Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 601-101-8 | CAS number: 111497-86-0
- 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
Endpoint summary
Administrative data
Key value for chemical safety assessment
- Toxic effect type:
- dose-dependent
Effects on fertility
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2010
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Qualifier:
- according to guideline
- Guideline:
- other: EPA OPPTS 870.3650 (Combined Repeated Dose Toxicity Study With the Reproduction/ Developmental Toxicity Screening Test)
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- other: Crl:CD(SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Each rat was uniquely identified by a Monel® metal ear tag (National Band and Tag Company, Newport, KY) displaying the animal number.TEST ANIMALS- Source: Charles River Laboratories, Inc., Raleigh, NC- Age at study initiation: approximately 10 weeks old at initiation of dosing - Weight at study initiation: Males 328 g to 415 g; Females 200 g to 257 g; female body weights ranged from 214 g to 289 g on gestation day 0. - Housing: Following receipt and until pairing, all F0 animals were housed individually in clean, stainless steel wire mesh cages suspended above cage board. Following positive evidence of mating, the males were housed in suspended wire mesh cages until the scheduled necropsy, and the females were transferred to plastic maternity cages with nesting material.- Diet: PMI Nutrition International, LLC Certified Rodent LabDiet® 5002 ad libitum except during the period of fasting prior to clinical pathology blood collection- Water: Reverse osmosis-purified (on site) drinking water, delivered by an automatic watering system ad libitum- Acclimation period: 14 days prior to the first day of treatment. ENVIRONMENTAL CONDITIONS- Temperature: Actual 21.2°C to 22.1°C- Humidity: 41.9% to 48.8% - Air changes: minumum of 10/hr- Photoperiod: 12 hour light (0600 hours to 1800 hours)/12 hour dark photoperiod. IN-LIFE DATES: From: 23 February 2010 To: 10 June 2010
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- The vehicle and test substance formulations were administered orally by gavage, via a 16 gauge (2.0 x L-70 mm) flexible, Teflon®-shafted, stainless steel ball-tipped dosing cannula (Natume, Japan).PREPARATION OF DOSING SOLUTIONS: The test substance formulations were prepared every 7-11 days as single formulations for each dosage level, divided into aliquots for daily dispensation, and stored at room temperature, protected from light. The test substance formulations were stirred continuously throughout the preparation, sampling, and dose administration procedures. The first dosing formulations were visually inspected by the Study Director and were found to be clear yellow, visibly homogeneous liquids and acceptable for administration.VEHICLEThe vehicle used in preparation of the test item formulations and for administration to the control group was corn oil .- Concentrations in vehicle: 20, 60 or 200 mg/mL- Dosage volume: 5mL/kg- Lot no. YF0793, exp. date: 22 May 2011- Supplier: Spectrum Chemical Manufacturing Corporation, New Brunswick, NJ.
- Details on mating procedure:
- - M/F ratio per cage: 1:1- Length of cohabitation: until evidence of mating, or a maximum of 14 days- Proof of pregnancy: vaginal copulatory plug or the presence of sperm following a vaginal lavage. The day when evidence of mating was identified was termed gestation day 0. - After successful mating each pregnant female was caged (how): plastic maternity cages with nesting material- Other: The animals were mated following 14 days of treatment. Pairing was in the home cage of the male.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Fourteen-day room temperature stability and resuspension homogeneity of the formulated test substance in the vehicle were established at concentrations of 10 mg/mL and 200 mg/mL in a previous study (Stump, Draft, WIL-738005)Prior to the initiation of dose administration, quadruplicate samples for homogeneity and concentration determinations were collected from the top, middle, and bottom strata of the 20, 60, and 200 mg/mL formulations prepared for the first week of dosing; samples for concentration analysis were also collected from the middle stratum of the vehicle control formulation. Thereafter, quadruplicate samples for concentration analysis were collected from the middle stratum of each dosing formulation (including the control group). One set of samples from each collection was subjected to the appropriate analyses. The remaining set of samples was stored frozen (approximately -70°C) as back-up. All analyses were conducted by the Analytical Chemistry Department at WIL Research Laboratories, LLC using a validated gas chromatography method using flame ionization detection.
- Duration of treatment / exposure:
- Males: Days 0-27 (14 days prior to pairing through 1 day prior to scheduled euthanasia) for a total of 28 doses. Females: Females received 14 daily doses prior to pairing and were dosed through lactation day 4 for a total of 40-44 doses. Females with no evidence of mating or that failed to deliver were dosed through the day prior to euthanasia (post-mating or post-cohabitation day 25) for a total of 39-52 doses.
- Frequency of treatment:
- Once daily, at approximately the same time each day.
- Details on study schedule:
- - Age at mating: approximately 12 weeksAll females were allowed to deliver naturally and rear their young to PND 4. On the day parturition was initiated (PND 0), pups were sexed and examined for gross malformations, and the numbers of stillborn and live pups were recorded. Individual gestation length was calculated using the date delivery started.
