Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2009-2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Standard Guideline OECD study according to GLP
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010
Report date:
2010

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2-aminobutan-1-ol
EC Number:
202-488-2
EC Name:
2-aminobutan-1-ol
Cas Number:
96-20-8
Molecular formula:
C4H11NO
IUPAC Name:
2-aminobutan-1-ol
Details on test material:
Test material: Hydrochloride salt of 2-aminobutanol (1:1 ratio of HCl:2-ab)
Supplier, City, State (Lot, Reference Number)
ANGUS Chemical Co., a wholly owned subsidiary of The Dow Chemical Company, Buffalo Grove, Illinois (lot # CEC-200901154-28)
Purity/Characterization (Method of Analysis and Reference)
The purity of the test material was 98.73 ± 0.03% by gas chromatography with 0.35 ± 0.01% (w/w). water by Karl Fischer coulometric titration. Identification was by nuclear magnetic resonance and gas chromatography mass spectrometry

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
Strain and Justification
Crl:CD(SD) rats were selected because of their general acceptance and suitability for toxicity testing, availability of historical background data and the reliability of the commercial supplier.
Supplier and Location
Charles River Laboratories Inc. (Portage, Michigan)

Age at Study Start
Approximately eight weeks of age at initiation of treatment.
Physical and Acclimation
Each animal was evaluated by a laboratory veterinarian, or a trained animal/toxicology technician under the direct supervision of a laboratory veterinarian, to determine the general health status and acceptability for study purposes upon arrival at the laboratory (fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International - AAALAC International). The animals were housed two-three per cage in stainless steel cages, in rooms designed to maintain adequate conditions (temperature, humidity, and photocycle), and acclimated to the laboratory for at least one week prior to the start of the study.

Housing
After assignment, animals were housed one per cage in stainless steel cages, except during breeding (one male and one female) and during the littering phases of the study. During littering, dams (and their litters) were housed in plastic cages provided with ground corncob nesting material from approximately gestation day (GD) 19 until completion of lactation. Cages had wire mesh floors and were suspended above catch pans. Non-woven gauze was placed in the cages to provide a cushion from the flooring for rodent feet. The gauze and pair housing provided environmental enrichment. In order to better visualize copulation and plugs, gauze was not placed in cages during the breeding phase. Cages contained a feed crock and a pressure activated lixit valve-type watering system. The environmental conditions were maintained as follows:
Temperature: 22 °C with a tolerance of ± 1°C (and a maximum permissible excursion of ± 3°C)
Humidity: 40-70%
Air Changes: 12-15 times/hour
Photoperiod: 12-hour light/dark (on at 6:00 a.m. and off at 6:00 p.m.)

Randomization and Identification
Prior to test material administration, 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 that were placed on study were uniquely identified via subcutaneously implanted transponders (BioMedic Data Systems, Seaford, Delaware) that were correlated to unique alphanumeric identification numbers.

Feed and Water
Animals were provided LabDiet Certified Rodent Diet #5002 (PMI Nutrition International, St. Louis, Missouri) in meal form. Feed and municipal water were provided ad libitum. Analyses of the feed were performed by PMI Nutrition International to confirm the diet provided adequate nutrition and to quantify the levels of selected contaminants. Drinking water obtained from the municipal water source was periodically analyzed for chemical parameters and biological contaminants by the municipal water department. In addition, specific analyses for chemical contaminants were conducted at periodic intervals by an independent testing facility. Copies of these analyses are maintained in the study file. Results of the feed and water analyses indicated no contaminants that would interfere with the conduct of the study or interpretation of the results.
Animal Welfare
In accordance with the U.S. Department of Agriculture animal welfare regulations, 9 CFR, Subchapter A, Parts 1-4, the animal care and use activities required for conduct of this study were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC). The IACUC determined that the proposed Activities were in full accordance with these Final Rules. The IACUC-approved Animal Care and Use Activities were DART 01, DCO 01, Neuro Tox 01, Subchronic/Chronic Tox 01, Humane Endpoints 01, and Animal ID 01.

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Male rats were fed diets for a total of 33 days including 14 days prior to mating during mating and after the completion of mating. Female rats were fed diets for two weeks prior to breeding, and continuing through breeding (two weeks), gestation (three weeks), and lactation up to postpartum day 4. Females were necropsied on postpartum day 5.

