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EC number: 406-850-2 | CAS number: 133855-98-8 BAS 480 F
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Toxicity to reproduction
Administrative data
- Endpoint:
- two-generation reproductive toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- Feb 1990 - Jan 1991
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 992
- Report date:
- 1992
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
- Version / remarks:
- 1983
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: Commission Directive 87/302/EEC of November 18, 1987 adapting to technical progress for ninth time Council Directive 67/548/EEC. pp. 47 — 50 (1988)
- Version / remarks:
- 1988
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: EPA/FIFRA Pesticide Assessment Guidelines, Subdivision F, NTIS, § 83—4, pp. 130 - 137, Nov. 1984.
- Version / remarks:
- 1984
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: Testing Guidelines for Toxicology Studies" pp. 45 - 48 (Japan/MAFF, 1985).
- Version / remarks:
- 1985
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- (2RS,3RS)-3-(2-chlorophenyl)-2-(4-fluorophenyl)-[(1H-1,2,4-triazol-1-yl)methyl]oxirane
- EC Number:
- 406-850-2
- EC Name:
- (2RS,3RS)-3-(2-chlorophenyl)-2-(4-fluorophenyl)-[(1H-1,2,4-triazol-1-yl)methyl]oxirane
- Cas Number:
- 133855-98-8
- Molecular formula:
- C17 H13 Cl F N3 O
- IUPAC Name:
- 1-{[(2R,3R)-3-(2-chlorophenyl)-2-(4-fluorophenyl)oxiran-2-yl]methyl}-1H-1,2,4-triazole
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on species / strain selection:
- This strain was selected since extensive experience is available on Wistar rats and the rat is the preferred animal species for reproduction studies according to the different test guidelines.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Karl Thomae, Biberach an der Riss, FRG
- Females nulliparous and non-pregnant: yes
- Age at study initiation: (P) 24 days (+/-) 1, 34 days at beginning of treatment
- Weight at study initiation: (P) Males: 129-155 g; Females: 110-133 g
- Fasting period before study: no
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 10 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12/12 (light from 6 am to 6 pm)
IN-LIFE DATES: From: Feb, 12 1990 To: F0 Generation: Sep 25, Sep 26, and Sep 28 1990. Oct 16 and Nov 6, 1990 for animals that had to be reevaluated for fertility. F1 generation: Jan 3. Jan 4, Jan 8, Jan 9, 1991. Jan 11, Jan 14, Jan 21, Jan 22 and Jan 30, 1991 for animals that had to be reevaluated for fertility
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- other: diet
- Details on exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): At intervals of not more than 32 days
- Mixing appropriate amounts with (Type of food): Kliba maintenance diet
- Storage temperature of food: not specified - Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: 3 weeks
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- After unsuccessful pairing replacement of first male by another fertile male or female animal of the control group each.
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): individually - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples of each one of the doses were sent for analysis to the analytical laboratory at the beginning of the study and then at approximately three-monthly intervals. The content in the test substance/food mixes was determined by HPLC-method.
- Duration of treatment / exposure:
- 48 weeks
- Frequency of treatment:
- continuous
- Details on study schedule:
- - F1 parental animals not mated until 98 days after selected from the F1 litters.
- Selection of parents from F1 generation: after weaning
- Age at mating of the mated animals in the study: 13 weeks
Doses / concentrationsopen allclose all
- Dose / conc.:
- 10 ppm (nominal)
- Remarks:
- average of 0.9 mg/kg bw/day
- Dose / conc.:
- 25 ppm (nominal)
- Remarks:
- average of 2.3 mg/kg bw/day
- Dose / conc.:
- 250 ppm (nominal)
- Remarks:
- average of 23 mg/kg bw/day
- No. of animals per sex per dose:
- 25
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale:
The doses were chosen on the basis of a previous reproduction toxicity study, which had to be discontinued before schedule for reasons which are explained below. In this study the test substance administered to groups of 25 male and 25 female Wistar rats as a
constant homogeneous addition to the food in doses of 0, 30, 300 and 1,500 ppm. At least 70 days after the beginning of treatment, the (F0) animals were mated to produce a litter (F1a). Groups of 25 males and females selected from the F1a pups of the 0, 30 and 300 ppm groups (no pups survived at 1,500 ppm) were raised for approximately 3 weeks; thereafter, due to the massive signs of systemic toxicity and adverse effects on the
reproductive function especially at the high dose level, the study was discontinued.