- Remarks:
- Doses / Concentrations:100, 300, and 1000 mg/kg/day administered at a dosage volume of 5 mL/kg (dosing forumlations were not adjusted for purity) Basis:
- No. of animals per sex per dose:
- 12 males/12 females
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Dosage levels were selected based on the results of a previous dose range-finding 14 days toxicity study of the test substance in rats (Stump, Draft, WIL 738005) and were provided by the Sponsor after consultation with the Study Director. In the previous study there were no effects on survival, clinical signs, body weights, body weight gains, food consumption, and organ weights and no remarkable macroscopic findings at dosage levels of 100, 500, and 1000 mg/kg/day. Based on these results, dosage levels of 100, 300, and 1000 mg/kg/day were selected for evaluation in the current study.- Rationale for animal assignment: computer randomization procedure
- Positive control:
- None
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: All rats were observed twice daily, once in the morning and once in the afternoon, for moribundity and mortality. Females expected to deliver were also observed twice daily during the period of expected parturition and at parturition for dystocia (prolonged labor, delayed labor) or other difficulties.CLINICAL OBSERVATIONS: A detailed physical examination was conducted weekly on each animal beginning approximately 1 week prior to the initiation of dose administration, including on the day of necropsy. These examinations were performed outside the home cage in an open field at approximately the same time each week and included, but were not limited to, evaluations for changes in appearance of skin and fur, eyes, mucous membranes, respiratory, circulatory, autonomic, and central nervous system function, somatomotor activity, and behavior. Each male and female was also observed for signs of toxicity immediately following dosing and approximately 1 hour following dose administration.BODY WEIGHT- Male: Individual male body weights were recorded beginning approximately 1 week prior to the initiation of dose administration, on the first day of dose administration, and weekly thereafter until the day prior to scheduled euthanasia. - Female: Individual female body weights were recorded beginning approximately 1 week prior to the initiation of dose administration, on the first day of dose administration, and weekly thereafter until the day evidence of copulation was observed. Once evidence of mating was observed, female body weights were recorded on gestation days 0, 4, 7, 11, 14, 17, and 20 and on lactation days 0 (when possible), 1, 4, and 5.FOOD CONSUMPTION: Individual food consumption was recorded on the corresponding weekly body weight days until pairing. Food intake was not recorded during the mating period. Once evidence of mating was observed, female food consumption was recorded on gestation days 0, 4, 7, 11, 14, 17, and 20 and on lactation days 1 and 4. Following mating, food consumption for all males was measured on a weekly basis until the scheduled euthanasia. Food consumption was reported as g/animal/day and g/kg/day for the corresponding body weight change intervals. Calculation of the comprehensive intervals excludes all erroneous values such as total food spillage.FOB ASSESSMENTS: FOB assessments were recorded for 6 animals/sex/group prior to dose administration on study day 27 (males) and lactation day 4 (females). FOB testing was performed without knowledge of the animal’s group assignment. All animals were observed for the following parameters:- Home Cage Observations: Posture, Convulsions/Tremors, Feces consistency, Biting, Palpebral (eyelid) closure.- Handling Observations: Ease of removal from cage, Lacrimation/Chromodacryorrhea, Piloerection, Palpebral closure, Eye prominence, Red/Crusty deposits, Ease of handling animal in hand, Salivation, Fur appearance, Respiratory rate/character, Mucous membranes/Eye/Skin color, Muscle tone.- Open Field Observations (2-min observation period): Mobility, Rearing, Convulsions/Tremors, Grooming, Bizarre/Stereotypic behavior, Time to first step (seconds), Gait, Arousal, Urination/Defecation, Gait score, Backing.- Sensory Observations: Approach response, Startle response, Pupil response, Forelimb extension, Air righting reflex, Touch response, Tail pinch response, Eyeblink response, Hindlimb extension, Olfactory orientation.- Neuromuscular Observations: Hindlimb extensor strength, Hindlimb foot splay, Grip strength hind and forelimb, Rotarod performance.- Physiological Observations: Catalepsy, Body temperature, Body weight.LOCOMOTOR ACTIVITY: Locomotor activity counts were recorded for 6 animals/sex/group prior to dose administration on study day 27 (males) and on lactation day 4 (females); the same animals evaluated for FOB were selected for locomotor activity assessment. Locomotor activity, recorded after the completion of the FOB, was measured automatically using a personal computer controlled system that utilizes a series of infrared photobeams surrounding a clear plastic, rectangular cage to quantify each animal’s motor activity. Four-sided black plastic enclosures were used to surround the clear plastic boxes to decrease the potential for distraction from extraneous environmental stimuli or stimuli from biologists or adjacent animals. The black enclosures rested on top of the photobeam frame and did not interfere with the path of the beams. The testing of treatment groups was done according to replicate sequence. Each animal was tested separately. Data were collected in twelve, 5 minute epochs and the test session duration was 60 minutes. These data were compiled as six, 10-minute subintervals for tabulation.CLINICAL PATHOLOGY: Blood samples for clinical pathology evaluations (hematology and serum chemistry) were collected from 6 animals/sex/group at the scheduled necropsies (study day 28 for males and lactation day 5 females); the same animals evaluated for FOB and locomotor activity were selected for clinical pathology assessment. All animals were food-fasted overnight prior to blood collection, with water available. Blood for serum chemistry (approximately 1.5 mL) and hematology (approximately 0.5 mL) was collected from the retro orbital sinus following isoflurane anesthesia. Blood for coagulation parameters (approximately 1.8 mL) was collected from the vena cava at the time of necropsy. Blood was collected into tubes containing EDTA (hematology), sodium citrate (clotting determinations), or no anticoagulant (serum chemistry). - Hematology: Total leukocyte count, Erythrocyte count, Hemoglobin, Hematocrit, Mean corpuscular volume, Mean corpuscular hemoglobin, Mean corpuscular hemoglobin concentration, Platelet count, Prothrombin time, Activated partial thromboplastin time, Reticulocyte count Percent / Absolute, Mean Platelet Volume, Red cell distribution width, Hemoglobin Distribution Width, Differential leukocyte count, Platelet estimate, Red cell morphology.- Clinical Chemistry: Albumin, Total protein, Globulin [by calculation], Albumin/globulin ratio [by calculation], Total bilirubin, Urea nitrogen, Creatinine, Alkaline phosphatase, Alanine aminotransferase, Aspartate aminotransferase, Gamma glutamyltransferase, Glucose, Total cholesterol, Calcium, Chloride, Phosphorus, Potassium, Sodium, Triglycerides, Bile acids.
