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EC number: 202-996-4 | CAS number: 102-01-2
- 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:
- toxicity to reproduction
- Remarks:
- other: REPRODUCTIVE/DEVELOPMENTAL TOXICITY SCREEN
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Well performed OECD and GLP guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 996
- Report date:
- 1996
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- yes
- Remarks:
- Only minor deviations exist that do not affect the validity of the study.
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Acetoacetanilide
- EC Number:
- 202-996-4
- EC Name:
- Acetoacetanilide
- Cas Number:
- 102-01-2
- Molecular formula:
- C10H11NO2
- IUPAC Name:
- 3-oxo-N-phenylbutanamide
- Details on test material:
- - Name of test material (as cited in study report): acetoacetanilide
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Crl:CD®BR(SD) VAF/Plus® (abbreviated as CD®)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- - Source: Charles River Laboratories, Inc, Portage, Michigan
- Number of Rats: 75 (male), 75 (female)
- Approx date of birth: 16 Jul 1995 (m), 9 Jul 1995 (f)
- Approx age at arrival: 58 days (m), 65 days (f)
- Weight (g) on day after arrival: 245 - 284 (m), 187 - 228 (f)
- Weight (g) at study assignment: 352 - 374 (m), 238 - 266 (f)
- Room temperature: 70 °F - 78 °F (+/- 2 %)
- Rel. humidity: 40% - 70%
- Diet: Certified Rodent Diet #5002, ad libitum
- Water: Local water processed through a reverse osmosis membrane and chlorinated, ad libitum, from automatic watering system.
- Artificial light: in 12 hr periods, dark period beginning at 1900 EST.
- Identification: Each rat was individually identified with a Monel self-piercing ear tag. F1 generation pups were not individually identified.
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: Aqueous 1.0% methylcellulose
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
- Dosing suspensions were prepared at approximately weekly intervals. The amount of the test substance used in the preparation of the dosing suspensions was not adjusted for the percent active ingredient since the test substance is > 99% pure. The amounts of suspensions that were used for dosage were documented each day. - Details on mating procedure:
- - Male and female rats were cohabitated in pairs during the breeding period, which lasted a maximum of 14 days
- Proof of pregnancy: observation of spermatozoa in a smear of the vaginal contents and/or a copulatory plug observed in situ.
- Each pair of rats was returned to individual housing after mating was confirmed.
- Rats that did not mate remained in cohabitation for the entire breeding period. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Dosing suspensions were analysed for the concentration of the test substance at Lancaster laboratories, PA. The methods used for these analyses are described in detail in the Analytical Report (Appendix 2 of the full study report).
- Duration of treatment / exposure:
- Parental generation male and female rats were administered the test substance once daily as a single daily dose. Dosage volumes were based on the most recently recorded body weights. Male rats were given the test substance once daily beginning 14 days before breeding and continued through the day before sheduled sacrifice. Male received a total of 47 to 49 doses. Female rats were given the test substance once daily beginning 14 days before breeding and continued through day 4 postpartum, when they were scrificed. Female rats received a total of 39 to 52 doses.
- Frequency of treatment:
- Male received a total of 47 to 49 doses. Female rats received a total of 39 to 52 doses.
- Details on study schedule:
- - Length of Study: approx. 8 weeks
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
Dosage: 0 mg/kg/day, Conc: 0 mg/l (in vehicle)
Basis:
nominal conc.
- Remarks:
- Doses / Concentrations:
Dosage: 3 mg/kg/day, Conc: 0.3 mg/l (in vehicle)
Basis:
nominal conc.
- Remarks:
- Doses / Concentrations:
Dosage: 30 mg/kg/day, Conc: 3 mg/l (in vehicle)
Basis:
nominal conc.
- Remarks:
- Doses / Concentrations:
Dosage: 100 mg/kg/day, Conc: 10 mg/l (in vehicle)
Basis:
nominal conc.
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Dosage levels were selected based on the results of 7-day repeated dose toxicity screen conducted prior to this study.Based on the results of that study a high dosage level of 100 mg/kg/day in this reproductive/developmental toxicity screen was expected to result in a significant amount of systemic toxicity (methemoglobinemia and hemolytic anemia) and was considered to be the highest dosage level that could be tolerated by pregnant animals in the study. The 30 mg/kg/day dosage level was expected to produce an intermediate degree of effect or no effect, and the 3 mg/kg/day dosage level was expected to produce no effect.
- Oral route of exposure and the gavage were selected for use because i) the oral route is one possible route of human exposure and ii) the daily dosage can be accurately administered using the gavage method
- F1 generation pups were not directly given the test substance but may have been exposed to the test substance during maternal gestation (in utero exposure) or via maternal milk during the lactation period
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- no effects observed
- Other effects:
- not specified
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
Details on results (P0)
- Body weight was slightly but significantly reduced in the high-dosage group in males between d1 and d8; at the end all weights were comparable
- Organ weights included enlarged spleens for 9 of 10 females in the high-dosage group
Effect levels (P0)
open allclose all
- Dose descriptor:
- NOEL
- Remarks:
- reproductive and developmental toxicity
- Effect level:
- >= 100 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no reproductive or developmental effects at any dose level tested
- Remarks on result:
- other: Generation: P and F1 (migrated information)
- Dose descriptor:
- NOEL
- Remarks:
- parental systemic toxicity
- Effect level:
- 3 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Systemic effects included methemoglobinemia at 30 and 100 mg/kg/day dosages and transient reductions in body weight and feed consumption values, indications of hemolytic anemia, and increases in the weight and/or size of the spleen at 100 mg/kg/day.
