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EC number: 204-709-8 | CAS number: 124-68-5
- 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:
- screening for reproductive / developmental toxicity
- Remarks:
- based on test type (migrated information)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP, guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 005
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- Remarks:
- Not specified in report
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 2-Amino-2-Methylpropanol Hydrochloride
- Cas Number:
- 3207-12-3
- IUPAC Name:
- 2-Amino-2-Methylpropanol Hydrochloride
- Test material form:
- solid: particulate/powder
- Details on test material:
- AMP-HCl (70% active AMP)
Constituent 1
- Specific details on test material used for the study:
- 2-methyl-2-aminopropanol hydrochloride salt ( Synonyms: AMP-HCl)
Supplier, City, State (lot, reference number)
Angus Chemical Company, a subsidiary of the Dow Chemical Company, Buffalo Grove,
Illinois (lot# CEC-200303541-12; received 2-5-2004).
Purity/Characterization (method of analysis and reference)
The purity of AMP HCl (lot CEC-200303541-12), corrected for water content (0.16%) was
99.7% as determined by gas chromatography (GC) after the sample was derivatized to
form volatile trimethylsilyl-species. No impurities (other than water) were present at
0.1% or higher. Infrared spectroscopy (IR) and GC/mass spectrometry (GC/MS) were
used to confirm the proposed structure of AMP (Barr et al., 2004).
Doses were based on the AMP HCl salt and were not adjusted for purity.
Characteristics
Appearance (physical state, color)
White crystalline
Molecular Formula
C4H11NO.HCL
Molecular Weight
125.6
AMP HCl is approximately 70% AMP; therefore a dose of 100 mg/kg bw/day AMP HCl corresponds to approximately 70 mg/kg bw/day AMP
Test animals
- Species:
- rat
- Strain:
- other: CD
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- CD (Crl:CD(SD)IGSBR) rats were obtained from a commercial supplier and were approximately eight weeks of age at the time of study initiation. Each animal was evaluated by a laboratory veterinarian or a trained animal/toxicology technician, under the direct supervision of a lab veterinarian to determine their general health status and acceptability for study purposes upon arrival at the laboratory. The animals were housed 2-3 per cage in stainless steel cages, in rooms designed to maintain adequate conditions (temperature, humidity, and photocycle), and acclimated to the laboratory for approximately two weeks prior to the start of the study. They were offered a commercial diet and water ad libitum. During the study, animals were housed one per cage (prebreeding) or two per cage (one male and one female during breeding) in stainless steel cage in rooms designed to maintain adequate conditions (temperature, humidity, and photocycle). Dams were housed one per cage (with their litter) in plastic cages provided with corn cob nesting material from approximately day 19 of gestation and throughout the lactation phase of the study. Animals were stratified by body weight and then randomly assigned to treatment groups using a computer program designed to increase the probability of uniform group mean weights and standard deviations at the start of the study. Animals placed on study were uniquely identified via subcutaneously implanted transponders (BioMedic Data Systems, Seaford, Delaware) which were correlated to unique alphanumeric identification numbers.
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- other: feed
- Details on exposure:
- Groups of 12 male and 12 female CD rats were fed diets supplying 0 (control), 100, 300, or 1000 mg/kg/day of AMP HCl. Males were exposed for at least two weeks prior to breeding and continuing throughout breeding for 37 days. The females were exposed for two weeks prior to breeding, continuing through breeding (up to two weeks), gestation (three weeks), and lactation (four days).
- Details on mating procedure:
- Breeding of the adults commenced after approximately two weeks of treatment. Each female was placed with a single male from the same dose level (1:1 mating) until pregnancy occurred or two weeks had elapsed. During the breeding period, daily vaginal lavage samples were evaluated for the presence of sperm as an indication of mating. The day on which sperm were detected or a vaginal copulatory plug was observed in situ was considered day 0 of gestation. The sperm or plug-positive (presumed pregnant) females then were separated from the male and returned to their home cages. If mating did not occur after two weeks, the animals were separated without further opportunity for mating.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Representative samples from the test diets were evaluated concurrently with the concentration verification analyses (see below) to ensure homogeneous distribution of the test material at the lowest and highest concentrations in the feed at least once during the study. Preliminary stability analyses of the test material in rodent diets at concentrations of 0.0005% and 0.005% and 5.0% were initiated prior to the start of the range-finding study. Analysis of all test diets from the first mix of the main study were initiated prior to the start of dosing using gas chromatography-mass spectrometry (GC-MS) incorporating an internal standard to determine target concentrations.