- Litter observations:
- PARTURITION:On the day parturition was initiated (PND 0), pups were sexed and examined for gross malformations, and the numbers of stillborn and live pups were recorded. Individual gestation length was calculated using the date delivery started.LITTER VIABILITY AND DEATHS: Each litter was examined daily for survival, and all deaths were recorded. All pups were individually identified by application of tattoo markings on the digits following completion of parturition. A daily record of litter size was maintained. CLINICAL OBERSERVATIONS: Litters were examined daily for survival and any adverse changes in appearance or behavior. Each pup received a detailed physical examination on PND 1 and 4. Any abnormalities in nursing behavior were recorded.BODY WEIGHTS: Pups were individually weighed on PND 1 and 4. Mean pup weights were presented by sex for each litter and by dose group.SEX DETERMINATION: Pups were individually sexed on PND 0 (if possible), 1, and 4.
- Postmortem examinations (parental animals):
- SACRIFICE: All F0 adults were euthanized by carbon dioxide inhalation. Males were euthanized following completion of the mating period. Females were euthanized on lactation day 5; the numbers of former implantation sites and corpora lutea were recorded. Gross necropsies were conducted on all animals. GROSS NECROPSYNecropsies included examination of the external surface, all orifices, the external surface of the brain, and the cranial, thoracic, abdominal, and pelvic cavities, including viscera. The following tissues and organs were placed in 10% neutral buffered formalin (except as noted): Adrenal glands, Aorta, Bone with marrow (sternebrae), Bone marrow smear(a), Brain (Cerebrum level, Cerebrum level, Cerebellum with medulla/pons), Coagulating gland, Eyes with optic nerve(b), Gastrointestinal tract, Esophagus, Stomach, Duodenum, Jejunum, Ileum, Cecum, Colon, Rectum, Heart, Kidneys, Liver (sections of 2 lobes), Lungs (including bronchi, fixed by inflation with fixative) Lymph nodes (Axillary, Mesenteric, Mandibular), Ovaries and oviducts(c), Pancreas, Peripheral nerve (sciatic), Pituitary gland, Prostate gland, Mandibular salivary glands, Seminal vesicles, Skeletal muscle (rectus femoris), Skin with mammary gland(d), Spinal cord (cervical), Spleen, Testes with epididymides(e), Thymus gland, Thyroids [with parathyroids, if present], Trachea, Urinary bladder, Uterus (f) with cervix and vagina, All gross lesions.ORGAN WEIGHTS: The following organs were weighed from all F0 animals at the scheduled necropsies: Adrenal glands, Brain, Epididymides, Heart, Kidneys, Liver, Ovaries with oviducts, Spleen, Testes, Thymus gland, Thyroids with parathyroids.HISTOPATHOLOGY: Microscopic examination was performed on all tissues from all animals in the control and 1000 mg/kg/day groups. In addition, gross lesions from animals at all dosage levels were examined microscopically. The evaluation of the testes and epididymides was sufficient to identify possible treatment-related effects such as retained spermatids, missing cell layers or types, micronucleated giant cells, or sloughing of spermatogenic cells into the lumen. Examination of the intact epididymides included the caput, corpus, and cauda, in addition to evaluation of leukocyte infiltration, change in prevalence of cell types, aberrant cell types, and phagocytosis of sperm. Microscopic examination of the ovary was sufficient to detect any relevant changes in the follicular development, follicular atresia, and corpora lutea formation.
