Reaction product of alkylarylsulphonic acid and cycloaliphatic amine

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

5/19/1988 to 7/25/1989

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: meets generally accepted scientific standards, well-documented, and acceptable for assessment

Remarks:

maximum dose level low and without effects

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1990

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 452 (Chronic Toxicity Studies)

GLP compliance:

yes (incl. QA statement)

Remarks:

contains an audit certificate

Limit test:

no

Test material

Reference

Name:

Unnamed

Type:

Constituent

Details on test material:

AMP-HCl (47.1% AMP)

Test animals

Species:

dog

Strain:

Beagle

Sex:

male/female

Details on test animals or test system and environmental conditions:

Twenty nine male and 29 female beagle dogs were received from Laboratory Research Enterprises, Kalamazoo, MI, and 25 of the healthiest of each sex were used for study. The animals were selected based on criteria of the US FDA (1982). The dogs were 4 months of age at arrival to the testing laboratory. Animals were identified by an assigned identification number on a collar, housed singly for an acclimation period, and were examined by a laboratory veterinarian for general health status. Animals were stratified by body weight, and assigned randomly to their treatment groups.

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: test material was dissolved in ethanol and then mixed into the feed

Details on oral exposure:

Animals were dosed via the diet, which was tested by the supplier (Purina) for contaminants. The test article was incorporated into the diet on a weight/weight basis using a premix. Fresh food was prepared with the test article weekly. The animals were offered 400g of the diets daily. Any uneaten food was weighed and recorded.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

1 year

Frequency of treatment:

continuous

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:0, 1.1, 11, 110 ppmBasis:nominal in diet

Doses / concentrations 2

Remarks:

Doses / Concentrations:0, 0.031, 0.31, 2.8 mg/kg bw/dayBasis:nominal in diet

No. of animals per sex per dose:

6/sex/dose

Control animals:

yes, concurrent vehicle

Details on study design:

Animals were dosed via the diet, which was tested by the supplier (Purina) for contaminants. The test article was incorporated into the diet on a weight/weight basis using a premix. Fresh food was prepared with the test article weekly. The animals were offered 400g of the diets daily. Any uneaten food was weighed and recorded. Drinking water was provided throughout the study ad libitum. Six males and six females were assigned to each of 4 dose groups (0, 1.1, 11, 110 ppm).Daily observations were made of the general appearance, behavior, the presence of any signs of toxicity or pharmacologic effects and mortality. Body weights were recorded prior to dosing, and weekly thereafter. The fasting terminal body weight was also recorded. While weighing, the animals were examined for lesions or other signs of toxicity. Each animal had an ophthalmoscopic examination once pre-study, weeks 1, month 3,6,9,12 by a veterinarian.Blood samples were obtained pre-study, and at 3, 6, 9, 12 months via venipuncture of fasted animals. The following parameters were recorded: hematocrit, hemoglobin, erythrocyte count, leukocyte count, platelet count, prothrombin time, MCH, MCHC, and MCV, Calcium, Phosphorous, Chloride, Sodium, Potassium, glucose, serum alkaline phosphatase, serum aspartate aminotransferase, serum analine aminotransferase, gamma glutamyl, transpeptidase, blood urea nitrogen, total protein, albumin, globulin, creatinine, bilirubin, and serum protein. Urine was examined for pH, specific gravity, volume and appearance, protein, glucose, acetone bodies, creatinine, and microscopic sediment.Post-mortem examinations included a complete gross examination of the external surfaces, all orifices, the cranial cavity, the external surface of the brain, the thoracic, pelvic, and abdominal cavities and their viscera, cervical tissues and organs, and the carcass. Two animals per sex per dose were sacrificed at 6 months, with the remainder at 12 months. Organ weights were recorded for the liver, kidneys, testes, thyroids, adrenals, and brain. Tissues that were removed and preserved are the same as current OECD guidelines

Positive control:

no

Examinations

Observations and examinations performed and frequency:

Daily observations were made of the general appearance, behavior, the presence of any signs of toxicity or pharmacologic effects and mortality. Body weights were recorded prior to dosing, and weekly thereafter. The fasting terminal body weight was also recorded. While weighing, the animals were examined for lesions or other signs of toxicity. Each animal had an ophthalmoscopic examination once pre-study, weeks 1, month 3,6,9,12 by a veterinarian.

