W.H. Lawrence

Mutagenic and Antifertility Sensitivities of Mice to Di-2-ethylhexyl Phthalate (DEHP) and Dimethoxyethyl Phthalate (DMEP)

Groups of male ICR mice were treated with a single ip injection of undiluted DEHP or DMEP representing 13, 12, and 23 of the acute LD50 dose. Immediately after injection, each male mouse was placed with 2 untreated virgin females for mating; the females were replaced on a weekly basis for a 12-week period. The high dose of both phthalates produced a distinct reduction in incidence of pregnancies, with lesser effects sometimes observed from the lower doses. This effect was more persistent with DEHP than with DMEP. Both phthalates produced some degree of dose- and time-dependent antifertility and mutagenic effects. There was a reduction in the number of implantations/pregnancy and of litter size, particularly in the first few weeks (postmeiotic stage) with the high dose of the compounds. Mutational effects, as expressed by an increase in early fetal deaths and reduced numbers of total implants, were seen at various weeks during the study, but most notably during the first few weeks. Thus, early fetal deaths and semisterility (decreased incidence of pregnancies, decreased number of implantations, and reduced number of offspring) constitute a spectrum of adverse reproductive and/or genetic effects noted with these 2 phthalate esters.

Embryonic-Fetal Toxicity and Teratogenic Effects of a Group of Methacrylate Esters in Rats

Monomers of five methacrylate esters and acrylic acid were administered at three dose levels to female rats on days 5, 10, and 15 of gestation. The incidences of resorptions, dead fetuses, gross abnormalities, and skeletal malformations are presented for each of these groups. Mean fetal weights also were determined for each group, and those of the monomer-treated groups were significantly smaller (P ≤ 0.01) than those of the untreated controls.

A toxicological investigation of some acute, short-term, and chronic effects of administering di-2-ethylhexyl phthalate (DEHP) and other phthalate esters☆

Twelve phthalic acid esters, including those commonly used as plasticizers for biomedical devices, were subjected to various biological tests for acute, short-term, and chronic toxicity. Certain aspects of subtle toxicity were investigated as well as overt toxic manifestations. The acute ip LD50 for these compounds in mice ranged from 3.22 to more than 100 g/kg. A comparison of acute LD50 to chronic LD50 reveals that most of these phthalates are 2–4 times more toxic chronically. However, the chronic toxicity of di-n-octyl phthalate was 21.74 times greater than its acute toxicity, while for di-2-ethylhexyl phthalate the chronic toxicity was 27.99 times greater. Most of these compounds produced a prolongation of pentobarbital sleeping time in mice pretreated with a phthalate ester.

Effects of parenteral di‐(2‐ethylhexyl)phthalate (DEHP) on gonadal biochemistry, pathology, and reproductive performance of mice

Male and female mice were treated subcutaneously (sc) with 1-100 ml/kg of di-(2-ethylhexyl) phthalate (DEHP) on d 1, 5, and 10 of the experiment and evaluated at d 21 for reproductive performance, selected biochemical parameters of the gonads, and histological alterations of the gonads. In both male and female treated mice there was a reduction in incidence of pregnancy. There were biochemical suggestions of reduced anabolic activity in the gonads (as reflected by decreased ATPase activity and of RNA, DNA, and protein content), and of increased catabolic activity in the gonads (as reflected by an increase in lysosomal enzyme activity and histological damage). Testicular, but not ovarian, weight was reduced in treated animals. Of the other parameters examined, the ovaries exhibited histological injury at lower doses of DEHP than the testes, but unlike testes, there was not a significant dose-related increase in histopathology. Biochemical changes were dose-related, for the most part, in both ovaries and testes, with the changes being more pronounced in testes. In general, reduced fertility appeared to be the most sensitive indicator for gonadotoxicity from DEHP, followed by biochemical changes and histological evidence of injury to the gonads.

Toxicological aspects of cyclohexanone

Abstract A toxicity evaluation of cyclohexanone was conducted using oral, intraperitoneal, dermal, intradermal, ophthalmic, and/or inhalation exposure to various species of animals. Cyclohexanone induced diverse reactions by virtue of a general vascular or tissue reaction and CNS depression. The ip LD50 for mice, rats, guinea pigs, and rabbits ranged from 0.93 to 1.54 g/kg, with guinea pigs being most sensitive. Intragastrically, the LD50 values were about 1.8 and 2.1 g/kg for rats and mice, respectively, with no significant differences between sexes. Inhalation exposure of mice to cyclohexanone (∼ 19 mg/liter) resulted in a mean time to death (LT50) of 99.9 min. Histological examination of lungs revealed acute congestion and edema with focal to diffuse hemorrhage of the lung parenchyma. Cyclohexanone behaved as a primary irritant intradermally, dermally, and ophthalmically. It was cytotoxic to mouse fibroblast cells in culture and produced a negative inotropic effect upon the isolated perfused rabbit heart. Three-day pretreatment with cyclohexanone did not significantly alter pentobarbital sleeping time of mice. Repeated ip administration exhibited a cumulative toxic effect in mice.

