Cancer weight of evidence for three lower acrylates: Conclusions and recommendations from an expert panel.

An international panel of experts was engaged to assess the cancer weight of evidence (WOE) for three lower acrylates: methyl acrylate, ethyl acrylate, and 2-ethylhexyl acrylate. The review was structured as a three-round, modified Delphi format, a systematic process for collecting independent and deliberative input from panel members, and it included procedural elements to reduce bias and groupthink. Based upon the available science, the panel concluded: (1) The MOA for point of contact tumors observed in rodent cancer bioassays that is best supported by available data involves increased cell replication by cytotoxicity and regenerative proliferation; (2) The WOE supports a cancer classification of "Not likely to be carcinogenic to humans" a conclusion that is more in line with an IARC classification of Group 3 rather than Group 2 B; (3) Quantitative cancer potency values based on rodent tumor data are not required for these chemicals; and (4) Human health risk assessment for these chemicals should instead rely on non-cancer, precursor endpoints observed at the point of contact (e.

Chiral kinetics and dynamics of ketorolac.

It has been shown that the analgesic and cyclooxygenase inhibitor activity of ketorolac tromethamine (KT), which is marketed as the racemic mixture of (-)S and (+)R enantiomers, resides primarily with (-)S ketorolac and that the ulcerogenic activity of this agent also resides in (-)S ketorolac. Resolution of individual enantiomers for analysis in plasma samples has been accomplished by two methods: derivatization to form diastereomers that are separated by HPLC, or direct HPLC using a chiral phase column. When mice and rats were given oral solutions of (-)S and (+) KT, it was found that the kinetics and interconversion of the enantiomers were species and dose dependent.

Subchronic dermal toxicity study of triethanolamine in C3H/HeJ mice.

Triethanolamine (TEA) was applied to the skin of male and female C3H mice (15 per sex per dose group) three times weekly for 95 days (37 applications). TEA was administered at concentrations of 0 (acetone vehicle), 10, 33 and 100% (undiluted) in a volume of 50 microliters. The approximate daily doses of TEA were 0.

Comparison of ketorolac tromethamine with other injectable nonsteroidal anti-inflammatory drugs for pain-on-injection and muscle damage in the rat.

The local tolerance of ketorolac tromethamine (Toradol, Syntex) was compared with that of four other injectable nonsteroidal anti-inflammatory drugs (NSAIDs) (diclofenac sodium, piroxicam, ketoprofen, and metamizol magnesium) in the rat paw-lick/muscle irritation assay as described previously. All drugs were tested at concentrations approved for clinical use. After subplantar (footpad) injection, ketorolac produced virtually no pain-on-injection as assessed by the number of paw-lick/lift responses during a 15 min observation period.

False positive result for a peptide drug in the gene conversion assay with Saccharomyces cerevisiae strain D7.

A battery of mutagenicity tests was performed with nafarelin, an agonist analogue of luteinizing hormone releasing hormone (LHRH) containing tryptophan (Trp) and histidine (His). Included were the Ames assay and the gene conversion assay with yeast strain D7. Both tests were negative without S9 activation, and the Ames test was negative with S9, but the yeast test was positive with S9 activation.

Acute and subchronic toxicity studies with detirelix, a luteinizing hormone-releasing hormone antagonist, in the rat and monkey.

Acute (single dose), 2-week, and 3-month toxicology studies were conducted with detirelix, a luteinizing hormone-releasing hormone (LHRH) antagonist, in rats and cynomolgus monkeys. Acute studies were conducted by intravenous and subcutaneous injection. Subchronic studies were conducted by daily subcutaneous injection.

Alternative approaches in median lethality (LD50) and acute toxicity testing.

The LD50 test was introduced by Trevan in 1927 for biological standardization of dangerous drugs. Since then, the LD50 has gained wide acceptance as a measure of acute toxicity of all types of substances. Recently, however, the LD50 test has been criticized as an unnecessary waste of resources.

Dermal oncogenicity studies on two methoxysilanes and two ethoxysilanes in male C3H mice.

The dermal oncogenic potential of beta-(3,4-epoxycyclohexyl)ethyltrimethoxysilane (EEMS), gamma-glycidoxypropyltrimethoxysilane (GPMS), beta-(3,4-epoxycyclohexyl)ethyltriethoxysilane (EEES), and gamma-glycidoxypropyltriethoxysilane (GPES) was assessed by applying 25-microliters aliquots of acetone solutions to the skin of 40 male C3H/HeJ mice. The concentrations applied were 100, 25, 10, and 10% by volume for EEMS, GPMS, EEES, and GPES, respectively. Applications were made thrice weekly until the death of the animals.

Dermal carcinogenic activity of petroleum-derived middle distillate fuels.

In general, the carcinogenic potential of petroleum-derived materials is related to the polycyclic aromatic hydrocarbon (PAH) content. Thus it has been assumed that liquids which boil below the PAH distillation range (i.e.

Dermal oncogenicity studies on various ethyleneamines in male C3H mice.

The dermal oncogenic potential of diethylenetriamine, high purity and commercial grades (DETA-HP and DE-TA-C), triethylenetetramine (TETA), tetraethylenepentamine (TEPA), and polyamine HPA No. 2 was assessed by applying 25-microliter aliquots of aqueous solutions to the skin of groups of 50 male C3H/HeJ mice. The concentrations applied were 5.