- Postmortem examinations (offspring):
- SACRIFICE: Following a detailed physical examination on PND 4, surviving F1 rats were euthanized via an intraperitoneal injection of sodium pentobarbital and discarded without internal examination. Intact offspring that were found dead were necropsied using a fresh dissection technique, which included examination of the heart and major vessels (Stuckhardt and Poppe, 1984). The carcass of each pup was then discarded.
- Statistics:
- Each mean was presented with the standard deviation (S.D.), standard error (S.E.), and the number of animals (N) used to calculate the mean. Where applicable, the litter was used as the experimental unit.
- Reproductive indices:
- The following reproductive indices were calculated: Male Mating Index, Female Mating Index, Male Fertility Index, Female Fertility Index, Male Copulation Index, Female Conception Index, Pre-Coital Interval (days).
- Offspring viability indices:
- The following parameters were calculated: Mean Live Litter Size, Postnatal Survival Between Birth and PND 0 or PND 4 (% Per Litter), Postnatal Survival for All Other Intervals (% Per Litter).
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Red and clear material around the mouth was noted for the 1,000 mg/kg bw/day group males and females at approximately 1 h post-dosing. However, because the number of occurrences per animal was low and generally sporadic throughout the study and severity was generally slight, these clinical findings were not considered adverse. Moreover, the increased incidence of clear material around the mouth was likely a sign of taste aversion. A low incidence of rales was also observed for the 1,000 mg/kg bw/day group females at the time of and approximately 1 h following dose administration. This finding was likely related to aspiration of the test substance.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- 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:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Mild hypertrophy of thyroid follicular epithelial cells was observed in 2 of 12 females at 1000 mg/kg bw/day. This change is not uncommon in rats and was of minimal severity. Hypertrophy of the thyroid follicular epithelial cells often occurs secondary to drug metabolizing enzyme induction in the liver, ultimately leading to thyroid gland hypertrophy. In the present study however, there was no evidence of hepatic enzyme induction in the females; therefore, this finding was treatment-related but considered non-adverse.
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- Male and female mating and fertility, male copulation and female conception indices, mean number of days between pairing and coitus, gestation length, and the process of parturition were unaffected by test substance administration at all dosage levels.
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- (systemic toxicity)
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects were observed at the highest level tested.
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- (Reproductive toxicity)
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects were observed at the highest level tested.
- Clinical signs:
- not examined
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- not examined
- Body weight and weight changes:
- not examined
- 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
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not examined
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- not examined
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- 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
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
- Other effects:
- not examined
- Behaviour (functional findings):
- not examined
- Developmental immunotoxicity:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- viability
- clinical signs
- mortality
- body weight and weight gain
- gross pathology
- Clinical signs:
- not examined
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- not examined
- Body weight and weight changes:
- not examined
- 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
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not examined
- Histopathological findings:
- not examined
- Other effects:
- not examined
- Behaviour (functional findings):
- not examined
- Developmental immunotoxicity:
- not examined
- Key result
- Reproductive effects observed:
- no
- Conclusions:
- Under the conditions, no test substance-related effects on reproductive performance, gestation length, parturition, reproductive organs, or neurobehavioral parameters were noted at any dosage level. Based on these results, a dosage level of 1000 mg/kg bw/day was considered to be the NOAEL for reproductive toxicity of the test substance when administered orally by gavage to Crl:CD(SD) rats. Due to the absence of adverse clinical findings and no test substance-related effects on mean body weights, body weight changes, and food consumption at all dosage levels, the NOAEL for systemic toxicity was considered to be 1000 mg/kg/day. In the absence of effects on the general physical condition of the F1pups, the NOAEL for neonatal toxicity was 1000 mg/kg bw/day.
- Executive summary:
The toxicity to reproduction of amine synergist was tested in a repeated dose and reproduction / developmental toxicity screening study (OECD 422 and OPPTS 870.3650) in rats.
The test substance in the vehicle, corn oil, was administered orally by gavage once daily to 3 groups of Sprague Dawley [Crl:CD(SD)] rats, each group consisting of 12 males and 12 females. Dosage levels were 100, 300, and 1000 mg/kg/day administered at a dosage volume of 5 mL/kg. A concurrent control group of 12 rats/sex received the vehicle (corn oil) on a comparable regimen. Males and females were approximately 10 weeks of age at the beginning of test substance administration. Males received 14 daily doses prior to mating. Males were dosed throughout the mating period through 1 day prior to euthanasia for a total of 28 doses. Females received 14 daily doses prior to pairing and were dosed through lactation day 4 for a total of 40-44 doses.
All animals were observed twice daily for mortality and moribundity. Clinical observations, body weights, and food consumption were recorded at appropriate intervals. FOB and locomotor activity data were recorded for6 males/group following approximately 28 days of dose administration and for 6 females/group on lactation day 4. All F0females were allowed to deliver and rear their pups until lactation day 4. Each litter was examined daily for survival and all deaths were recorded. F1 clinical observations and body weights were recorded on postnatal day (PND) 1 and 4. Pups were euthanized and discarded on PND 4. Clinical pathology evaluations (hematology and serum chemistry) were performed on 6 F0animals/sex/group at necropsy. F0males were euthanized following completion of the mating period and F0females were euthanized on lactation day 5. Complete necropsies were conducted on all F0animals, and selected organs were weighed. Selected tissues were examined microscopically from all F0animals in the control and high-dose groups; gross lesions from all animals in all dosage groups were also examined microscopically.