Dominant lethal mutations and antifertility effects of di-2-ethylhexyl adipate and diethyl adipate in male mice

Abstract Some adipates have been shown to produce teratogenic effects in the rat fetus. To ascertain whether or not these plasticizers might also affect postmeiotic and/or premeiotic germ cells, diethyl and di-2-ethylhexyl adipates were studied in ICR mice to evaluate their effects on fertility and dominant lethal mutations. A single ip dose was given to the males, which were then mated with 2 virgin females/week for 8 wk. Both adipates produced dose-dependent antifertility and mutagenic effects, as indicated by reduced percentage of pregnancies and increased numbers of early fetal deaths, respectively. The highest dose of di-2-ethylhexyl adipate and the two higher doses of diethyl adipate produced a distinct reduction in incidence of pregnancies, especially during the first 3 or 4 wk; this effect was less evident with the lower doses. There was a reduction in the number of implantations and live fetuses/pregnancy for one or more dose levels of both adipates. Mutational effects, expressed by an increase in early fetal deaths/pregnancy, occurred mainly during the postmeiotic stage of spermatogenesis in mice for both adipates. Adverse effects upon the premeiotic stage were also observed with di-2-ethylhexyl adipate. Thus, early fetal deaths and semisterility constitute some of the genetic and reproductive effects elicited from ip administration of the adipates to male mice subsequently mated to untreated females.

Embryotoxicity and fetotoxicity from maternal inhalation of methyl methacrylate monomer in rats.

Inhalation of methyl methacrylate (MMA) has been reported to produce systemic toxicity in laboratory animals, and parenteral administration of MMA has induced embryo-fetal growth retardation and some fetal malformations in rats. To ascertain whether or not inhalation of MMA might also have an effect on reproduction, pregnant rats were exposed to air containing approximately 110 mg/liter MMA. The acute LT50 was determined to be 72.2 min. Pregnant rats were exposed daily to approximately one-quarter and three-quarters of the acute LT50 on Days 6 through 15 of gestation. Data from MMA-treated groups were compared to two groups of controls, a group similarly exposed to air only, and an untreated group. Significant differences (p<0.05) were indicated between one or both treated groups and one or both controls for maternal weight and food consumption, and for fetal weight, crown-rump length, early fetal deaths, and for certain gross and skeletal anomalies, but not for numbers of fetuses per litter or resorptions.

Further Evaluation of a Quantitative Mathematical Model for Predicting Acute Toxicity of Acrylate and Methacrylate Esters

In a previous study (LAWRENCE ET AL, J Dent Res 51: 526-535, 1972), the authors reported quantitative structure-activity correlations of the acute LDM values in mice with several physicochemical properties for a series of acrylate and methacrylate esters. The Hansch free energyrelated (or extrathermodynamic) model (J Am Chem Soc 86: 1616-1626, 1964) was used. Eight additional compounds were obtaineda and evaluated for acute toxicity (LD50) by the same procedures to test the predictive capabilities of the previously derived best-fit equations. These compounds consist of four acrylate esters (npropyl, iso-propyl, n-decyl, and lauryl) and four methacrylate esters (n-propyl, iso-propyl, 2ethylhexyl, and n-decyl). The toxicity of the compounds was predicted on the basis of the appropriate best-fit equations from the earlier study, and the results ase tabulated along with experimentally determined LDw value and its 95% confidence interval (Table) . The predictive equations used ase: General equation-combined acrylates + methacrylatesb (based on 15 compounds): -log (LD,,) =-0.0179ir2 + 88.21Qar (C) 15.34 (eq 1) (R2 = 0.94; explained variance =; 0.93; significance level = 99.5%.) Acrylate subseries equation (based on six compounds) -log (LD.0) = 0.04707Xr2 0.26657r + 69.3084 Qa (C) 12.0226 (eq 2) . (R20.99; explained variance 0.97; significance level 97.5%.) Methacrylateb subseries equation (based on nine compounds): -log (LD.) = 0.0596V2 + 0.3171r+ II3.13 Qo(C) -19.86 (eq 3) . (R20.95; explained variance = 0.92; significance level = 99.5%.) These equations relate activity of a given analog to its partition coefficient, A, and the quantum mechanical o--electron charge on the carbonyl carbon atom, Qa (C) . Equations 2 and 3 indicate that acrylates and methacrylates, as classes, may elicit their toxicogenic activity via slightly different modes of action. Examination of the tabulated data reveals that use of the specific subseries equation resulted in a closer approximation of the experimental LDM values in six of the eight compounds. Two of the predicted values were within the experimental 95% confidence interval, two others were less than 1% outside these limits, and two additional ones were less than