The high-dose level was based upon data obtained from a preliminary range-finding study and was expected to induce some toxic effects, but not death or obvious suffering. The lower dose levels were selected to provide dose-response data for any toxicity that may have been observed among the high-dose group rats and to establish a no-observed-effect level (NOEL).

Diets were prepared by serially diluting a concentrated test material-feed mixture (pre-mix) with ground feed. The particle size of the test material was reduced via mortar and pestle prior to mixing with ground feed. In addition, the pre-mix was run through a Quadro Co-mil to ensure a homogeneous mix. The test material concentration was not adjusted for purity. Pre-mixes were prepared periodically throughout the study based on stability data. Diets were prepared weekly during the pre-mating period and were mixed periodically based on stability data during the breeding, gestation and lactation phases of the study. Following breeding, the male diet was prepared weekly until necropsy. The concentrations of the test material in the diets were calculated from the most recent body weight and feed consumption data. Initial concentrations of test material in the diet were calculated from pre-exposure body weights and feed consumption data. To avoid potential overdosing during the breeding period, co-housed animals were provided with either the male or female diet, whichever was of lower concentration. During gestation and lactation, females from each dose group were provided with the appropriate dietary concentration of 2-amino-1-butanol hydrochloride salt given during breeding.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dose Confirmation and Homogeneity
Dose confirmation analyses of all dose levels, plus control and premix, were determined from the first mix prior to the start of dosing. The homogeneity of the low-dose and the high-dose test diets was determined concurrent with dose confirmation. The method used for analyzing the test material in the diet was gas chromatography-mass spectrometry (GC-MS) to determine target concentrations.
Stability
Stability of the test material in the vehicle was initiated prior to the start of the range-finding study at dietary concentrations of 0.0005, 0.005, and 10%. 2-amino-1-butanol was stable for 25 days at concentrations ranging from 0.0005 to 10%. Test diets for the current study were prepared and used within these stability limits. These concentrations encompass the range of dietary concentrations used in this study.
Retainer Samples
Retained samples (one/dose level/mix) were stored in sealed vials in a manner consistent with the sample retention policy of the laboratory.
Duration of treatment / exposure:
Male rats: 33 days
Females: c.a.64 days
Frequency of treatment:
Male rats were fed diets for a total of 33 days including 14 days prior to mating during mating and after the completion of mating. Female rats were fed diets for two weeks prior to breeding, and continuing through breeding (two weeks), gestation (three weeks), and lactation up to postpartum day 4. Females were necropsied on postpartum day 5.
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 10, 50 and 300 mg/kg bw
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
0, 11.1, 56.1, or 322 mg/kg/day
Basis:
other: Time weighted average for the males
Remarks:
Doses / Concentrations:
0, 10.5-14.3, 54.3-70.5, or 318mg/kg/day (pre-breeding only)
Basis:
other: Time weighted average for the females (pre-breeding)
No. of animals per sex per dose:
12 males and 12 females per dose
Control animals:
yes, plain diet
Details on study design:
Groups of 12 male and 12 female Crl:CD(SD) rats were fed diets targeted to supply 0 (control), 10, 50, or 300 mg/kg/day 2-amino-1-butanol hydrochloride salt. Female rats were fed diets for approximately two weeks prior to breeding, continuing through breeding (two weeks), gestation (three weeks), and through lactation day 4. Male rats were fed diets for two weeks prior to breeding and continuing through breeding (two weeks) until necropsy (TD 33). Effects on general toxicity, neurobehavioral activity, clinical pathology parameters, gonadal function, mating behavior, conception, development of the conceptus, parturition and early postnatal growth and survival were evaluated. In addition, a gross necropsy of the adults was conducted with histopathologic examination of tissues. The key study parameters and study schedule are presented in Table 1. Test material administration for both males and females began on July 23, 2009. The adult males were necropsied on August 24, 2009. The adult females were necropsied on September 1, 2009 to September 15, 2009. In the offspring, litter size, pup survival, sex, body weight, and the presence of gross external abnormalities were assessed. Pups were euthanized on postnatal day 4.
Positive control:
not applicable

