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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study of acceptable quality with documentation sufficient for assessment

Data source

Reference Type:
study report

Materials and methods

Test guideline
no guideline available
Principles of method if other than guideline:
The purpose of this study was to make a preliminary evaluation of the maternal toxicity and embryo/fetal lethality potential of 2-methyl-2-aminopropanol hydrochloride (AMP-HCl) in Crl:CD(SD) rats following repeated dermal administration.
GLP compliance:
Limit test:

Test material

Constituent 1
Reference substance name:
EC Number:
EC Name:
Cas Number:

Test animals


Administration / exposure

Route of administration:
other: deionized water
Details on exposure:
Groups of eight time-mated female rats received AMP-HCl by occluded dermal application, six hours/day at targeted dose levels of 0, 100, 300 or 400 mg/kg/day on gestation days (GD) 6-20.

AMP-HCl solutions were prepared in deionized water at concentrations of 100, 300, and 400 mg/ml and pH adjusted to 9.5 ± 0.15 with NaOH. This pH is similar to the pH used in commercial preparations. The solutions were administered at a dose volume of
1 ml/kg body weight in order to achieve the targeted dose levels. Dose volumes were adjusted daily based on individual body weights. Due to the length of the dosing period, dose solutions were prepared periodically throughout the study.
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
Concentration Verification
Concentrations of the low- and high-dose solutions were verified in conjunction with the stability and homogeneity analyses.
The low- and high-dose solutions from the first mix was analyzed prior to the start of dosing to verify homogeneous distribution of the test material in vehicle.
The stability of 0.25 and 400 mg/ml dose solutions were determined concurrent with the study using GC/MS and internal standards.
Details on mating procedure:
Sexually mature virgin females were naturally mated with males of the same strain (one male:one female) at CRL. Females were checked for in situ copulation plugs the following morning and those found with such a plug were removed from the males’ cages. The day on which a vaginal plug was detected was considered GD 0. The animal supplier provided GD 0 body weights, and these were maintained in the study records. Rats arrived in our laboratory on GD 1.
Duration of treatment / exposure:
Frequency of treatment:
Duration of test:
6 hours per day
Doses / concentrations
Doses / Concentrations:
0, 100, 300 or 400 mg/kg/day
nominal in water
No. of animals per sex per dose:
8 time-mated female rats/dose
Control animals:
yes, concurrent vehicle
Details on study design:
The purpose of this study was to make a preliminary evaluation of the maternal toxicity and embryo/fetal lethality potential of 2-methyl-2-aminopropanol hydrochloride (AMP-HCl) in Crl:CD(SD) rats following repeated dermal administration. Groups of eight time-mated female rats received AMP-HCl by occluded dermal application, six hours/day at targeted dose levels of 0, 100, 300 or 400 mg/kg/day on gestation days (GD) 6-20. In-life parameters evaluated for all groups included clinical observations, body weight, body weight gain, feed consumption, and dermal grading of the test site. Blood samples were collected approximately three hours after dermal application, from 2-3 rats/group on GD 20 to evaluate dermal absorption of AMP-HCl. On GD 21, all surviving rats were euthanized and examined for gross pathologic alterations. Liver and kidney weights, the number of corpora lutea, implantations, resorptions, and live/dead fetuses were recorded.


Maternal examinations:
In-Life Observations
Clinical examinations were conducted daily throughout the study period. This examination included careful, hand-held evaluations of the skin, fur, mucous membranes, respiration, nervous system function (including tremors and convulsions), swelling, masses and animal behavior at the time of dosing. Following daily removal of the wrapping material, animals were observed for general behavior and appearance, respiration, nervous system function (including tremors and convulsions) and any other signs of clinical toxicity. In this study, the time interval between dosing and the appearance of clinical signs varied with the dose of AMP-HCl administered; therefore, some animals were examined at several time points to ensure that clinical findings were not overlooked.
Each morning and afternoon, a cage-side examination was conducted and to the extent possible, the following were evaluated: skin, fur, mucous membranes, respiration, nervous system function (including tremors and convulsions), animal behavior, moribundity, mortality, and the availability of feed and water.