- Rationale for animal assignment (if not random): random
- Fasting period before blood sampling for clinical biochemistry: no - Positive control:
- not included
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Parameters checked: Signs of toxicity
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
- Parameters checked: nesting. littering. and lactation behavior
BODY WEIGHT: Yes
- Time schedule for examinations: Weekly and additionally during gestation and lactation on days 0, 7, 14, and 20, on day of parturition and on days 4, 7, 14, and 21 after birth
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Time schedule: weekly and additionally during gestation and lactation
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
HAEMATOLOGY: No
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: F0 males and females: Sep 18, 1990 F1 males: Jan 3, 1991 females: Jan 4, 1991
- Animals fasted: No
- Anesthesia: no
- How many animals: 12 (F0 and F1) males and females each
- Parameters checked: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, serum-gamma-glutamyltransferase, sodium, potassium, chloride, inorganic phosphate, calcium, urea, creatinine, glucose, total bilirubin, total protein, albumin, globulins, triglycerides, cholesterol, magnesium - Oestrous cyclicity (parental animals):
- Not examined
- Sperm parameters (parental animals):
- Not examined
- Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 4/sex/litter as nearly as possible
PARAMETERS EXAMINED
The following parameters were examined in F1 / F2 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities
GROSS EXAMINATION OF STANDARDIZED PUPS, STILLBORN PUPS, AND DEAD PUPS:
yes, for external and internal abnormalities
DEVELOPMENTAL STAGES: Yes
- Parameters checked: pinna unfolding (PND 4), opening of the auditory canal (PND 13), opening of the eyes (PND 15)
ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY: yes; Gripping reflex, hearing test, pupillary reflex
ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY: no - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: 200
- Maternal animals: 200
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations
- Organ weights: Liver and adrenal glands
HISTOPATHOLOGY / ORGAN WEIGHTS
- Adrenal glands, coagulating glands, epididymides, liver, ovaries, pituitary gland, prostate gland. seminal vesicles, testes, uterus (including cervix), vagina, and all organs or tissues with macroscopic abnormalities. - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at day 4 (culled pups) and day 21 (surplus pups)
- These animals were subjected to postmortem examinations (macroscopic)
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations
HISTOPATHOLOGY / ORGAN WEIGTHS
not examined - Statistics:
- Dunnett's test, Fisher's Exact test, ANOVA
- Reproductive indices:
- Male and female mating index, male and female fertility index, gestation index, live birth index
- Offspring viability indices:
- viability index, lactation index, sex ratio
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- - 250 ppm: 6 dams with vaginal hemorrhages during gestation for F1a litters: 2 of these dams were unable to deliver and died shortly after the expected delivery date; another dam died during gestation (F1b)
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- - 250 ppm: Three dams died during gestation. Two dams died without delivering their litters on days 23 and 25 p.c. The third dam died on day 7 p.c. of the gestation period for the F1b litter
All intercurrent deaths have to be related to the test substance administration. - Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- All differences are assessed to be within the expected range of biological variation.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- - 250ppm: Reduced food consumption of females during lactation period of F1a litters on days 4-7 and 7-14 post partum
- 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:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- No effects observed in the nesting, littering, and lactation behavior of dams.
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Histopathological findings: non-neoplastic:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- effects observed, treatment-related
- Description (incidence and severity):
- - 250 ppm: prolonged cohabitation time (concerning F1a and F1b) and prolonged duration of the gestation period (concerning F1a only). Lower male and female fertility indices (concerning F1b): however, finally fertility for all F0 sires and dams could be proven. Lower gestation index (73%) due to a high number of dams with only stillborn pups (concerning F1a litter). Clearly lower number of delivered pups/dam (concerning F1a litters)
Details on results (P0)
Moreover, after parturition, umbilical cords were not cut in some F1a and F1b pups by dams of different groups without any relation to the dose.
The male fertility index varied between 96% and 88% (concerning F1a) and between 100% and 78% (concerning F1b) and was lowest for the high dose group males. Even if all males proved their fertiliftu finally, the increased number of 250 ppm males for which fertility could not be proven within the mating period for F1b litters, might be substance-related. The fertility index calculated for this group (78%) is just outside the historical control range (80 - 100%).
The female fertility index varied between 96% and 88% (concerning F1a) and between 100% and 78% (concerning F1b) and was lowest for the high dose group animals. Even if for all dams fertility was confirmed at least in one of the scheduled matings or in the reevaluation of fertility, the increased number of 250 ppm dams which did not become pregnant after mating for F1b litters took place, might be related to the test substance administration. The fertility index calculated for this group (78%) is outside the historical control range.
The mean duration of gestation for the F1a litter was statistically significantly prolonged in the high dose dams (22.8 days) which is mainly caused by dams Nos. 185 and 188 (died delivering on days 23/25 p.c.). This has to be attributed to the test substance administration.