- Duration of treatment / exposure:
- Males were exposed for at least two weeks prior to breeding and continuing throughout breeding for 37 days. The females were exposed for two weeks prior to breeding, continuing through breeding (up to two weeks), gestation (three weeks), and lactation (four days).
- Frequency of treatment:
- Continuous
Doses / concentrations
- Remarks:
- Doses / Concentrations of AMP HCl :0, 100, 300, 1000 mg/kg/day (0, 70, 210, 700 mg/kg/day AMP) Basis:nominal in diet
AMP HCl is approximately 70% AMP; therefore a dose of 100 mg/kg bw/day AMP HCl corresponds to approximately 70 mg/kg bw/day AMP
- No. of animals per sex per dose:
- 12/sex/dose
AMP HCl is approximately 70% AMP; therefore a dose of 100 mg/kg bw/day AMP HCl corresponds to approximately 70 mg/kg bw/day AMP - Control animals:
- yes, concurrent vehicle
- Details on study design:
- Groups of 12 male and 12 female CD rats were fed diets supplying 0 (control), 100, 300, or 1000 mg/kg/day of AMP HCl (0, 70, 210, 700 mg/kg/day AMP). Males were exposed for at least two weeks prior to breeding and continuing throughout breeding for 37 days. The females were exposed for two weeks prior to breeding, continuing through breeding (up to two weeks), gestation (three weeks), and lactation (four days). Effects on gonadal function, mating behavior, conception, development of the conceptus, parturition, litter size, pup survival, sex, pup body weight and the presence of gross external morphological alterations were assessed. In addition, a gross necropsy and histopathology of the adults was conducted with an emphasis on organs of the reproductive system. Males were dosed via the diet for at least 14 days prior to mating, continuing throughout mating, for 37 days. Females were dosed by dietary exposure for 14 days prior to breeding, and continuing through breeding (up to two weeks), gestation (three weeks), and lactation (four days).
- Positive control:
- no
Examinations
- Parental animals: Observations and examinations:
- Daily ObservationsA cage-side examination was conducted twice daily, designed to detect significant clinical abnormalities that were clearly visible upon a limited examination, and to monitor the general health of the animals for all males pre-exposure and weekly throughout the study. Clinical examinations were conducted on all females pre-exposure and weekly throughout the pre-breeding and breeding periods. Mated (sperm-positive or plug-positive) females received clinical examinations on GD 0, 7, 14 and 20. Females that delivered litters were subsequently evaluated on LD 0, 1 and 4, and on additional days if warranted by observations made during daily cage-side examinations. Females that failed to mate or deliver a litter were examined weekly. Clinical observations included a careful, hand-held examination of the animal with an evaluation of abnormalities in the eyes, urine, feces, gastrointestinal tract, extremities, movement, posture, reproductive system, respiration, skin/hair-coat, and mucous membranes, as well as an assessment of general behavior, injuries or palpable mass/swellings. Body Weights/Body Weight GainsBody weights for males were recorded on test days -1, 1, 4, 7, and weekly thereafter. Females were weighed on test days 1, 4, 7, and 14 during the pre-breeding period. During gestation, females were weighed on GD 0, 7, 14, and 20. Females that delivered litters were weighed on LD 1 and 4. Females that failed to mate or deliver a litter were not weighed during the gestation or lactation phases. Body weight gains were determined for the following intervals: GD 0-7, 7-14, 14-20, 0-20, and LD 1-4.Feed ConsumptionFeed consumption for all animals was measured on test days 1, 4, 7 and 14 during the pre-breeding period by weighing feed containers at the start and end of a measurement cycle. During breeding, feed consumption was not measured in males or females due to co-housing. Following breeding, feed consumption was measured weekly for males. For mated females, feed consumption was measured on GD 0, 7, 14, and 20. For females delivering litters, feed consumption was measured on LD 1 and 4. Feed consumption was not recorded for females that failed to mate or deliver a litter.