Dermal Grading
Dermal grading was performed at the test site (clipped dorsal surface) of each female rat following each daily six hour dermal application. In addition, necrosis, scabs and/or scars were noted if present; however, they were not graded.

Body Weights
Body weights were recorded on GD 0 at CRL, daily during the dosing period, and on GD 21. Statistical analyses of body weight were performed using data collected on GD 0, 6, 9, 12, 15, 18, and 21. Body weight gain was statistically analyzed using data collected over gestation intervals 0-6, 6-9, 9-12, 12-15, 15-18, 18-21, 6-21, and 0-21.

Feed Consumption
Feed consumption for all animals was recorded and statistically analyzed over the following intervals: GD 3-6, 6-9, 9-12, 12-15, 15-18, and 18-21.

On GD 21, all surviving adult females (not fasted) were submitted for a complete necropsy conducted by a veterinary pathologist assisted by a team of trained individuals. The necropsy included an examination of the external tissues and all orifices. The animals were euthanized via CO2 inhalation, the trachea was exposed and clamped, and the animal decapitated. Blood samples from designated animals were collected from the orbital sinus to be analyzed for content of AMP. The cranial cavity was 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. The liver and kidneys were weighed and organ-to-body weight ratios calculated. Sections of liver and kidneys were preserved in neutral phosphate buffered 10% formalin. Histopathologic evaluation of preserved tissue was not performed.

Ovaries and uterine content:
A detailed examination of the reproductive tract was performed and the number and position of implantations, viable fetuses, and resorptions were recorded. Resorptions were classified as either “early” or “late” based on the presence (late resorption) or absence (early resorption) of grossly recognizable embryonic/fetal forms. For females with one or more viable fetuses, the number of ovarian corpora lutea was counted. The uteri of females lacking visible implantations were stained with a 10% aqueous solution of sodium sulfide (Kopf et al., 1964) and examined for evidence of early resorptions in order to verify pregnancy status.
Fetal examinations:
A detailed fetal examination was not performed, although any external malformations of fetuses observed during the necropsy were noted. The fetuses were euthanized via sublingual deposition of sodium pentobarbital and discarded.
See below
Calculation of Pre- and Post-implantation Loss
· Pre-implantation loss* = ((No. corpora lutea-implantations)/No. corpora lutea) x 100

· Post-implantation loss* = ((No. implantations – viable fetuses)/No. implantations) x 100

* Note: Percent pre- and post-implantation loss were determined for each litter, followed by calculation of the mean of these litter values

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Fetal abnormalities

not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Dermal administration of AMP-HCl at dose levels of 100, 300 and 400 mg/kg/day resulted in no maternal toxicity and no indication of adverse embryo/fetal effects. Administration of the test material by the dermal route was well tolerated by all animals, without significant adverse dermal effects.  Analyses of blood samples taken on the last day of dosing indicated a dose-responsive increase in systemic exposure, although the study was not designed to quantify percent absorption.  Based on these results, the no-observed-effect level (NOEL) for maternal and embryo/fetal development was
400 mg/kg/day, which was the highest dose level tested.
As no significant adverse dermal effects were noted in the developmental toxicity probe study, a two-week dermal follow-up study using male and non-pregnant female rats was initiated (Phase II).
  Solubility issues were encountered with AMP-HCl when it was prepared again using the hydrochloride salt.  As a result, the base form of AMP was used in the prepration of the dose formulations for this study, and this alleviated the difficulties with solubility.  AMP base (pH 9.5) at 300, 400 and 500 mg/kg/day was administered once daily, by the dermal route to the animals.  Significant adverse dermal effects (scabbing, redness, tenderness to touch) were noted at the two highest dose levels (400 and 500 mg/kg/day) after a few days of dosing.  This resulted in the immediate termination of treatment to these two dose groups.  However, the low-dose of 300 mg/kg/day showed only slight dermal effects after 11 days of dosing and was, therefore, used as the high-dose level for the definitive developmental toxicity study.
Based on the results obtained from this follow-up work and the developmental toxicity probe study, dose levels of 0, 30, 100, or 300 mg/kg/day of AMP base were selected for a definitive dermal developmental toxicity study in rats.

Applicant's summary and conclusion