Toxicity of chloroprene, 1,3-dichlorobutene-2, and 1,4-dichlorobutene-2.

A review of the toxicity of 1,3-dichlorobutene-2 (1,3-DCB), 1,4-dichlorobutene-2 (1,4-dcb), and 2-chlorobutadiene, 1,3 (beta-chloroprene) was undertaken with an emphasis on assessing the hazards of these materials in the industrial situation. 1,3-DCB is a by-product of beta-chloroprene from the acetylene route, with 1,4-DCB is an intermediate in the production of beta-chloroprene from the butadiene route, the production route used in the U.S. Presented in the review is a summary of the acute toxicity including mutagen testing, skin, eye, and inhalation testing of these compounds. In addition, subacute inhalation testing, embryotoxicity, teratogenicity, and carcinogenicity are also reviewed where the information is available.

Evaluation of the oral toxicity of acetaldehyde and formaldehyde in a 4-week drinking-water study in rats.

A subacute oral toxicity study of acetaldehyde and formaldehyde was carried out in rats. Groups of ten male and ten female 5-wk-old rats received one of the aldehydes in the drinking-water for a period of 4 wk, acetaldehyde being given at dose levels of 25, 125 and 675 mg/kg body weight/day and formaldehyde at dose levels of 5, 25 and 125 mg/kg body weight/day. A group of 20 males and 20 females served as controls and received unsupplemented drinking-water ad lib. An additional group of ten males and ten females was given unsupplemented drinking-water in an amount equal to the amount of liquid consumed by the group given the top dose of formaldehyde. Food and liquid intake were decreased in the groups on the top dose of both acetaldehyde and formaldehyde. Hyperkeratosis of the forestomach, observed only in the top-dose rats, was the only adverse effect of acetaldehyde detected. Effects of formaldehyde, also observed only in the top-dose group, were yellow discoloration of the fur, decreased protein and albumin levels in the blood plasma, thickening of the limiting ridge and hyperkeratosis in the forestomach, and focal gastritis in the glandular stomach. It was concluded that in this study the no-observed-adverse-effect levels of acetaldehyde and formaldehyde were 125 and 25 mg/kg body weight/day, respectively.

Comparison of the maximum tolerated dose (MTD) dermal response in three strains of mice following repeated exposure to acrylic acid.

The dermal response of three strains of mice (ICR, C3H and B6C3F1) exposed to repeated doses of 0, 1 or 4% acrylic acid was examined over 13 wk. Microscopic and gross changes to the skin were classified as being indicative of exceeding the maximum tolerated dose (MTD), reaching the MTD, or tolerating the dose based on proposed MTD guidelines established in US Environmental Protection Agency (EPA) Workshops on dermal carcinogenesis bioassays. A significant number of animals in all three strains with repeated exposure to 4% acrylic acid experienced skin irritation that was classified as having reached or exceeded the MTD compared with animals exposed to either 1% acrylic acid or the 0% acrylic acid acetone control. These results were observed within the first 3 wk of exposure, but there was some accommodation to irritation by 8 wk of exposure. Microscopic findings provided a more sensitive index for exceeding MTD than gross observations taken only at autopsy, but generally correlated well for MTD if gross observations were taken at regular intervals during treatment. That is, to set MTD, gross observations could be used if taken over the entire course of the exposure, but using microscopic findings was generally a more reliable or sensitive measure. EPA guidelines suggest that it is inappropriate to conduct a dermal bioassay at concentrations that exceed the MTD. Acrylic acid at 4% in acetone clearly exceeded the MTD based on microscopic or gross observation criteria. At 4%, strain differences were evident by gross observation only, with the ICR strain being less susceptible to irritation than C3H or B6C3F1 strains. These strain differences were not apparent with microscopic examination. Acrylic acid at 1% in acetone, although demonstrating signs of minimal irritation, was fairly well tolerated by all mice in all strains. Thus, acrylic acid at 1% in acetone, one-quarter of the concentration that was in clear excess of the MTD, would be the appropriate dose concentration for lifetime skin studies based on MTD criteria.