- Litter observations:
- Litter DataFemales were observed for signs of parturition beginning on or about GD 20. In so far as possible, parturition was observed for signs of difficulty or unusual duration. The day of delivery was recorded as the first day the presence of the litter was noted and was designated as LD 0. Litters were examined as soon as possible after delivery. The following information was recorded on each litter: the date of parturition, litter size on the day of parturition (day 0), the number of live and dead pups on LD 0, 1, and 4, and the sex and the weight of each pup on LD 1 and 4. Any visible physical abnormalities or demeanor changes in the neonates were recorded as they are observed during the lactation period. Any pups found dead or sacrificed in moribund condition were sexed and examined grossly, to the extent possible, for external and visceral defects and discarded.
- Postmortem examinations (parental animals):
- Adult NecropsyA complete necropsy of all the adults was performed. All males were necropsied on test day 38, while females that delivered litters were necropsied on LD 4. Females that did not deliver a litter were necropsied at least 24 days after the last day of the mating period. In all cases, dosing continued until the day prior to sacrifice at which time the animals were fasted overnight. Fasted adult rats submitted alive for necropsy were anesthetized by the inhalation of carbon dioxide, weighed, and their tracheas exposed and clamped. The animals were then euthanized by decapitation.A complete necropsy was conducted on all animals by a veterinary pathologist assisted by a team of trained individuals. The necropsy included an examination of the external tissues, and all orifices. The head was removed, the cranial cavity opened and the brain, pituitary and adjacent cervical tissues were examined. The eyes were examined in situ by application of a moistened microscope slide to each cornea. The nasal cavity was flushed via the nasopharyngeal duct and the lungs were distended to an approximately normal inspiratory volume with neutral, phosphate-buffered 10% formalin using a hand-held syringe and blunt needle. The skin was reflected from the carcass, the thoracic and abdominal cavities were opened and the viscera examined. All visceral tissues were dissected from the carcass, re-examined and selected tissues were incised. The uteri of all females were stained with a 10% solution of sodium sulfide stain for approximately two minutes and were examined for the presence and number of implantation sites (Kopf et al., 1964). After evaluation, the uteri were gently rinsed with saline and preserved in neutral phosphate 10% formalin. Weights of the epididymides, kidneys, liver, and testes were recorded, and organ:body weight ratios calculated. HistopathologyTissues with relevant gross lesions was conducted on all adult rats from the control and high-dose groups. The histopathological examination of the testes included a qualitative assessment of stages of spermatogenesis. Examination of tissues from the remaining groups was limited to the liver (males and females), cervix, ovaries, oviducts, uterus, vagina, and relevant gross lesions. The histopathological examination of the testes included a qualitative assessment of stages of spermatogenesis. The presence and integrity of the 14 stages of spermatogenesis was qualitatively evaluated following the criteria and guidance of Russell et al. (1990). Microscopic evaluation included a qualitative assessment of the relationships between spermatogonia, spermatocytes, spermatids, and spermatozoa seen in cross sections of the seminiferous tubules. The progression of these cellular associations defined the cycle of spermatogenesis. In addition, sections of both testes were examined for the presence of degenerative changes (e.g., vacuolation of the germinal epithelium, multinucleated giant cells, a decrease in the thickness of the germinal epithelium, a preponderance of Sertoli cells, sperm stasis, inflammatory changes, mineralization, and fibrosis). Selected histopathologic findings were graded to reflect the severity of specific lesions to evaluate: 1) the contribution of a specific lesion to the health status of an animal, 2) exacerbation of common naturally occurring lesions as a result of the test material, and 3) dose-response relationships for treatment related effects. Very slight and slight grades were used for conditions that were altered from the normal textbook appearance of an organ/tissue, but were of minimal severity and usually with less than 25% involvement of the parenchyma. This type of change would not be expected to significantly affect the function of the specific organ/tissue nor have a significant effect on the overall health of the animal. A moderate grade was used for conditions that were of sufficient severity and/or extent (up to 50% of the parenchyma) that the function of the organ/tissue may have been adversely affected, but not to the point of organ failure. The health status of the animal may or may not have been affected, depending on the organ/tissue involved, but generally lesions graded as moderate would not be life threatening. A severe grade was used for conditions that were extensive enough to cause significant organ/tissue dysfunction or failure. This degree of change in a critical organ/tissue may be life threatening.The above grading criteria were not sufficiently flexible to accurately characterize the liver microscopic vacuolization consistent with fatty change found in this study. Therefore, the following criteria were applied only to the observation of "liver vacuolization, consistent with fatty change, hepatocyte, multifocal": grade 1 - infrequently observed, grade 2 - occasionally observed, and grade 3 - readily observed.