Sacrifice and pathology:

Blood samples were obtained pre-study, and at 3, 6, 9, 12 months via venipuncture of fasted animals. The following parameters were recorded: hematocrit, hemoglobin, erythrocyte count, leukocyte count, platelet count, prothrombin time, MCH, MCHC, and MCV, Calcium, Phosphorous, Chloride, Sodium, Potassium, glucose, serum alkaline phosphatase, serum aspartate aminotransferase, serum analine aminotransferase, gamma glutamyl, transpeptidase, blood urea nitrogen, total protein, albumin, globulin, creatinine, bilirubin, and serum protein. Urine was examined for pH, specific gravity, volume and appearance, protein, glucose, acetone bodies, creatinine, and microscopic sediment.Post-mortem examinations included a complete gross examination of the external surfaces, all orifices, the cranial cavity, the external surface of the brain, the thoracic, pelvic, and abdominal cavities and their viscera, cervical tissues and organs, and the carcass. Two animals per sex per dose were sacrificed at 6 months, with the remainder at 12 months. Organ weights were recorded for the liver, kidneys, testes, thyroids, adrenals, and brain. Tissues that were removed and preserved are the same as current OECD guidelines

Statistics:

yes

Results and discussion

Results of examinations

Clinical signs:

no effects observed

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:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

Test material intake is estimated based on week 36 body weights and food consumption.Males estimated (mg/kg/day)Control 01.1ppm .03111ppm 0.31110ppm 2.98Females estimated (mg/kg/day)Control 01.1ppm .02911ppm 0.31110ppm 2.55There were no general in-life observations made for any treated or control animal. Likewise, there were no ophthalmoscopic observations noted for any animal. Neither an ANOVA or a Kruskal-Wallis non-parametric ANOVA revealed any statistical significance in food consumption patterns for any dose level in either sex. There was no statistically significant differences in body weights for any of the animals throughout the study. Clinical chemistry findings for males revealed a slight decrease in the low and mid-dose groups' albumin-globulin ratio. Since there was no dose-response (the high dose group was not different than the control), it was judged to be a spurious finding and not treatment-related. High-dose males at 9 and 12 months showed differences in serum albumin via serum electrophoresis, but was not corroborated by actual clinical chemistry measurements, and was not considered by the authors to be biologically-significant. Throughout the study, findings for females included differences in serum sodium, serum ALT, and serum AST, but were transient, did not appear dose-related, and were judged by the authors to be not related to the administration of AMP. There was no effect of AMP administration on hematology, and likewise the urinalysis revealed no treatment-related effects. There were no effects on organ weights or organ/body weight ratios that were attributed to test material administration by the authors.At necropsy, evaluation of the tissues revealed several isolated observations, none of which were attributed to the administration of the test material. There were no neoplastic observations in any of the dogs sacrificed at either 6 months or one year of administration in their diets.

Effect levels

Dose descriptor:

NOAEL

Effect level:

> 110 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Dose equivalent to 2.8 mg/kg bw/day based on average male and femal test material consumption

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Based on the findings under these study conditions, there is no effect at any dose level on general appearance, behavior, body weight, food consumption, ophthalmoscopic exams, clinical chemistry, hematology, organ weights, or tissue histopathology. Based on the absence of statistically and biologically significant findings in dose-response patterns, the No-Observed Effect Level for AMP in the diets of Beagle dogs in greater than 110 ppm (>2.8 mg/kg bw).