.
- Mortality:
- no mortality observed
- Description (incidence):
- There were no treatment-related mortalities of the parental animal. One female of the P generation was killed an day 63 of treatment. This female showed a tumor underneath the right forelimb.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Body weight gain for males during the premating period was similar in all groups. Body weight gain of females during the premating, the gestation, and the lactation period was comparable in all groups.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Mean food consumption in the treated groups of males and females was generally similar to the control groups.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Endocrine findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The histopathological findings in the testis and epididymis (one animal group 4 - 500 ppm, one animal group 1 - 0 ppm respectively) are spontaneous lesions. All lesions in the seminal vesicles and prostates are signs of focal inflammations. There is no difference between control animals (group 1) and treated animals (group 4). There were no compound-related histopathological findings in the sexual organs of the male animals of group 4.
The focal hemosiderosis of the endometrium in the uterus in female animals is a sign of resorption of blood during or after pregnancy. There is no difference between control animals (group 1) and treated animals (group 4). There were no compound-related histopathological findings in the sexual organs of the female animals of group 4. - Histopathological findings: neoplastic:
- not examined
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- no effects observed
- Description (incidence and severity):
- No treatment-related histopathological changes in testis and epididymis have been observed. Sperm enumeration, motility and morphology were not examined.
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- There was no effect of treatment on mating performance or fertility. All pregnant animals littered on gestational day 21 or 22. The mean duration of gestation was normal in all groups.
Effect levels (P0)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- fertility
- Effect level:
- 500 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No effect observed up to highest dose tested.
- Remarks on result:
- other: corresponding to ≥ 36.9 mg/kg bw/day
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- systemic
- Effect level:
- 500 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No effect observed up to highest dose tested.
- Remarks on result:
- other: corresponding to ≥ 36.9 mg/kg bw/day
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):
- No treatment-related changes in appearance, behavior, and general condition were observed.
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Body weight gain of males during the premating period was similar in all groups. In group 3 (100 ppm) and group 4 (500 ppm) mean body weights of females prior to mating were slightly lower than in the control group. Mean body weights of females in group 2 (20 ppm) were higher than in the control group. Mean body weights of the females during gestation was slightly lower in group 4 (500 ppm). These lower body weights resulted from a slightly lower initial weight. Body weight gain of the females during lactation was similar in all groups.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Mean food consumption in the treated groups of males and females was comparable with the control group.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Endocrine findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Necropsy of males and females revealed a few isolated findings in all groups as crystals in the renal pelvis and/or dilatation of the renal pelvis. These findings were considered to be not related to treatment.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Males: The histopathological findings in the epididymides (two animals group 4) are spontaneous lesions. All lesions in the prostate are signs of focal inflammations. There is no difference between control animals (group 1) and treated animals (group 4). There were no compound-related histopathological findings in the sexual organs of the male animals of group 4.
Females: The focal hemosiderosis of the endometrium in the uterus is a sign of resorption of blood during or after pregnancy. There is no difference between control animals (group 1) and treated animals (group 4). There were no compound-related histopathological findings in the sexual organs of the female animals of group 4. - Histopathological findings: neoplastic:
- not examined
Reproductive function / performance (P1)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- no effects observed
- Description (incidence and severity):
- No treatment-related histopathological changes in testis and epididymis have been observed. Sperm enumeration, motility and morphology were not examined.
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- Mating performance and fertility index were comparable in all groups. The mean duration of gestation was comparable in all groups.
Effect levels (P1)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- fertility
- Effect level:
- 500 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No effect observed up to highest dose tested.
- Remarks on result:
- other: corresponding to ≥ 41.8 mg/kg bw/d
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- systemic
- Effect level:
- 500 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No effect observed up to highest dose tested.
- Remarks on result:
- other: corresponding to ≥ 41.8 mg/kg bw/d
Target system / organ toxicity (P1)
- Key result
- Critical effects observed:
- no
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- Concerning all the physical parameters examined (pinna unfolding, hair growth, incisor eruption, eye opening), the onset of the observations was comparable in all F1 pups.
- Mortality / viability:
- mortality observed, non-treatment-related
- Description (incidence and severity):
- Between day 1 and 4 post-partum isolated F1 pup losses were observed in all groups. After adjustment of litter size (day 4 p.p.) pup loss was similar in all groups.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Mean pup weight was similar in all groups.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- no effects observed
- Anogenital distance (AGD):
- not examined
- Nipple retention in male pups:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- The employed functional tests (pupillary reflex, startle response, water maze) revealed no effect of treatment.
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not examined
Effect levels (F1)
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 500 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No effect observed up to highest dose tested.
Target system / organ toxicity (F1)
- Key result
- Critical effects observed:
- no
Results: F2 generation
General toxicity (F2)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- The onset of all physical parameters examined (pinna unfolding, hair growth, incisor eruption, eye opening) was comparable in all groups.