Two-year drinking-water study of formaldehyde in rats.

Formaldehyde was administered in the drinking-water to groups of 70 male and 70 female Wistar rats for up to 24 months. Survivors of subgroups of ten rats/sex/group each were killed after 12 or 18 months. The mean formaldehyde doses administered were 0, 1.2, 15 or 82 mg/kg body weight/day for males, and 0, 1.8, 21 or 109 mg/kg/day for females. There were no adverse effects on general health, survival or haematological or clinical chemistry parameters. Body weight and food intake were decreased in the high-dose group. Liquid intake was decreased by 40% in the high-dose group in both sexes in comparison with the controls. There was a slight temporary increase in the density of urine, whereas there was a tendency towards lower urine production in the high-dose group. The relative kidney weights were increased in the high-dose females. Gross examination at autopsy revealed a raised and thickened limiting ridge of the forestomach in most high-dose rats. In addition, several rats in the high-dose group showed irregular mucosal thickenings in the fore- and/or glandular stomach. Treatment-related histopathological gastric changes seen in most of the animals of the high-dose group included papillary epithelial hyperplasia frequently accompanied by hyperkeratosis and focal ulceration in the forestomach and focal chronic atrophic gastritis, occasionally accompanied by ulceration and/or glandular hyperplasia, in the glandular stomach. A higher incidence and/or degree of renal papillary necrosis occurred in the high-dose rats. From this study it appeared that the 'no-observed-adverse-effect level' of formaldehyde was 15 and 21 mg/kg body weight/day for male and female rats, respectively. Oral administration of formaldehyde at doses of 82 and 109 mg/kg/day to male and female rats, respectively, caused severe damage to the gastric mucosa but did not result in gastric tumours or tumours at other sites. The study did not provide any evidence of carcinogenicity of formaldehyde after oral administration.

Methyl tert butyl ether systemic toxicity.

In male F344 rats exposed in a chronic inhalation study to methyl tertiary butyl ether (MTBE) a treatment related increase in severity of chronic nephropathy and mortality and an increase in hyaline droplets in the kidney were noted. Liver weights were increased in both rats and mice but no histological lesions other than hypertrophy are seen. Transient CNS effects but no indications of permanent nervous system effects were noted. MTBE is not a reproductive or developmental hazard. MTBE is rapidly absorbed. MTBE with some metabolite, tertiary butyl alcohol (TBA) and a little CO2 are excreted in the air. The urinary excretion products in animals are TBA metabolites, while in humans the urinary excretion products are MTBE and TBA. A comparison of the systematic responses of the possible metabolites TBA and formaldehyde indicate that they are not responsible for toxicity associated with MTBE, except that TBA may be partially responsible for the kidney effects reported. Animals and humans are similar in the uptake and excretion though with some differences in metabolism of MTBE. This supports the use of the animal data as a surrogate for humans.

Review of the toxicity of multifunctional acrylates.

Multifunctional acrylates and methacrylates (MFA) represent a class of materials with considerable chemical reactivity that are used in many applications with opportunity for contact exposure. They represent appreciable eye and skin contact hazards, and several members of the class may be absorbed from skin to cause systemic effects. A number of MFAs have been identified as sensitizers. While the acute toxicity of MFAs is certain, the effects of repeated or chronic exposure are less clear. Data are presented that suggest that MFAs are not appreciable fetotoxic or teratogenic hazards and do not elicit a strong carcinogenic response following chronic dermal exposure. The use of these data for product safety purposes and research needs is discussed.

Subchronic inhalation toxicity of 3.5-microm diameter carbon fibers in rats.