All animals survived to the scheduled necropsies. Red and clear material around the mouth were noted for the 1000 mg/kg/day group males and females at approximately 1 hour post-dosing. However, because the number of occurrences per animal was low and generally sporadic throughout the study, and the severity of these findings was generally slight, these clinical findings were not considered adverse. Moreover, the increased incidence of clear material around the mouth was likely a sign of taste aversion. A low incidence of rales was also observed for the 1000 mg/kg/day group females at the time of and approximately 1 hour following dose administration. This finding was likely related to aspiration of the test substance.
Mean body weights, body weight changes, and food consumption were unaffected by test substance administration in the 100, 300, and 1000 mg/kg/day group males and females throughout the study. No test substance-related effects were noted during the FOB assessments or locomotor activity evaluations at any dosage level. Higher mean absolute and relative (to final body and brain weights) liver and thyroid/parathyroid weights were noted for the 1000 mg/kg bw/day group males and females, respectively. Because there were no microscopic correlations for these findings, the increased organ weights were considered to be test substance-related but nonadverse. Mild hypertrophy of thyroid follicular epithelial cells was observed in 2 of 12 females of the 1000 mg/kg bw/day group. This change is not uncommon in rats and was of minimal severity in the affected females. Hypertrophy of the thyroid follicular epithelial cells often occurs secondary to drug metabolizing enzyme induction in the liver, ultimately leading to thyroid gland hypertrophy. In the present study, however, there was no evidence of hepatic enzyme induction in the females; therefore, this finding was test substance-related but considered nonadverse and toxicologically unimportant. There were no test substance‑related changes in clinical pathology parameters or gross necropsy observations at any dosage level. Male and female mating and fertility, male copulation and female conception indices, mean number of days between pairing and coitus, gestation length, and the process of parturition were unaffected by test substance administration at all dosage levels. Mean numbers of corpora lutea, unaccounted-for sites, and implantation sites, mean number of pups born, live litter size, the percentage of males at birth, and postnatal survival in the 100, 300, and 1000 mg/kg bw/day groups were similar to the control group values. Mean pup body weights and body weight gains at all dosage levels were unaffected by dose administration. No test substance-related clinical findings or macroscopic findings for F1pups that were found dead were noted at any dosage level.
Under the conditions of this screening study, no test substance-related effects on reproductive performance, gestation length, parturition, reproductive organs, or neurobehavioral parameters were noted at any dosage level. Based on these results, a dosage level of 1000 mg/kg bw/day was considered to be the NOAEL for reproductive toxicity of the test substance when administered orally by gavage to Crl:CD(SD) rats. Due to the absence of adverse clinical findings and no test substance-related effects on mean body weights, body weight changes, and food consumption at all dosage levels, the NOAEL for systemic toxicity was considered to be 1000 mg/kg bw/day. In the absence of effects on the general physical condition of the F1pups, the NOAEL for neonatal toxicity was 1000 mg/kg bw/day.
Reference
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
The toxicity to reproduction of amine synergist was tested in a repeated dose and reproduction/developmental toxicity screening study (OECD 422 and OPPTS 870.3650) in rats, in compliance with GLP.
The substance was administered by gavage once daily to 3 groups of Sprague Dawley [Crl:CD(SD)] rats, each group consisting of 12 males and 12 females. Dosage levels were 100, 300 and 1,000 mg/kg bw/day (5 mL/kg bw). A concurrent control group of 12 rats/sex received the vehicle (corn oil) on a comparable regimen. Males and females were approximately 10 weeks of age at test start. Males received 14 daily doses prior to mating then were dosed throughout the mating period through 1 day prior to euthanasia for a total of 28 doses. Females received 14 daily doses prior to pairing and were dosed through Lactation Day 4 for a total of 40-44 doses. All animals were observed twice daily for mortality. Clinical observations, bodyweight and food consumption were recorded at appropriate intervals. Functional observation battery (FOB) and locomotor activity data were recorded for 6 males/group following approximately 28 days of dose administration and for 6 females/group on Lactation Day 4. All F0 females were allowed to deliver and rear their pups until Lactation Day 4. Each litter was examined daily for survival and all deaths were recorded. F1 clinical observations and bodyweights were recorded on Postnatal Day 1 and 4. Pups were euthanized and discarded on Postnatal Day 4. Clinical pathology evaluations (hematology and serum chemistry) were performed on 6 F0 animals/sex/group at necropsy. F0 males were euthanized following completion of the mating period and F0 females were euthanized on Lactation Day 5. Complete necropsies were conducted on all F0 animals, and selected organs were weighed. Selected tissues were examined microscopically from all F0 animals in the control and high-dose groups; gross lesions from all animals in all dosage groups were also examined microscopically.