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
HEMATOLOGY
|
|
0 (VEHICLE) |
3 MG/KG/DAY |
30 MG/KG/DAY |
100 MG/KG/DAY |
Methhemoglobin in % |
male |
1.0 |
1.4 |
2.3 |
4.4 |
|
female |
0.3 |
0.6 |
1.6 |
3.0 |
Red blood cells in millions per microliter |
male |
7.8 |
7.7 |
7.4 |
6.4 |
|
female |
5.9 |
6.0 |
5.9 |
4.9 |
Applicant's summary and conclusion
- Conclusions:
- Based on the data collected in this study, repeated oral administration of acetoacetanilide to rats did not produce reproductive or developmental toxicity at dosage levels that produced systemic toxicity in the parental rats. Systemic effects included methemoglobinemia at 30 and 100 mg/kg/day dosages and transient reductions in body weight and feed consumption values, indications of hemolytic anemia, and increases in the weight and/or size of the spleen at 100 mg/kg/day. The no-observable-effect level (NOEL) for reproductive and developmental toxicity in this study was at least 100 mg/kg/day. The no effect level for systemic toxicity was 3 mg/kg/day.
- Executive summary:
Male and female rats (10/sex/group) were orally administered suspensions of acetoacetanilide at dosage levels of 0, 3, 30 and 100 mg/kg/day. The suspensions of acetoacetanilide were prepared in 1% aqueous methylcellulose and were administered at a dose volume of 10 mL/kg body weight based on the most recent body weight. Male rats were treated daily for a minimum of six weeks comprised of a two-week prebreed period, a breeding period of two weeks maximum, and a two to four week postbreed period. Female rats were treated daily during a two-week prebreed period and throughout gestation and lactation until sacrifice on day 5 postpartum. Animals in the control group received 1% methylcellulose according to the same dosing regimen.
The rats were observed for viability at least twice each day. The rats also received a detailed clinical examination before and approximately one hour after each dose. Body weight and feed consumption were measured weekly throughout the study for male rats and weekly until gestation for female rats and then on gestation days (GD) 0, 7, 14 and 20 and on days 1 (birth) and 5 postpartum. Reproductive and developmental end points evaluated in the study included mating performance, gestation length, fertility and gestation indices, number of implantation sites, number and sex of offspring, litter size, and pup viability indices.
Parental animals were sacrificed after the postbreed period for males and on day 5 postpartum for females. Just prior to sacrifice, blood samples were collected from each rat and evaluated for methemoglobin, counts of erythrocytes, leucocytes and platelets, hematocrit, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration. All male and female rats were subjected to a detailed necropsy examination. The spleen and, in male rats, the epididymides and testes were weighed, and these tissues were retained along with the pituitary and the prostate and seminal vesicles in male rats and the ovaries, uterus, vagina in female rats. Histopathological evaluation of the epididymides, testes and ovaries were conducted for rats in the control and high dosage groups. Female rats that did not deliver a litter or that did not have a confirmed mating date were sacrificed on GD 25 of presumed gestation, necropsied, and examined for pregnancy.
The pups were examined for physical abnormalities once each day during the 5-day postpartum period and pup body weight and observations of nursing behavior were recorded on days 1 and 5 postpartum. Pups found dead were necropsied and, evaluated to determine if they were alive at birth. All remaining pups were sacrificed on postpartum day 5 and necropsied.
No deaths occurred during the study. Treatment-related clinical signs of toxicity in the parental animals were limited to excess salivation for five of ten male rats in the 100 mg/kg/day dosage group. Body weight gain and feed consumption for male rats in the 100 mg/kg/day dosage group were reduced during days 1 through 8 of the prebreed period. In female rats, prebreed body weight and body weight gain were unaffected by treatment with the test substance. However, body weight gain during gestation was decreased for female rats in the 100 mg/kg/day dosage group as compared with the control group. There were no other differences in body weight, body weight gain, or feed consumption for parental males or females that were attributed to treatment with the test substance.
Treatment-related hematology changes were observed for male and female rats in the 30 and 100 mg/kg/day dosage groups. These included methemoglobinemia for animals in the 30 and 100 mg/kg/day dosage groups, and increases in the total leucocyte cell counts and apparent hemolytic anemia for animals in the 100 mg/kg/day dosage group. Evidence for hemolytic anemia in the high dosage group male and female rats included reductions in the erythrocyte cell count, hemoglobin and hematocrit and increases in the mean corpuscular volume and mean corpuscular hemoglobin content as well as increased spleen size and/or weight. There were no other changes in the hematology endpoints evaluated in this study that could be clearly attributed to treatment with the test substance.
There were no treatment-related necropsy findings for parental animals or F1 generation pups, and there were no treatment-related microscopic alterations observed in the testes and epididymides of the parental male rats or in the ovaries of the parental female rats in the high-dosage group. Spleen weights were increased for male and female parental animals in the 100 mg/kg/day dosage group. There were no other treatment-related organ weight changes observed.
Mating and fertility for male and female parental rats were unaffected by treatment with the test substance. In addition, there were no treatment-related effects on the duration of gestation and the number of implantation sites per dam, the number of stillborn pups or the gestation and viability indices. Average litter size, liveborn litter size, surviving pups per litter, percent male pups per litter, average pup weight, and the incidences of clinical and necropsy observations in the pups were also comparable among the four dosage groups.
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