No effects were seen when rats were exposed for 6 h day(-1), 5 days per week, for 16 weeks to an atmosphere of 20 mg m(-3) of carbon fibers (25 x 10(6) fibers m(-3)) and small amounts of fiber particulate resulting from preparation of the ultimate test material. The carbon fibers were made from polyacrylonitrile fiber. They were 3.5 microm in diameter and 72% were 10-60 microm long. Histopathological evaluations were made after each of 4, 8, 12 and 16 weeks of exposure and after 36 and 80 weeks of recovery. No effects due to the exposure were seen, as judged by clinical signs, body weight, organ weight, organ-body weight ratios, organ-brain weight ratios, gross and microscopic examination of internal organs, special stains of lung tissue for fibrous tissue, reticulin and fat and pulmonary function measurements. Non-fibrous particles were seen in the pulmonary lymphoid clearance system and in alveolar histiocytes (macrophages) at each histopathological evaluation period. Non-fibrous particles were seen in histiocytes in the mucociliary clearance system after 12 and 16 weeks of exposure. Fibers were seen in the nasal cavity at each histopathological examination. Fibers also occasionally were seen in tissue sections from the lower respiratory tract, but their exact location in life could not be determined. There was no indication of fibrosis.

Subchronic inhalation toxicity of methanol.

The subchronic inhalation toxicity of methanol was evaluated in rats and monkeys. Animals were exposed to 0, 500, 2000, and 5000 ppm methanol vapor for 6 h/d, 5 d/w, for 4 wk. The only treatment-and dose-related effect noted was that of mucoid nasal discharge in rats, which was considered reflective of upper respiratory tract irritation. No consistent treatment-related effects were found for organ or body weights or for histopathologic or ophthalmoscopic examinations. Overall, these findings support the use of the present American Council of Governmental Industrial Hygienists threshold limit value (TLV) of 200 ppm and short-term exposure limit (STEL) of 250 ppm for exposure to methanol vapor.

Subchronic inhalation toxicology of carbon fibers.

Male Sprague Dawley rats were exposed to carbon fibers 7 microns in diameter and 20 to 60 microns in length, for six hours a day and five days a week for up to 16 weeks at an average chamber concentration of 20 mg/m3. Rats were killed at 4, 8, 12, and 16 weeks of exposure and after a 32-week postexposure recovery period. A similar number of control rats exposed only to air were killed at the same times. Pulmonary function tests, conducted just prior to the animals' death, did not demonstrate any significant or consistent changes. The only pulmonary finding that could be causally related to the subchronic inhalation of carbon fibers was phagocytosis of the inhaled particles by alveolar macrophages. This physiologic response was not accompanied by any local reactive pulmonary inflammation or fibrosis.

A 26-week inhalation toxicity study with formaldehyde in the monkey, rat, and hamster.

This inhalation study involved simultaneous exposure of five groups of 6 male Cynomolgus monkeys, 20 male and 20 female Fischer 344 rats, and 10 male and 10 female Syrian golden hamsters for 22 hr per day, 7 days per week for 26 weeks to formaldehyde gas. The cumulative mean exposure concentrations were 0, 0, 0.19, 0.98, and 2.95 ppm for the two control groups, low-, mid-, and high-level exposure groups, respectively. There was no treatment-related mortality during the study. In monkeys, the most significant findings were hoarseness and congestion and squamous cell metaplasia in the nasal turbinates of the 2.95-ppm exposure group. There were no signs of toxicity in the lower-level exposure groups. In the rat, the only observations of possible responses to exposure were found in the 2.95-ppm exposure group. These findings consisted of squamous metaplasia in the nasal turbinates, decreased body weights starting during the second week of the study, and decreased liver weights. In contrast to monkeys and rats, hamsters did not show any significant responses to exposure even at 2.95 ppm. It was concluded that nearly continuous exposure of monkeys and rats for six months at a level of 2.95 ppm of formaldehyde clearly elicited an effect while exposures below this level did not appear to demonstrate an effect. It further appeared that the monkey and rat were more sensitive to formaldehyde exposure than the hamster.

Safety assessment of lactate esters.