All animals survived to the scheduled necropsies. Red and clear material around the mouth was noted for the 1,000 mg/kg bw/day group males and females at approximately 1 h post-dosing. However, because the number of occurrences per animal was low and generally sporadic throughout the study and severity was generally slight, these clinical findings were not considered adverse. Moreover, the increased incidence of clear material around the mouth was likely a sign of taste aversion. A low incidence of rales was also observed for the 1,000 mg/kg bw/day group females at the time of and approximately 1 h following dose administration. This finding was likely related to aspiration of the test substance. Mean bodyweight, bodyweight change and food consumption were unaffected compared to controls at 100, 300, and 1000 mg/kg bw/day. No treatment-related effects were noted during the FOB or locomotor activity evaluations at any dosage level. Higher mean absolute and relative (to final body and brain weights) liver and thyroid/parathyroid weights were noted at 1,000 mg/kg bw/day. Because there were no microscopic correlations for these findings, the increased organ weights were considered to be treatment-related but non-adverse. Mild hypertrophy of thyroid follicular epithelial cells was observed in 2 of 12 females at 1000 mg/kg bw/day. This change is not uncommon in rats and was of minimal severity. Hypertrophy of the thyroid follicular epithelial cells often occurs secondary to drug metabolizing enzyme induction in the liver, ultimately leading to thyroid gland hypertrophy. In the present study however, there was no evidence of hepatic enzyme induction in the females; therefore, this finding was treatment-related but considered non-adverse. There were no treatment-related changes in clinical pathology parameters or gross necropsy observations at any dosage level. Male and female mating and fertility, male copulation and female conception indices, mean number of days between pairing and coitus, gestation length, and the process of parturition were unaffected by test substance administration at all dosage levels. Mean numbers ofcorpora lutea, unaccounted-for sites, implantation sites, mean number of pups born, live litter size, the percentage of males at birth and postnatal survival in the 100, 300, and 1000 mg/kg bw/day groups were similar to the control group values. Mean pup bodyweight and bodyweight gain at all dosage levels were unaffected by dose administration. No treatment-related clinical or macroscopic findings for F1 pups that were found dead were noted at any dosage level.
Under the conditions of this screening study, no treatment-related effects on reproductive performance, gestation length, parturition, reproductive organs or neurobehavioral parameters were noted at any dose level. Based on these results, 1,000 mg/kg bw/day was considered to be the NOAEL for reproductive toxicity of the test substance when administered orally by gavage to Crl:CD(SD) rats. Due to the absence of adverse clinical findings and no treatment-related effects on mean bodyweight, bodyweight change and food consumption at all dose levels, the NOAEL for systemic toxicity was considered to be 1,000 mg/kg bw/day. In the absence of effects on the general physical condition of the F1 pups, the NOAEL for neonatal toxicity was 1,000 mg/kg bw/day (Stump, 2011).
Effects on developmental toxicity
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 21 October 2015 - 09 May 2016
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL- Source and lot/batch No.of test material: JBLE0012T- Expiration date of the lot/batch: May 2016STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL- Storage condition of test material: Controlled room temperature protected from lightTREATMENT OF TEST MATERIAL PRIOR TO TESTING- Treatment of test material prior to testing: None
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS - Source: Charles River Laboratories, Sulzfeld, Germany - Age at study initiation: 11 weeks old at mating - Weight at study initiation: 197-233 g - Fasting period before study: - Housing: - Diet (e.g. ad libitum): ssniff SM R/M "Autoclavable Complete Feed for Rats and Mice - Breeding and Maintenance" - Water (e.g. ad libitum): tap water - Acclimation period: 5 days ENVIRONMENTAL CONDITIONS - Temperature (°C): 20.0 - 23.8°C - Humidity (%): 39-70% - Air changes (per hr): 15-20/hour - Photoperiod (hrs dark / hrs light):12 / 12 IN-LIFE DATES: From: 17 November 2015 To: 07 December 2015
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: VEHICLE - Justification for use and choice of vehicle (if other than water): corn oil - Lot/batch no. (if required): MKBQ9948V / MKBS6944V- 3 mL/kg
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analysis of test substance for concentration and/or homogeneity by validated GC method.Duplicate samples (top, middle and bottom samples) taken from the test formulation two times during the study (second and last weeks of treatment). One duplicate sample taken on each occasion from vehicle control for concentration measurement.