Evaluation of the teratogenicity of ethylenediamine dihydrochloride in Fischer 344 rats by conventional and pair-feeding studies.

Ethylenediamine dihydrochloride (EDA.2HCl) was fed to groups of 20 (40 controls) timed-pregnant rats on Gestation Days 6 through 15 at 1.0, 0.

Influence of housing conditions for mice on the results of a dermal oncogenicity bioassay.

Male C3H/HeJ mice were thrice weekly given 25 microliter applications of 0.25, 0.05, or 0.

Three-generation reproduction and dominant lethal mutagenesis studies of ethylene glycol in the rat.

To assess the possible effects of ethylene glycol (EG) on reproductive performance and mutagenesis, three-generation reproduction and dominant lethal mutagenesis studies were performed in the Fischer 344 rat. EG was included in the diet at approximate dosages of 1.0, 0.

Chronic toxicity and oncogenicity studies of ethylene glycol in rats and mice.

These studies were performed to assess the chronic toxicity and oncogenicity of ethylene glycol (EG) in rats and mice. Groups of 130 Fischer 344 rats and 80 CD-1 mice per sex were fed diets yielding approximate dosages of 1.0, 0.

Evaluation of the dermal carcinogenic potential of tar sands bitumen-derived liquids.

The carcinogenic potential of Athabasca tar sands and six experimental liquids derived from crude bitumen was evaluated utilizing the mouse epidermal carcinogenesis model. Tar sands, bitumen, and untreated naphtha produced few, if any, tumors. Three thermally and catalytically cracked liquids, light (nominal boiling range: 149-316 degrees C) and heavy (nominal boiling range: greater than 316 degrees C) gas oils and gas oil blend (boiling range: greater than 316 degrees C), produced a significant number of epidermal neoplasms.

Aldicarb sulfoxide/aldicarb sulfone mixture in drinking water of rats: effects on growth and acetylcholinesterase activity.

A 1:1 mixture of aldicarb sulfoxide/aldicarb sulfone was administered to young adult Wistar rats via the drinking water at nominal concentrations of 19.2, 4.8, 1.

Dermal oncogenicity bioassays of monofunctional and multifunctional acrylates and acrylate-based oligomers.

Several important components of photocurable coatings were studied for dermal tumorigenic activity by repeated application to the skin of mice. The substances tested were 2-ethylhexyl acrylate (EHA) and methylcarbamoyloxyethyl acrylate (MCEA) (monomers); neopentyl glycol diacrylate (NPGDA), esterdiol-204-diacrylate (EDDA), and pentaerythritol tri(tetra)acrylate (PETA) (cross-linkers); and three acrylated urethane oligomers. For each bioassay, 40 C3H/HeJ male mice were dosed 3 times weekly on the dorsal skin for their lifetime with the highest dose of the test agent that caused no local irritation or reduction in body weight gain.

Dermal oncogenicity studies on ethylenediamine in male C3H mice.

The dermal oncogenic potential of ethylenediamine (EDA) was assessed by applying 25 microliter of a 1% solution in deionized water to the skin of 50 male C3H/HeJ mice. This was the highest concentration not producing irritation or weight changes in a preliminary 2-week study. Two EDA samples (Nos.

Dermal oncogenicity bioassays of di-sec-butoxyacetophenone and diethoxyacetophenone.

Groups of 40 male C3H/HeJ mice were treated 3 times per week for their lifetime on the skin of the back with undiluted di-sec-butoxyacetophenone (DBAP), or with diethoxyacetophenone (DEAP), undiluted and as a 50% dilution in acetone. Approximate doses per application were 22.4 mg for DBAP, and 25.

Dermal oncogenicity bioassays of acrylic acid, ethyl acrylate, and butyl acrylate.

Male C3H/HeJ mice (40 per group) were treated with 25-microliter applications of undiluted ethyl acrylate, 1% acrylic acid, or 1% butyl acrylate on the dorsal skin 3 times weekly for their lifetime. A negative control group received acetone (diluent) only, and a positive control group received 0.1% 3-methylcholanthrene (MC).

Subchronic and reproductive toxicology studies on acrylic acid in the drinking water of the rat.

In the subchronic study acrylic acid was incorporated in the drinking water of Fischer 344 rats (15 per group) for three months at dosage levels of 0.75, 0.25, 0.

Comparison of teratogenic effects of aspirin and hydroxyurea in the Fischer 344 and Wistar strains.

The Fischer 344 rat is being used increasingly in toxicology studies. There have been few reports in which rats of this strain were used in teratology and reproduction studies, but comparison of teratologic data with other toxic and points and kinetic information would be greatly facilitated by using the same strain. Therefore, the embryotoxic effects of two positive teratogens, aspirin and hydroxyurea, were compared in Fischer rats and in the commonly used Wistar rats.

Feedback control of cholesterol biosynthesis in mice fed the liver carcinogens benzidine and 2-acetylaminofluorene.

Dietary feedback control (DFC) of hepatic cholesterol synthesis is absent or defective in hepatomas of trout, mouse, rat and man. DFC has also been shown to be defective in rats fed several liver carcinogens including 2-acetylaminofluorene (AAF). These studies have led to the hypothesis that loss of normal DFC is an early and consistent event in the development of liver cancer.