Examinations

Observations and examinations performed and frequency:
Daily In-Life Observations
A cage-side examination was conducted at least twice daily. This examination was typically performed with the animals in their cages and was designed to detect significant clinical abnormalities that were clearly visible upon a limited examination, and to monitor the general health of the animals. The animals were not handheld for these observations unless deemed necessary. Significant abnormalities that could have been observed included, but were not limited to: decreased/increased activity, repetitive behavior, vocalization, incoordination/limping, injury, neuromuscular function (convulsion, fasciculation, tremor, and twitches), altered respiration, blue/pale skin and mucous membranes, severe eye injury (rupture), alterations in fecal consistency, and fecal/urinary quantity. In addition, all animals were observed for morbidity, mortality, and the availability of feed and water at least twice daily.
Cage-side examinations were conducted on dams and their litters, at least twice daily. These examinations were conducted as described above.
Clinical Observations
Clinical observations were conducted on all animals pre-exposure. Females were observed for signs of parturition beginning on or about GD 20 Females that delivered litters were subsequently evaluated on LD 0, 1, and 4. Clinical observations were not conducted on females that failed to deliver a litter, unless deemed appropriate based on cage-side observations. Clinical observations included a careful, handheld 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.
Detailed Clinical Observations
Detailed clinical observations (DCO) were conducted on all rats pre-exposure and weekly throughout the study. Mated females received DCO examinations on GD 0, 7, 14, and 20, and LD 3. The DCO was conducted at approximately the same time each examination day prior to dosing, according to an established format. The examination included cage-side, hand-held and open-field observations, which were recorded categorically or using explicitly defined scales (ranks).

Functional Tests
The functional tests (sensory evaluation, rectal temperature, grip performance and motor activity) were conducted pre-exposure and during the last week of the treatment period. For the females, this took place on LD 4. Females of the 300 mg/kg/day group were not tested on LD 4 per protocol because they did not deliver a litter.
Sensory Evaluation
The sensory evaluation included a test for nociception (responsiveness to tail pinch) and for startle response (responsiveness to sharp noise). The evaluation was conducted in a clear plastic box. Details of the methods for each test and specific definitions of the ranks are in Appendix B.
Rectal Temperature
Rectal temperature was measured by carefully placing a rectal thermistor (Physitemp, Clifton, New Jersey) approximately 4 cm into the rectum for approximately 10 seconds. Temperature was then recorded. The thermistor was validated at 37C before, during and after the study. The instrument was re-calibrated if the temperature recordings differ from the reference thermometer by more than  0.5C.
Grip Performance
Hindlimb grip performance was tested according to the procedure described by Mattsson et al. (1986). Briefly, the observer placed the rat’s forelegs on a plastic bench and the hindfeet were set on a horizontal screen attached to an electronic strain gauge (Chatillon, Greensboro, North Carolina). The observer then smoothly but firmly pulled backward on the tail until the rat’s grip on the screen was broken (Appendix C). An electronic strain gauge was used to record the rat’s resistance to the pull in grams. The average of three trials was used for statistical analysis. Forelimb grip performance was similarly tested. In this application, a bench was not used, and the rats were placed so that the forefeet were on the screen and the hindfeet were suspended approximately 10 cm above the plastic platform.
Instrument Validation: A standard 500-gram weight attached to a fine-gauge wire was suspended from the load cell and was checked just before and just after testing (a 1% tolerance, i.e., 500  5 grams, was acceptable).
Motor Activity
An automated system was used for motor activity (MA) data collection (Appendix D). No entry into the MA test room was allowed during the testing period. Each test session consisted of eight 8-minute epochs, totaling 64 minutes of testing per animal per test session. This duration was chosen based on the results of a validation study indicating that performance of control animals approached asymptote in 50-60 minutes in CD rats (Marty and Andrus, 2007). Activity counts for each epoch were recorded.
Motor Activity Cage Calibration
Cages were calibrated prior to testing each day. Calibration was performed with a rod attached to a rotary motor that broke the infrared beam at a constant speed. The duration of each beam break was calculated to ensure equivalence across chambers.
Motor Activity Cage Allocation
Rats were allocated to the motor activity cages in such a way that the counterbalancing of treatment groups and sexes across cages and test times was maximized.
Body Weights/Body Weight Gains
All rats were weighed at least once during the pre-exposure period, twice during the first week and once during the second week of the study. Male body weights continued to be recorded weekly throughout the study. 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 analyses were conducted for the following days: GD 0, 7, 14, and 20 and LD 1 and 4. Body weight gains were determined for the following intervals: GD 0-7, 7-14, 14-20, 0-20, and LD 1-4.
Feed Consumption
Feed consumption was determined twice during the first week and once during the second week for all animals 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. 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 measured for females that failed to mate or deliver a litter. Feed consumption was calculated using the following equation:
Feed consumption (g/day) = (initial weight of crock - final weight of crock)
(# of days in measurement cycle)