- Details on mating procedure:
- - Impregnation procedure: cohoused - If cohoused: - M/F ratio per cage: 1:1 - Length of cohabitation: 2 hours - Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- Duration of treatment / exposure:
- GD 6 to GD 19
- Frequency of treatment:
- Daily
- Duration of test:
- Until GD 20
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 24 mated females/group
- Control animals:
- yes
- Details on study design:
- - Dose selection rationale: based on available data, including an OECD 422 study
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes - Time schedule: Twice daily each day DETAILED CLINICAL OBSERVATIONS: Yes / No / No data - Time schedule: at the onset of treatment (GD 6) then weekly BODY WEIGHT: Yes - Time schedule for examinations: GD 0, 3, 6, 8, 10, 12, 14, 16, 18 and 20 FOOD CONSUMPTION: Yes - Time schedule: GD 0, 3, 6, 8, 10, 12, 14, 16, 18 and 20 POST-MORTEM EXAMINATIONS: Yes - Sacrifice on gestation day 20 - Organs examined: viscera, ovaries, uterus, OTHER:
- Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes Examinations included: - Gravid uterus weight: Yes - Number of corpora lutea: Yes - Number of implantations: Yes - Number of early resorptions: Yes - Number of late resorptions: Yes
- Fetal examinations:
- - External examinations: Yes: all per litter - Soft tissue examinations: Yes: half per litter - Skeletal examinations: Yes: half per litter - Head examinations: Yes:half per litter
- Statistics:
- SPSS PC+4.0
- Historical control data:
- Yes
- Clinical signs:
- effects observed, non-treatment-related
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Statistically significantly decreased bodyweight and bodyweight gain were seen in the high dose group on several days/periods. However, the difference in terminal bodyweight and bodyweight gain during the study (GD 0 - 20) was less than 10%. Furthermore, the bodyweight loss duing the treatment period (GD 6 - 20) was not considered statistically significant. Therefore, these findings were not considered as clear treatment-related adverse effects. A similar but stronger effect was detected for the corrected terminal bodyweight, corrected bodyweight gain and corrected net bodyweight gain. The corrected bodyweight gain and corrected net bodyweight gain values were significantly lower compared to the control group (by 22 and 29%, respectively). These adverse effects were considered related to administration of the test substance.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- A slight effect on food consumption was observed for all test groups. Statistically significant decreased food consumption was seen for the high dose 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
- 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:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
- Number of abortions:
- not examined
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- not examined
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined - Changes in number of pregnant:
- not examined
- Other effects:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed - Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- not examined
- Changes in litter size and weights:
- not examined
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Visceral malformations:
- no effects observed
- Other effects:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- not specified
- Remarks on result:
- other: Embryotoxicity
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- not specified
- Remarks on result:
- other: Foetotoxicity
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- not specified
- Remarks on result:
- other: Teratogenicity
- Key result
- Abnormalities:
- no effects observed
- Key result
- Developmental effects observed:
- no
- Executive summary:
A study was conducted to assess the effect of amine synergist on the embryonic and fetal development of Hannover Wistar rats in their first pregnancy according to OECD Guideline 414, in compliance with GLP. Groups of 24 pregnant females were administered the substance diluted in corn oil (3 mL/kg) at 0, 100, 300 and 1000 mg/kg/day from Gestation Day 6 to 20. Cesarian sections, necrospy of dams and examinations of uterine content were performed on GD 20.
Dose formulations were analysed for test substance concentration twice during the treatment period using a validated GC method. Parameters monitored during the study included mortality and clinical observations, body weight, body weight gain and individual food consumtion. Maternal reproductive parameters associated with uterine examination were evaluated, and the foetuses were weighed ande xamined for external, visceral and skeletal abnormalities. Placentas were examined macroscopically. The number of confirmed pregnant, evaluated dams in the dose groups treated was 24 in the control group and 23, 24 and 24 in the low, mid and high dose groups, respectively.
All formulations were within the range of 92 to 107% of nominal concentration an were found to be homogenous. No test item was detected in the control samples. Based on these results, test item formulations were considered suitable for the study purposes. There was no unscheduled mortality or treatment related clinical signs in the study. Statistically significantly decreased body weight or body weight gain values were observed for the High dose group (100 mg/kg bw/day) on several days / periods. However, the difference in the terminal body weight and the body weight gain during the study (GD0-20) was less than 10%. Furthermore the body weight loss during the treatment period GD6-20) was not considered statistically significant. Therefore these findings were not considered as a clear test item related adverse effect. A similar but stronger effect was detected for the corrected terminal body weight, corrected body weight gain and corrected net body weight gain. The corrected body weight gain and corrected net body weight gain values were significantly lower compared to the control group (by 22% and 29% respectively). These adverse effects were considered related to the administration of the test item. A slight effect on the food consumtpion was observed in the study for all test groups. Additionally, statistically significant decreased food consumption was observed for the high dose group. There were no toxicologically significant differences, or test item related-changes in the reproductive parameters examined in the conditions of this study. The number of corpora lutea, implantation sites and pre-implantation loss mean values were comparable to the control for the test item treated groups at all dose levels. There were no effects on the early and late embryonic loss, post-implantation (total resorption, including the early and late embryonic loss) or total intrauterine mortality in the test item-related dams. No remarkable internal or external observations were recorded for any pregnant animals during necropsy. No abnormalities were observed on the placentas in any examined groups. The mean number of viable foetuses in all test item treated groups as well as their sex distribution were comparable with the control.
The weight of foetuses in the low, mid and high dose groups did not differ significantly from the control mean, when evaluated by both litter mean and group mean.