As it was demonstrated that the test substance causes hormonal imbalance at high dose levels, it is reasonable to infer that some of the adverse effect observed in the adults (prolonged cohabitation time and duration of gestation) and possibly in their progency may have been caused by altered hormone concentrations.
Effect levels (P0)
- Dose descriptor:
- NOAEL
- Effect level:
- 2.3 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- mortality
- reproductive performance
Target system / organ toxicity (P0)
open allclose all
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 23 mg/kg bw/day (actual dose received)
- System:
- female reproductive system
- Organ:
- uterus
- Treatment related:
- yes
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 23 mg/kg bw/day (actual dose received)
- System:
- endocrine system
- Treatment related:
- yes
Results: P1 (second parental generation)
General toxicity (P1)
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - 250 ppm: only a spontaneous skin lesion at the neck was observed in one male. One female showed vaginal hemorrhage on day 25 p.c. It was not able to deliver the pups, which were palpable around this gestation day in the abdomen. In addition, 3 dams with positive sperm detection did not deliver F2 pups
- 10 ppm: 3 dams with positive sperm detection did not deliver F2 pups
After parturition a few dams of all groups did not cut the umbilical cords; this is a spontaneous finding and not related to the test substance administration. - Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- - 250 ppm: clearly lower body weights in comparison to the controls and slightly impaired weight gains in the males (during the whole study period). In total, the weight gain of the 250 ppm males was significantly lower (11%) than that of the male control group
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- -250 ppm: reduced food consumption of the males especially at the beginning of the premating period; the dams showed slightly to markedly diminished food intake during gestation and lactation periods of F2 litter
- 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:
- no effects observed
- Urinalysis findings:
- not examined
- 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):
- - 250 ppm: increased absolute and relative liver weights in the females without any histopathological correlate
The absolute and relative organ weights of the adrenal glands were decreased in males of groups 10, 25, and 250 ppm (p<.05, p<.05, p<.01, respectively). The absolute liver weight was decreased in males of
group 250 ppm (p<.01). The histologic examination did not reveal any morphologic correlate of these organ weight changes. The significance of the recorded organ weight changes is therefore considered to be of little if any toxicological relevance. - Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- - 250 ppm: decreased fatty change in the liver of the males
Reproductive function / performance (P1)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- effects observed, treatment-related
- Description (incidence and severity):
- -250 ppm: prolonged cohabitation time and slightly prolonged duration of the gestation period; slightly reduced gestation index. One dam with vaginal hemorrhage during the gestation period; it did not deliver pups after prolonged gestation
Details on results (P1)
Three low dose males and 4 high dose males were not able to prove their fertility during the scheduled matings for F2 litters; however, for all these males fertility was confirmed during the reevaluation of fertility. Therefore, the observable differences concerning the male fertility indices between test groups 0, 10, 25 and 250 ppm are finally assessed as being of spontaneous nature and not related to the test substance administration.
The female mating index reached 100% for test groups 0, 10 and 25 ppm, in test group 250 ppm it was only 96%. The mean duration until sperm could be detected (day 0 p.c.) varied between 2.6 and 3.6 days;it was prolonged for the high dose females.
The female fertility indices varied between 100% and 88%. Because these values are inside the historical range and all females proved their fertility later on, the differences concerning the female fertility index are finally assessed as being of spontaneous nature. The mean duration of gestation was marginally longer in the 250 ppm group, i.e. 22.3 days in comparison to the actual control value (22.0), but was still within the historical control range. A clearer substance-related effect on the duration of gestation was recorded for the first parental generation (F0 females (F1a litter)).
Nearly all pregnant females gave birth to litters with liveborn pups; only one pregnant high dose dam, which had palpable pups in the abdomen, could not deliver. Consequently the gestation index was 100% in all groups. except test group 250 ppm where it was 95%. The number of stillborn pups was markedly increased in the high dose group while the mean number of delivered F2 pups was not influenced by the test substance administration. The percentage of liveborn F2 pups, however, was markedly reduced in test group 250 ppm, whereas there were no substantial differences in this respect between the control and the other substance—treated groups.
Consequently, the live birth index was reduced in the 250 ppm group and the number of stillborn F2 pups was clearly increased.
As it was demonstrated that the test substance causes hormonal imbalance at high dose levels, it is reasonable to infer that some of the adverse effect
observed in the adults (prolonged cohabitation time and duration of gestation) and possibly in their progency may have been caused by altered hormone concentrations.