Test Material Intake
Test material intake (TMI) was calculated for the adults using test material concentrations in the feed, actual body weights, and measured feed consumption
Sacrifice and pathology:
Clinical Pathology
Animals were fasted overnight prior to blood collection. Blood samples were obtained from the orbital sinus following anesthesia with O2/CO2 at the scheduled necropsy. Blood was not obtained from animals that died or were euthanized in a moribund condition prior to their scheduled necropsy. Blood samples were not obtained from females that failed to deliver a litter.
Hematology
Sample Preparation
Blood samples for a complete blood count were mixed with ethylenediamine-tetraacetic acid (EDTA). Blood smears were prepared, stained with Wright-Giemsa stain, cover-slipped and archived for potential future evaluation if warranted.
Hematologic parameters were assayed using the Bayer Advia 120 Hematology Analyzer (Siemens Medical Solutions Diagnostics, Tarrytown, New York).
Assays
Hematocrit (HCT)
Hemoglobin (HGB) concentration
Red blood cell (RBC) count
Total white blood cell (WBC) count
Differential WBC count
Platelet (PLT) count
Reticulocyte (RET) count
RBC indices:
Mean Corpuscular Hemoglobin (MCH)
Mean Corpuscular Volume (MCV)
Mean Corpuscular Hemoglobin Concentration (MCHC)
Coagulation
Sample Preparation
Blood samples were collected in sodium citrate tubes, centrifuged, plasma collected, and assayed using the Instrumentation Laboratory ACL9000 Analyzer (Beckman Coulter, Inc., Miami, Florida).
Assay
Prothrombin time (PT)

Clinical Chemistry
Sample Preparation
Blood samples were collected and serum was separated from cells as soon as possible. Serum parameters were measured using a Hitachi 912 Clinical Chemistry Analyzer (Roche Diagnostics, Indianapolis, Indiana).
Enzyme Activities of:
Alkaline phosphatase (ALP)
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Concentrations of:
Albumin (ALB)
Cholesterol (CHOL)
Creatinine (CREA)
Electrolytes (NA, K, PHOS, CL and CA)
Glucose (GLUC)
Total bilirubin (TBIL)
Total protein (TP)
Triglycerides (TRIG)
Urea nitrogen (UN)
Urinalysis
Urine samples were obtained from all males the week prior to the scheduled necropsy. Animals were housed in metabolism cages and the urine collected overnight (approximately 16 hours). Feed and water were available during this procedure.
Assays
Color, appearance, specific gravity (refractometer) and urine volume
Semiquantitative analysis of the following were conducted using Multistix Reagent Strips (Bayer Corporation, Elkhart, Indiana) on the Bayer HealthCare Clinitek Advantus Analyzer (Siemens Medical Solutions Diagnostics, Tarrytown, New York):
pH
Bilirubin
Glucose
Protein
Ketones
Blood
Urobilinogen

Microscopic Exam
A urine sample was collected from each male by manual compression of the urinary bladder. The urine samples were pooled from each group, and the microsediment were characterized microscopically.