Lactate esters have an oral LD50 greater than 2000 mg/kg and the inhalation LC50 is generally above 5000 mg/m3 and they may be potential eye and skin irritants, but not skin sensitizers. No evidence of teratogenicity or maternal toxicity was observed in an inhalation (2-ethylhexyl-l-lactate) or dermal study (ethyl-l-lactate). Subacute inhalation studies have been conducted at concentration up to 600 mg/m3 or higher on four lactate esters (ethyl, n-butyl, isobutyl, and 2-ethylhexyl-l-lactate). Degenerative and regenerative changes in the nasal cavity were noted in all studies. The NOAEL in ethyl, n-butyl, and isobutyl-l-lactate vapor studies was 200 mg/m3. For aerosol exposure, 2-ethylhexyl-l-lactate, the most toxic of the lactates, minimal damage to the nasal epithelium was noted at 75 mg/m3 with vapor being slightly less toxic than the aerosol. Lactates do not appear to cause systemic toxicity, except at very high concentrations (1800 mg/m3 or higher). These systemic effects may be secondary to severe irritation seen at high doses. Sensory irritation tests suggest that a vapor exposure limit of 75 mg/m3 ( approximately 15 ppm) should prevent irritation in humans and therefore an occupational exposure level for vapor of 75 mg/m3 is recommended. However, aerosol exposure should be kept as low as possible. The low vapor pressure of the higher molecular weight esters would tend to keep vapor exposure low and the odor of lactate esters serves as a warning of exposure. These lactate esters are readily biodegradable, suggesting little concern from an environmental point of view.

Evaluation of potential neurotoxic effects of occupational exposure to (L)-lactates.

Organo psycho syndrome (OPS) or chronic toxic encephalopathy (CTE) is a neurotoxic condition reported following long-term exposure to paints containing organic solvent and to other solvents. Lactate esters are finding wider use as solvents. Lactate esters have been well studied in standard toxicity tests, but specific neurotoxicity studies have not been conducted. No clinical signs of chronic neurotoxicity have been observed in standard toxicity tests. Lactate esters are rapidly hydrolyzed in the body to lactic acid and the corresponding alcohol. Alcohols have been reported to have acute neurotoxic effects, usually following high levels of ingestion. The literature on alcohols was reviewed to establish the no-observed-adverse-effect level (NOAEL) for acute neurotoxicity and to look for any evidence of chronic neurotoxicity from the alcohols produced by hydrolysis of the lactate esters. The NOAELs were compared with the potential amounts of alcohol produced by hydrolysis of different lactate esters at 200 mg//m(3) (the NOAEL for most of the lactate esters). In all cases neither acute nor chronic neurotoxicity would be expected based on the amounts of alcohol produced by hydrolysis of the lactate esters at their NOAELs. L-Lactic acid is a normal metabolite in the body and is not considered neurotoxic. Based on this information there is no evidence to suggest that L-lactate esters can cause any chronic neurotoxicity, OPS, or CTE.

Absorption, distribution and excretion of terephthalic acid and dimethyl terephthalate.

Data from a radiotracer study in rabbits and rats to determine the absorption, distribution, and excretion of terephthalic acid (TA) and dimethyl terephthalate (DMT) following oral, intratracheal, dermal and ocular administration indicate the following: (1) a rapid absorption and excretion of 14C-TA and 14C-DMT with no evidence of tissue accumulation in rats following single or repeated oral and intratracheal administration; (2) no evidence of skin irritation in rats after a single or repeated dermal application of 80 mg of 14C-TA or 14C-DMT and no significant skin absorption of 14C-TA; (3) recovery of approximately 11% of a single dose and 13% of five repeated cutaneous doses of 14C-DMT from the urine and feces of rats within 10 days after initial dosing; (4) no significant absorption of 14C-TA when applied to the conjunctival sac of one eye of eight rabbits; (5) excretion of approximately 33% of a single ocular dose (50 mg) of 14C-DMT in the urine and feces of rabbits within 10 days after instillation with no evidence of tissue accumulation or ocular damage. These results suggest that TA and DMT are rapidly absorbed and excreted and that no significant quantities of these compounds accumulate in the tissues following single or repeated oral, intratracheal, dermal, or ocular administration to laboratory animals.