Effect levels (P1)
- Dose descriptor:
- NOAEL
- Effect level:
- 2.3 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- organ weights and organ / body weight ratios
- histopathology: non-neoplastic
- reproductive performance
Target system / organ toxicity (P1)
open allclose all
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 23 mg/kg bw/day (actual dose received)
- System:
- endocrine system
- Treatment related:
- yes
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 23 mg/kg bw/day (actual dose received)
- System:
- female reproductive system
- Organ:
- uterus
- Treatment related:
- yes
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- -250 ppm: two F1a litters where pups showed poor general state during the first days after birth, which might be related to the test substance administration
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- mortality observed, treatment-related
- Description (incidence and severity):
- - 250 ppm: The mean number of delivered F1a pups/dam and the percentage of liveborn F1a and F1b pups were clearly reduced; markedly increased number of F1a and F1b pups which were stillborn; clearly lower percentage of liveborn pups (F1a and F1b). Reduced viability index (concerning F1b litter)
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- -250 ppm: slightly reduced pup body weight gains (concerning F1a and F1b litters) during some intervals of the lactation period
- 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:
- not examined
- 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, treatment-related
- Description (incidence and severity):
- Due to the increased mortality of the high dose pups (F1a and F1b), the numbers of pups with post mortem autolysis (F1a only) and the numbers of partly
cannibalized pups (F1b only) were significantly increased. - Histopathological findings:
- not examined
- Other effects:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - No effects observed regarding sex ratio of live F1a and F1b pups
- statistically significantly higher number of F1a pups of the substance-treated groups with pinna unfolding on time (spontaneous effect).For the F1b pup generation, statistically significantly less pups of the substance—treated groups showed pinna unfolding and/or eye opening on time (spontaneous effect)
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- no effects observed
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not examined
Details on results (F1)
markedly decreased and the number of stillborn pupsand/or pups which died during the rearing period was significantly increased in all 3 pup generations (F1a,
F1b and F2). Furthermore retarded growth was observed in all pup generations, while slight signs of retarded development were only seen in the F2 pups: however, no signs of substance—induced teratogenic effects were observed for the pups of all pup generations (F1a, F1b, F2), especially no increased incidence of cleft palate was seen.
Effect levels (F1)
open allclose all
- Dose descriptor:
- NOAEL
- Generation:
- F1a
- Effect level:
- 2.3 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- mortality
- gross pathology
- Dose descriptor:
- NOAEL
- Generation:
- F1b
- Effect level:
- 2.3 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- mortality
- gross pathology
Target system / organ toxicity (F1)
- Critical effects observed:
- no
Results: F2 generation
General toxicity (F2)
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- mortality observed, treatment-related
- Description (incidence and severity):
- - 250 ppm: markedly increased number of F2 pups which were stillborn, died or were cannibalized during the rearing period; clearly lower percentage of liveborn pups; consequently reduced viability and lactation indices
The higher number of pups of the 10 ppm and the 25 ppm groups, however, that died during rearing is not assessed as a substance-related but spontaneous finding. - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- - 250 ppm: distinctly lower pup body weight (days 7 - 21 post partum) and impaired pup body weight gains (the mean body weight of the 250 ppm pups was about 12% lower than that of the relevant controls)
- 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:
- not examined
- 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
- Description (incidence and severity):
- Only very few of the large number of examined pups of all groups showed some spontaneous findings like incisors sloped, wounds by biting, cataract, hernia
diaphragmatica, dilated renal pelvis, hydroureter, anophthalmia and hydrocephaly without a clear relation to dosing: most of these findings can be found at a comparable frequency in the historical control data - Histopathological findings:
- not examined
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- - 250 ppm: higher number of F2 pups with negative test result in one developmental stage monitored (pinna unfolding)
- no effects on sex ratio
Developmental neurotoxicity (F2)
- Behaviour (functional findings):
- no effects observed
Developmental immunotoxicity (F2)
- Developmental immunotoxicity:
- not examined
Details on results (F2)
In the highest dose group clear adverse substance induced effects were noted for the progeny of the F0 and F1 parents. The number of liveborn pups was
markedly decreased and the number of stillborn pupsand/or pups which died during the rearing period was significantly increased in all 3 pup generations (F1a,
F1b and F2). Furthermore retarded growth was observed in all pup generations, while slight signs of retarded development were only seen in the F2 pups: however, no signs of substance—induced teratogenic effects were observed for the pups of all pup generations (F1a, F1b, F2), especially no increased incidence of cleft palate was seen.
