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Study on the developmental toxicity of orally administered isobutylidenediurea in rats
Abstract
Developmental toxicity of isobutylidenediurea (IBDU) was determined by oral administration to Wistar rats. The substance was administered as an aqueous suspension to 22-24 pregnant rats per group by gavage in daily doses of 100, 400 and 1000 mg/kg body weight from day 6 post-coitum (p.c.) to day 15 p.c. The control group received the vehicle only (0.5% aqueous carboxymethyl cellulose solution). There were no substance-related effects in the dams concerning food consumption, body weight, body weight gain, uterine weights and clinical or autopsy observations even at the highest dose of 1000 mg/kg body weight/day. The reproduction data revealed no biologically relevant differences between the control and treated groups. The incidence and type of the foetal external, soft tissue and skeletal findings, which were classified as malformations, variations and/or retardations observed in the treated foetuses were similar to the concurrent and/or historical control data. Thus, under the conditions of this study, no signs of maternal toxicity or embryo/foetotoxicity were induced by IBDU and the no-observable-adverse-effect level on the maternal and developing organism was 1000 mg/kg body weight/day.
Condensation products of urea and different aldehydes (formaldehyde, isobutyraldehyde, crotonaldehyde) are used in large amounts (more than 300,000 tons per year) as resins, binders, and insulating materials for industrial applications, as well as in controlled-release nitrogen fertilizer for greens, lawns, or bioremediation processes. The biodegradability of these condensates and the enzymic mechanism of their degradation was studied in mircoorganisms isolated from soil, which were able to use these compounds as the sole source of nitrogen for growth. Different pure cultures of both gram-positive and gram-negative bacteria completely degraded methylenediurea, dimethylenetriurea, isobutylidenediurea, and crotonylidenediurea to urea, ammonia, and the corresponding aldehydes and carbon dioxide. Enzymes initiating this degradation were purified and characterized and turned out to be different with regard to their regulation of expression, their physicobiochemical properties, and their reaction mechanism.
In the absence of toxicological data on a chemical, the threshold of toxicological concern (TTC) approach provides a system to estimate a conservative exposure below which there is a low probability of risk for adverse health effects. The original toxicology dataset underlying the TTC was based on NOELs from repeat dose studies. Subsequently there have been several efforts to assess whether or not these limits are also protective for reproductive/developmental effects. This work expands the database of chemicals with reproductive and developmental data, presents these data in a comprehensive and transparent format and groups the chemicals according to the TTC "Cramer Class" rules. Distributions of NOAELs from each of these classes were used to assess whether the previously proposed TTC values based on repeat dose data are protective for reproductive/developmental toxicity endpoints as well. The present analysis indicates that, for each Cramer Class, the reproductive and developmental endpoints would be protected at the corresponding general TTC tiers derived by Munro et al. (1996).
A new enzyme (isobutylidenediurea amidinohydrolase) catalyzing the hydrolysis of isobutylidenediurea (a condensation product of urea and isobutyraldehyde widely used as a slow-release nitrogeneous fertilizer) was characterized from a strain of Rhodococcus erythropolis. The enzyme was purified 1,250-fold to apparent homogeneity and shown to hydrolyze the fertilizer to urea and isobutyraldehyde at a molar ratio of 2: 1. No activity was observed with ureido- or other structurally related compounds. Its molecular mass was determined by native polyacrylamide gelelectrophoresis and matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry to be 15 kDa (+/-2 kDa) and 16.4 kDa, respectively. Growth of the bacterium in the presence of isobutylidenediurea led to an increased expression of the constitutively synthetized enzyme.
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Some time ago, a multiple comparison procedure for comparing several treatments simultaneously with a control or standard treatment was introduced by the present author (Dunnett [1955]). The procedure was designed to be used either to test the significance of the differences between each of the treatments and the control with a stated value 1 - P for the joint significance level, or to set confidence limits on the true values of the treatment differences from the control with a stated value P for the joint confidence coefficient. Thus the procedure has the property of controlling the experimentwise, rather than the per-comparison, error rate associated with the comparisons, in common with the multiple comparison procedures of Tukey [unpublished] and Scheffe [1953]. In the earlier paper, tables were provided enabling up to nine treatments to be compared with a control with joint confidence coefficient either .95 or .99. Tables for both one-sided and two-sided comparisons were given but, as explained in the paper, the two-sided values were inexact for the case of more than two comparisons as a result of an approximation which had to be made in the computations. The main purpose of the present paper is to give the exact tables for making two-sided comparisons. The necessary computations were done on a General Precision LGP-30 electronic computer, by a method described in section 3 below. The tables are given here as Tables II and III; these replace Tables 2a and 2b, respectively, of the previous paper. In addition to providing the exact values, a method is given for adjusting the tabulated values to cover the situation where the variance of the control mean is smaller than the variance of the treatment means, as occurs for example when a greater number of observations is allocated to the control than to any of the test treatments. Furthermore, the number of treatments which may be simultaneously compared with a control has been extended to twenty. 482
A rapid method for examining rat fetuses is presented. The technique consists of fixing the fetuses in Bouin's solution, serially sectioning the head, neck and lower trunk with a razor blade and doing sagittal sections of the heart after opening the thoracic cavity. Examples of sections from normal 20 day rat fetuses are given as well as some with the following abnormalities: cleft palate produced by chlorcyclizine and eye and heart malformations resulting from anti-adult rat kidney serum.
Guidelines for Testing of Chemicals, Section 4: Health Effects
- OECD
Algorithmus zur Erzeugung gleich verteilter Permutationen
- Nijenhuis