- Postmortem examinations (offspring):
- Offspring NecropsyAll pups surviving to LD 4 were euthanized by oral administration of sodium pentobarital solution, examined for gross external alterations, and then discarded. Any pups found dead were examined to the extent possible.
- Statistics:
- see below
- Reproductive indices:
- Calculation of Reproductive Indices Reproductive indices were calculated for female and male mating indices, male conception index, female and male fertility indices, gestation index, gestation survival index, post-implantation loss, and days 1 and 4 pup survival indices.
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Dams at 300 mg/kg/day exhibited non-statistically weight decrease
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Hepatcellular changes in 12/12 males was observed in the 1000 mg/kg/day, characterized by slight diffuse cyto;plasmic microvacuolization of the periportal heptaocytes. Similar effects were seen in 3/12 control female rats and nearly all of the treated female rats. In the female rats of all treated groups the incidence and severity of hepatic fatty change was increased compared to respective controls
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- not examined
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- effects observed, treatment-related
- Description (incidence and severity):
- Dose-related increases in post-implantation loss (embryo resorption)
Details on results (P0)
Effect levels (P0)
open allclose all
- Key result
- Dose descriptor:
- other: NOEL (toxicity)
- Effect level:
- 300 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- organ weights and organ / body weight ratios
- Remarks on result:
- other: Generation not specified (migrated information)
- Key result
- Dose descriptor:
- other: NOEL (toxicity)
- Effect level:
- < 100 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- histopathology: non-neoplastic
- Remarks on result:
- other: Generation not specified (migrated information)
- Dose descriptor:
- other: NOEL (reproductive effects)
- Effect level:
- 100 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- reproductive performance
- Remarks on result:
- other: Generation not specified (migrated information)
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- mortality observed, treatment-related
- Description (incidence and severity):
- Increased post-implantation loss at 300 mg/kg/day and higher.(210 mkd AMP)
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Mean pup body weights in the 300 mg/kg/day group ((210 mkd AMP) were increased on days 1 and 4 postpartum, with the male mean pup weights identified as statistically different. These increases were most likely due to the decreased litter size at this dose level, as pup body weight varies inversely with litter size (Agnish and Keller, 1997). Mean pup body weights of dams given 1000 mg/kg/day (700 mkd AMP) could not be evaluated due to a lack of viable litters.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- 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:
- no effects observed
- Histopathological findings:
- not examined
- Other effects:
- no effects observed
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- no effects observed
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not examined
Details on results (F1)
Effect levels (F1)
- Key result
- Dose descriptor:
- other: No effects observed
- Generation:
- F1
- Effect level:
- > 100 - < 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- viability
- mortality
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
No effects on mating or conception. Liver effects in females at 100 mg/kg/day (70 mg/kg/day AMP) and higher, increased post-implantation loss at 300 mg/kg/day (210 mg/kg/day AMP) and higher.
Applicant's summary and conclusion
- Conclusions:
- Dietary exposure of male rats to 1000 mg/kg/day of AMP HCl (700 mg/kg/day AMP) caused increases in absolute and relative liver weights, accompanied by a very slight degree of microvacuolization of periportal hepatocytes, with or without vacuolization of hepatocytes consistent with fatty change. Females in all treatment groups exhibited similar histopathological changes in the liver, but in the absence of an organ weight change. Absolute and relative kidney weights were increased in the 1000 mg/kg/day of AMP HCl in males (700 mkd AMP), but these were not considered toxicologically significant due to the absence of histopathological changes. AMP HCl had no effect on mating performance or conception, but caused marked, dose-related increases in post-implantation loss (embryo resorption). At the high dose level of of AMP HCl, all 12 pregnant females showed evidence of complete litter resorption (100% post-implantation loss), while at 300 mg/kg/day (210 mkd AMP), post-implantation loss was 70% (vs. 10% in controls). Effects associated with, or secondary to the post-implantation loss increase at 300 mg/kg/day (210 Mkd AMP) included decreased litter size, increased pup body weight, and decreased gestation body weight and body weight gain. There were no treatment related effects on reproductive performance in the 100 mg/kg/day group for AMP HCl (70 mkd AMP).The no-observed effect level (NOEL) for general toxicity in males was 300 mg/kg/day, (210 mkd for AMP) while the general toxicity NOEL for females could not be determined, based upon the presence of very slight microscopic liver effects. The NOEL for reproductive effects was considered to be 100 mg/kg/day (70 mkd AMP).
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