Anatomic Pathology
Adult Necropsy
Adult males (fasted) were submitted for necropsy after four weeks of exposure. Adult females (fasted) were terminated on LD 5, or at least 24 days after the end of the mating period for females not producing a litter. The animals were anesthetized by the inhalation of CO2/O2 and weighed. Blood was collected from the orbital sinus (all males, all females that littered), their tracheas was exposed and clamped, and the animals were 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 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 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 uteri of all females were stained with an aqueous solution of 10% sodium sulfide stain (Kopf et al., 1964) for approximately two minutes and were examined for the presence and number of implantation sites. After evaluation, uteri were gently rinsed with saline and preserved in neutral phosphate-buffered 10% formalin.
Weights of the adrenals, brain, epididymides, heart, kidneys, liver, spleen, testes, thymus, and thyroid with parathyroids (weighed after fixation) were recorded, and organ:body weight ratios calculated.
Representative samples of tissues listed in Table 4 were collected and preserved in neutral, phosphate-buffered 10% formalin, with the exception of the testes and epididymides that were fixed in Bouin’s solution. Portions of the left lateral liver lobe of all surviving females were either preserved in RNA-later or snap frozen in liquid nitrogen, and stored at -80°C for possible RNA isolation or phospholipid/phospholipid precursor analyses. RNA isolation and phospholipid/phospholipid precursor analyses were not conducted and these sample were later discarded. Transponders were removed and placed in jars with the tissues.
During routine working hours, any animals found dead or euthanized prior to the scheduled necropsy were necropsied on that day. However, animals euthanized or found dead outside working hours were refrigerated until the next scheduled workday, at which time they were necropsied. Similar necropsy procedures were followed for these animals except that terminal body and organ weights were not recorded and the testes and epididymides were preserved in neutral, phosphate-buffered 10% formalin.
Offspring Necropsy
All pups surviving to lactation day 4 were euthanized by an i.p. administration of sodium pentobarbital solution, examined for gross external alterations, and then discarded. Any pups found dead or which were euthanized in moribund condition were examined to the extent possible and discarded.
Histopathology
Histologic examination of the tissues indicated in Table 4 was conducted on all control and high-dose adult rats. Examination of tissues from the remaining groups was limited to liver and relevant gross lesions. Paraffin embedded tissues were sectioned approximately 6 µm thick, stained with hematoxylin and eosin and examined by a veterinary pathologist using a light microscope.
The histopathological examination of the testes included a qualitative assessment of stages of spermatogenesis. A cross section through the approximate center of both testes of control and high-dose males was embedded in paraffin, sectioned at 5 µm and stained with modified periodic acid-Schiffs-hematoxylin. The presence and integrity of the stages of spermatogenesis were 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, 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 was neither 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 was adversely affected, but not to the point of organ failure. The health status of the animal may or may not be affected, depending on the organ/tissue involved, but generally lesions graded as moderate would not be life threatening.
A complete set of tissues (listed in Table 4) was examined from rats found dead or moribund. Histological examination was conducted in a similar manner as described above, except that the testes were stained with hematoxylin and eosin.
Statistics:
Various statistical analyses were performed

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
signs of irritation on the skin in high dose females and 1 high dose male
Mortality:
mortality observed, treatment-related
Description (incidence):
signs of irritation on the skin in high dose females and 1 high dose male
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
high dose males and females only
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
high dose animals only
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
High dose males: slight increases in urea nitrogen, cholesterol and chloride levels and alanine aminotransferase and aspartate aminotransferase activities
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Increase in relative liver weights in mid and high dose males; relative adrenal weight in mid dose females increased
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
slight vacuolation of hepatocytes in high dose males
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed

Effect levels

Dose descriptor:
NOEL
Effect level:
10 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Body weight decrease in high dose animals, increase in relative liver weight in males in mid and high dose and increase in relative adrenal weight in mid dose females.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Dietary exposure to 300 mg/kg/day or 50 mg/kg/day of 2-AB-HCl produced treatment-related systemic toxicity in parental animals. In the 300 mg/kg/day group, male and female adult toxicity included decreased body weight and feed consumption, dermal irritation (acanthosis, inflammation, erosions and/or ulcers) possibly induced by feed contact during grooming, and an increased incidence of very slight centrilobular/midzonal hepatocyte hypertrophy, a finding associated with increased relative liver weight in males but not females. In high-dose males there were treatment-related increases in serum urea nitrogen, alanine aminotransferase, aspartate aminotransferase, and cholesterol, with the increased urea nitrogen and cholesterol likely being secondary to the lower body weight and reflective of a marginal change in protein catabolism and fat mobilization. In the 50 mg/kg/day group, parental toxicity was limited to increases in relative liver weights in males and adrenal weights in females. There was no systemic toxicity in the animals given 10 mg/kg/day. There were no neurologic effects in any dose level tested.

Applicant's summary and conclusion

Conclusions:
The toxicity of 2-aminobutanol in this OECD 422 study was limited to some affects on bodyweight (possibly related to decreased food consumption) and increases in liver weight (associated with some evidence of slight hepatocyte vacuolation in the high dose group). The NOEL for 2-aminobutanol-HCl salt from this study for the repeated dose toxicity was 10 mg/kg bw/day. This is equivalent to 7.1 mg/kg bw/day of actual 2-aminobutanol. The effects on reproductive toxicity are recorded in the reproductive toxicity section.