Effect levels (F2)
- Dose descriptor:
- NOAEL
- Generation:
- F2
- Effect level:
- 2.3 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- mortality
- body weight and weight gain
- other: higher number with negative test result in one developmental stage monitored (pinna unfolding)
Target system / organ toxicity (F2)
- Critical effects observed:
- no
Overall reproductive toxicity
- Reproductive effects observed:
- yes
- Lowest effective dose / conc.:
- 23 mg/kg bw/day (actual dose received)
- Treatment related:
- yes
- Relation to other toxic effects:
- reproductive effects in the absence of other toxic effects
- Dose response relationship:
- yes
Applicant's summary and conclusion
- Executive summary:
The test substance was administered to groups of 25 maleand 25 female immature rats (F0 parental generation) as a constant homogeneous addition to the food in different dose levels (0, 10, 25 or 250 ppm). At least70 days after the beginning of treatment, F0 animalswere mated to produce a first litter (F1a) and subsequently remated to produce a second litter (F1b retained only until weaning). Groups of 25 males and 25females selected from F13 pups as F1 parental generation were offered diets containing 0, 10, 25 and250 ppm of the test substance post weaning, and thebreeding program was repeated to produce F2 litter. The study was terminated with the terminal sacrifice of F2 weanlings and F1 adult animals. Test diets containing the test substancewere offered continuously throughoutthe study.
At the 250 ppm level in F0 parental animals, the following findings were observed;reduced food consumption of the females during the
lactation period of F1a litters,6 dams with vaginal hemorrhages during gestation forF1a litters: 2 of these dams were unable to deliverand died shortly after the expected delivery date and another dam died during gestation (F1b), prolonged cohabitation time (concerning F1a and F1b) and prolonged duration of the gestation period (concerning F1a only),lower male and female fertility indices (concerning F1b): however, finally fertility for all F0 sires and dams could be proven,lower gestation index due to a high number of damswith only stillborn pups (concerning F13 litter),clearly lower number of delivered pups/dam (concerning F1a litters). At 250 ppm, F1a and F1b pups showed markedly increased number of F1a and F1b pups which were stillborn with a clearly lower percentage of livebornpups (F13 and F1b) and reduced viability index (concerningF1b litter),slightly impaired pup body weight gains (concerningF1a and F1b litters),two F1a litters where pups showed poor general stateduring the first days after birth. F1 parental animals at 250 ppm showedreduced food consumption of the males especially atthe beginning of the premating period; the damsshowed slightly to markedly diminished food intakeduring gestation and lactation periods of F2 litter,clearly lower body weights in comparison to thecontrols and slightly impaired weight gains in themales (during the whole study period),one dam with vaginal hemorrhage during the gestationperiod; it did not deliver pups after prolongedgestation,prolonged cohabitation time and slightly prolongedduration of the gestation period; slightly reducedgestation index,increased absolute and relative liver weights in the females without any histopathological correlate and decreased fatty change in the liver of the males. At 250 ppm in F2 pups,markedly increased number of F2 pups which werestillborn, died or were cannibalized during therearing period; clearly lower percentage of livebornpups; consequently reduced viability and lactationindices,distinctly lower pup body weight (days 7 – 21 post-partum)and impaired pup body weight gains andhigher number of F2 pups with negative test result inone developmental stage monitored (pinna unfolding).
It can be said in conclusion that the dietary administration of the test substance to rats in doses of 250 ppm(9 approx. 23 mg/kg body weight/day) caused clear signsof systemic toxicity in the F0 females and in the F1 parental animals and their progeny. At this dose level some of the reproductive parameters were impaired (e.g. lower male and female fertility indices in the F0parents (concerning F1b only). prolonged cohabitationtime and/or gestation period), however, fertility ofall parental animals of both generations could befinally confirmed within in the scheduled periods or inthe reevaluation of fertility. There were no indications for any substance—induced teratogenic effect inthe F1a, F1b or F2 pups.
As it was demonstrated that the test substance causeshormonal imbalance at high dose levels, it isreasonable to infer that some of the adverse effectobserved in the adults (prolonged cohabitation time and duration of gestation) and possibly in their progeny
may have been caused by altered hormone concentrations. 10 and 25 ppm (2 approx. 0.9 or 2.3 mg/kg body weight/
day) were tolerated by the parental animals of bothgenerations and by all litters (F1a, F1b, and F2) without any substance—related adverse effects.
Therefore, the NOAEL (no observable adverse effect level) concerning reproductive function and the NOAELconcerning systemic toxicity of the test substance is 25 ppm (approx. 2.3 mg/kg body weight/day) for bothparental generations (F0 and F1 males and females)andfor their progeny (F1a, F1b and F2 pups).
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