The number of body weight retarded foetuses in the test item treated groups was lower than in the control group. All abnormalities observed at external, visceral or skeletal examination in this study were considered as incidental findings, which were also observed in the concurrent study control group. The findinds lauid within historical control (HC) data or were considered to be spontaneous events unrelated to treatment.
In conclusion, when administered daily by oral gavage to pregnant Hannover Wistar rats from gestation days GD 6 to 19, amine synergist caused a slight maternal body weight and food intake effect in the high dose group, demonstrating an adequate but relatively minor maternal toxicity. There was no evidence of any adverse maternal effects in the mid and low dose groups. There were no toxicologically significant differences, or test item related-changes in the reproductive parameters examined in the conditions of this study. No foetal effects were seen at external, visceral and/or skeletal examination of foetuses in the study which could be related to the test item administration. The following NOAELs were derived (Hargitai, 2016):
NOAELmaternal toxicity:300 mg/kg bw/day
NOAELembryotoxicity:1000 mg/kg bw/day
NOAEL foetotoxicity: 1000 mg/kg bw/day
NOAELteratogenicity: 1000 mg/kg bw/day
Reference
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Toxicity to reproduction: other studies
Additional information
A study was conducted to determine the potential developmental toxicity of amine synergist to Hannover Wistar rats in accordance with OECD Guideline 414, in compliance with GLP. Groups of 24 pregnant females were administered the substance by gavage at 0, 100, 300 and 1000 mg/kg/day from Gestation Day (GD) 6 to 20.
Dose formulations were analysed for test item concentration twice during the treatment period using a validated GC method. Parameters monitored during the study included mortality and clinical observations, body weight, body weight gain and individual food consumtion. Maternal reproductive parameters associated with uterine examination were evaluated, and the foetuses were weighed and examined for external, visceral and skeletal abnormalities. Placentas were examined macroscopically.
The number of confirmed pregnant, evaluated dams in the dose groups treated was 24 in the control group and 23, 24 and 24 in the low, mid and high dose groups, respectively.
All formulations were within the range of 92 to 107% of nominal concentration an were found to be homogenous. No test item was detected in the control samples. Based on these results, test item formulations were considered suitable for the study purposes. There was no unscheduled mortality or treatment related clinical signs in the study. Statistically significantly decreased body weight or body weight gain values were observed for the high dose group on several days / periods. However, the difference in the terminal body weight and the body weight gain during the study (GD0-20) was less than 10%. Furthermore the body weight loss during the treatment period GD6-20) was not considered statistically significant. Therefore these findings were not considered as a clear test item related adverse effect. A similar but stronger effect was detected for the corrected terminal body weight, corrected body weight gain and corrected net body weight gain. The corrected body weight gain and corrected net body weight gain values were significantly lower compared to the control group (by 22 and 29% respectively). These adverse effects were considered related to the administration of the test item. A slight effect on the food consumtpion was observed in the study for all test groups. Additionally, statistically significant decreased food consumption was observed for the High dose group. There were no toxicologically significant differences, or test item related-changes in the reproductive parameters examined in the conditions of this study. The number of corpora lutea, implantation sites and pre-implantation loss mean values were comparable to the control for the test item treated roups at all dose levels. There were no effects on the early and late embryonic loss, post-implantation (total resorption, including the early and late embryonic loss) or total intrauterine mortality in the test item-related dams. No remarkable internal or external observations were recorded for any pregnant animals during necropsy. No abnormalities were observed on the placentas in any examined groups. The mean number of viable foetuses in all test item treated groups as well as their sex distribution were comparable with the control.
The weight of foetuses in the low, mid and high dose groups did not differ significantly from the control mean, when evaluated by both litter mean and group mean. The number of body weight retarded foetuses in the test item treated groups was lower than in the control group. All abnormalities observed at external, visceral or skeletal examination in this study were considered as incidental findings, which were also observed in the concurrent study control group. The findings were within historical control (HC) data or were considered to be spontaneous events unrelated to treatment.
In conclusion, amine synergist, when administered daily by oral gavage to pregnant Hannover Wistar rats from GD 6 to 19, caused a slight maternal body weight and food intake effect in the high dose group, demonstrating an adequate but relatively minor maternal toxicity. There was no evidence of any adverse maternal effects in the mid and low dose groups. There were no toxicologically significant differences, or test item related-changes in the reproductive parameters examined in the conditions of this study.
No foetal effects were seen at external, visceral and/or skeletal examination of foetuses in the study which could be related to the test item administration. The following NOAELs were derived (Hargitai, 2016):
NOAEL maternal toxicity:
300 mg/kg bw/day
NOEL embryo toxicity: 1000 mg/kg bw/day
NOEL foetotoxicity: 1000 mg/kg bw/day
NOEL teratogenicity: 1000 mg/kg bw/day
Justification for classification or non-classification
Based on the NOAELs for developmental toxicity of 1,000 mg/kg/day from an OECD Guideline 422 and an OECD Guideline 414 study in which no treatment-related effects were observed, it can be concluded that amine synergist does not require classification for this endpoint according to CLP (EC 1272/2008) criteria.
Additional information
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.