J. Autian

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.

BIOLOGICAL MODEL SYSTEMS FOR THE TESTING OF THE TOXICITY OF BIOMATERIALS

An increasing number of medical items, classified as medical devices, are being manufactured, distributed and used for the saving of lives, prolongation of life, and in all aspects of health care. These items can range from heart valves to disposable plastic syringes. Presently, it is estimated that approximately 3, 000 to 4, 000 firms are manufacturing approximately 20, 000 medical devices of one type or another. The 1974 market value for these items is estimated to range from

Mutagenicity evaluation of phthalic acid esters and metabolites in salmonella typhimurium cultures

3 billion to

Antifertility and mutagenic effects in mice from parenteral administration of di‐2‐ethylhexyl phthalate (DEHP)

5 billion, and this figure is expected to increase significantly in the next five years.

Toxicological aspects of cyclohexanone

The mutagenic potential of dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutyl phthalate (DBP), and di-2-ethylhexyl phthalate (DEPH), as well as metabolites of DEHP--i.e., mono-2-ethylhexyl phthalate (MEHP), 2-ethylhexanol (2-EH), and phthalic acid (PA)--were tested in Salmonella typhimurium cultures using the Ames test procedure. The compounds were tested on strains TA98, TA100, TA1535, TA1537, TA1538, and TA2637 for base-pair substitution or frameshift-type mutations. Spot tests yielded negative responses for all compounds with the strains tested. Each compound was tested for a dose-effect relationship in the TA98, TA100, TA1535, and TA1538 systems. DEP and DBP exhibited a mildly positive response in both TA100 and TA1535 cultures, and DMP showed a similar response in TA1535. Normalization of the data for cytotoxicity of DMP suggests TA100 has a mildly positive effect. The higher doses of these compounds exhibited some cytotoxic effects. The mutagenic effects were apparently abolished by the addition of S9 fraction in TA100 and TA1535 cultures, while no effect, other than cytotoxicity, was observed in the TA98 and TA1538 systems. DEHP, MEHP, 2-EH, and PA exhibited no mutagenicity in any of the strains of Salmonella typhimurium tested, with or without S9 metabolic activation. MEHP and 2-EH, however, exhibited a moderate cytotoxic effect in most cultures.

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

The subcutaneous administration of 1-10 mg of undiluted di-(2-ethylhexyl)phthalate di-(2-ethylhexyl)phthalate (DEHP) to adult male ICR mice on d 1, 5, and 10 was followed by mating, one to one, with untreated adult virgin females. A single mating at d 21 resulted in a reduction in the incidence of pregnancies in the DEHP-treated groups. On the other hand, repeated matings with fresh females starting on d 2, 6, 11, 16, and 21, and at weekly intervals through 8 wk, revealed no perceptible effect of DEHP on the incidence of pregnancy. Examination of surgically exposed uteri and ovaries of pregnant females on d 13 of gestation revealed an increase in the incidence of preimplantation losses and early fetal deaths in the DEHP-treated groups; consequently, there were fewer viable fetuses per pregnancy. Mutagenic indices for DEHP, calculated as percent ratios of (1) preimplantation losses/implantations per pregnancy and (2) early fetal deaths/implantations per pregnancy, suggested a dominant lethal mutation effect in the treated mice. These effects tend to be more pronounced on the postmiotic stage of germ-cell development.

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

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.