- Mortality / viability:
- mortality observed, non-treatment-related
- Description (incidence and severity):
- Between day 1 and 4 post-partum, isolated pup losses were observed in all groups. After adjustment of litter size (day 4 p.p.), pup loss was low and showed no significant intergroup variations.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Mean pup weight was similar in all groups.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- no effects observed
- Anogenital distance (AGD):
- not examined
- Nipple retention in male pups:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- effects observed, non-treatment-related
- Histopathological findings:
- not examined
Developmental neurotoxicity (F2)
- Behaviour (functional findings):
- not examined
Developmental immunotoxicity (F2)
- Developmental immunotoxicity:
- not examined
Effect levels (F2)
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F2
- Effect level:
- 500 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No effect observed up to highest dose tested.
Target system / organ toxicity (F2)
- Key result
- Critical effects observed:
- no
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- no
Any other information on results incl. tables
Mean daily substance intake in mg/kg bw:
| Generation | Nominal concentration of test substance in diet | ||
20 ppm | 100 ppm | 500 ppm | ||
Males, prior to mating | P | 1.5 ± 0.1 | 7.4 ± 0.3 | 36.9 ± 1.6 |
Females, prior to mating | 1.6 ± 0.1 | 8.1 ± 0.4 | 40.0 ± 1.8 | |
Females, during gestation | 1.6 ± 0.1 | 7.9 ± 0.3 | 39.5 ± 2.8 | |
Females, during lactation | 3.5 ± 0.3 | 16.4 ± 1.5 | 85.1 ± 8.7 | |
Males, prior to mating | F1 | 1.9 ± 0.1 | 9.6 ± 0.4 | 48.2 ± 2.4 |
Females, prior to mating | 2.1 ± 0.2 | 10.5 ± 0.6 | 53.4 ± 2.3 | |
Females, during gestation | 1.7 ± 0.1 | 8.2 ± 0.4 | 41.8 ± 2.3 | |
Females, during lactation | 3.6 ± 0.3 | 18.5 ± 1.5 | 89.3 ± 10.6 | |
Fertility indices (P generation):
Parameter | Group 1 [0 ppm] | Group 2 [20 ppm] | Group 3 [100 ppm] | Group 4 [500 ppm] |
Number of mated animals | 24 | 25 | 25 | 25 |
Number of inseminated animals | 24 | 25 | 24 | 25 |
Mating performance [days] | 2.5 ± 2.8 | 2.5 ± 2.3 | 2.1 ± 1.1 | 2.2 ± 1.3 |
Insemination index [%] | 100.0 | 100.0 | 96.0 | 100.0 |
Number of pregnant animals | 20 | 23 | 19 | 21 |
Fertility index [%] | 83.3 | 92.0 | 79.2 | 84.0 |
Pregnancy index [%] | 83.3 | 92.0 | 76.0 | 84.0 |
Gestation index [%] | 95.0 | 100.0 | 100.0 | 95.2 |
Viability and rearing data (P generation):
Parameter | Group 1 [0 ppm] | Group 2 [20 ppm] | Group 3 [100 ppm] | Group 4 [500 ppm] |
Duration of gestation in days | 21.6 ± 0.5 | 21.6 ± 0.5 | 21.5 ± 0.5 | 21.7 ± 0.5 |
Number of implantations per dam | 14.8 ± 2.8 | 15.0 ± 2.2 | 15.1 ± 2.1 | 14.8 ± 2.2 |
Live birth index [%] | 98.7 | 99.3 | 100.0 | 99.8 |
Viability index [%] | 98.5 | 96.0 | 99.5 | 98.4 |
Weaning index [%] | 97.3 | 92.6 | 96.7 | 99.0 |
Fertility indices (F1 generation):
Parameter | Group 1 [0 ppm] | Group 2 [20 ppm] | Group 3 [100 ppm] | Group 4 [500 ppm] |
Number of mated animals | 25 | 25 | 25 | 25 |
Number of inseminated animals | 24 | 25* | 25 | 25 |
Mating performance [days] | 3.9 ± 2.9 | 3.2 ± 2.9 | 3.7 ± 2.2 | 3.6 ± 3.4 |
Insemination index [%] | 96.0 | 00.0 | 100.0 | 100.0 |
Number of pregnant animals | 23 | 21 | 25 | 25 |
Fertility index [%] | 95.8 | 84.0 | 100.0 | 100.0 |
Pregnancy index [%] | 92.0 | 84.0 | 100.0 | 100.0 |
Gestation index [%] | 100.0 | 100.0 | 100.0 | 100.0 |
* in one pregnant animal sperm could not be detected, therefore day 0 not determinable
Viability and rearing data (F1 generation):
Parameter | Group 1 [0 ppm] | Group 2 [20 ppm] | Group 3 [100 ppm] | Group 4 [500 ppm] |
Duration of gestation in days | 21.5 ± 0.5 | 21.6 ± 0.5 | 21.5 ± 0.6 | 21.4 ± 0.6 |
Number of implantations per dam | 15.7 ± 1.7 | 16.3 ± 1.6 | 16.2 ± 1.8 | 15.8 ± 2.4 |
Live birth index [%] | 100.0 | 99.5 | 98.5 | 99.0 |
Viability index [%] | 98.1 | 98.0 | 98.8 | 98.6 |
Weaning index [%] | 98.3 | 97.1 | 96.8 | 97.2 |
Applicant's summary and conclusion
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
