J.M. King

Petroleum hydrocarbon toxicity studies

Abstract The suggested hygienic standard of 0.44 mg/liter (90 ppm) is based solely upon animal response to inhalation of “60 Solvent” vapor. Rats were affected at 0.85 mg/liter (170 ppm), but this concentration as well as 1.7 mg/liter (350 ppm) was well tolerated by human volunteers in sensory threshold studies. The LC50 for rats that inhaled the vapor for 4 hr was 24 (22–30) mg/liter or 4900 (4500–6100) ppm. Half this concentration caused loss of coordination, but 3.4 mg/liter (690 ppm) caused no visible response. Similar responses occurred in beagles at 9.5 mg/liter (1900 ppm) and 4.0 mg/liter (820 ppm). Cats died within 4 hr at 20 mg/liter (4100 ppm). The rat Lt50 was 150 min at 38.0 mg/liter (7700 ppm). There were slight increases in liver and kidney weights of beagles on the 5.7- and 2.8-mg/liter levels after 65 exposures (6 hr/day) with no other findings statistically significant. Dilated kidney tubules and pink homogeneous material at the cortico-medullary junction were found in rats that had inhaled 5.7, 2.8, and 1.4 mg/liter (1200, 570, and 290 ppm, respectively), for 13 weeks. In an extension of this study with rats only at 0.85, 0.44, and 0.20 mg/liter (170, 90, and 41 ppm, respectively), there was a statistically significant increased frequency of moderate kidney tubular regeneration and, in our opinion, an unrelated decrease in blood urea nitrogen after 13 weeks of inhalation of 0.85 mg/liter. The odor threshold, as determined by 6 people, was approximately 0.01 mg/liter (2 ppm). Based upon 15-min inhalation periods by humans and the animal findings, the concentration judged acceptable for 8 hr/day, 5 days/week of inhalation was 0.44 mg/liter (90 ppm).

Petroleum hydrocarbon toxicity studies: III. Animal and human response to vapors of Stoddard Solvent

Abstract The suggested hygienic standard for inhalation of Stoddard Solvent for man is 1.2 mg/liter (200 ppm) based upon the results of inhalation studies with rats and dogs and sensory response of human subjects. Inhalation of 8.2 mg/liter (1400 ppm), substantial saturation at 25°C, caused the death of 1 of 15 rats at the termination of 8 hr. Beagle dogs had clonic spasms in 5 hr and cats died between 2.5 and 7.5 hr in roughly equivalent concentrations after signs indicative of central nervous system effect. There were no statistically significant differences between the controls and groups of beagle dogs that inhaled 1.9 mg/liter (330 ppm), 1.1 mg/liter (190 ppm) and 0.48 mg/liter (84 ppm) 6 hr daily, 5 days/wk for 13 wk or 65 exposure days in any of the criteria used for hematology, clinical chemistry, and histopathology. However, rats exposed to 1.9 mg/liter (330 ppm) level for 65 days exhibited slight pathological changes in the kidney, which were related at least in part to the inherent murine nephrosis of the Harlan-Wistar rats employed. The odor threshold as determined in a sniff test by six people is below 0.005 mg/liter (0.9 ppm). In a 15-min inhalation period only slight eye irritation was reported by one of six persons at 0.85 mg/liter (150 ppm). Olfactory fatigue occurred in a short time but 10 min in fresh air restored acuity.

Petroleum hydrocarbon toxicity studies. V. Animal and human response to vapors of mixed xylenes

Abstract The suggested hygienic standard of 0.46 mg/liter (110 ppm) for mixed xylenes is based solely on sensory response of human subjects because of the relatively low toxicity of the vapor. The Lt50 was 92 min for rats that inhaled 46 mg/liter (11,000 ppm) of mixed xylenes, a concentration which approaches air saturated at room temperature. The LC50 for rats in a 4-hr inhalation period was 29 mg/liter (6700 ppm). Cats succumbed within 2 hr at 41 mg/liter (9500 ppm) with signs suggestive of central nervous system effect. No statistically significant differences from control groups, receiving only the uniformly shared dilution air, occurred among groups of beagles and rats that inhaled measured concentrations 6 hr/day, 5 days/wk for 13 wk at levels of 3.5(810), 2.0(460), and 0.77 mg/liter (180 ppm). The odor threshold was determined by a panel of six people to be on the order of 0.0045 mg/liter or 1 ppm. In a 15-min inhalation period, the only common sign of discomfort at 2.0 mg/liter (460 ppm) was eye irritation in four of six subjects. Some transitory olfactory fatigue occurred with recovery in 10 min.

Petroleum hydrocarbon toxicity studies: I. Methodology☆

Abstract The objectives, protocols, and procedures followed in the study of the inhalation toxicity of a series of petroleum hydrocarbons are presented herein. To conserve journal space reference will be made to this report in order to avoid repetition in succeeding reports on selected commercially available petroleum hydrocarbons. The compounds are arranged in a matrix based on boiling range and aromaticity. It is hoped that the information gathered in this series of 12 or more studies will provide a basis for predicting the toxicity of closely related hydrocarbon mixtures that are articles of commerce.

Response of dogs to repeated intravenous injection of polyethylene glycol 4000 with notes on excretion and sensitization

Repeated intravenous injections of sterile 10% polyethylene glycol 4000 in 0.85% aqueous NaCl caused no detectable ill effects in groups of 9 beagles on dosages of 90, 30, 10, and 0 mg/kg/day. Two dogs from each level were killed after 43 daily injections in 2 months, 2 more after 99 injections in 6 months, and the remaining 5 after 178 injections in 12 months. There were no statistically significant differences between any of the injected groups and the control group that received the 0.85% NaCl vehicle in an amount equivalent to the volume of the highest dosage, i.e., 9 ml. The criteria of effect included body and organ weights, hematology, biochemical tests, gross and histopathologic examination of cranial, thoracic, and abdominal organs. Two importantly related studies reveal that PEG 4000 is not a sensitizing agent in guinea pigs and that the major routes of excretion of 14C equivalents by rats after iv and po administration are via urine in the first instance and feces in the second. Its proposed use as a complexing agent in the preparation of a high purity antihemophilic factor for human intravenous use prompted these studies.

Petroleum hydrocarbon toxicity studies: VI. Animal and human responses to vapors of “60 Solvent”

Abstract The suggested hygienic standard of 0.44 mg/liter (90 ppm) is based solely upon animal response to inhalation of “60 Solvent” vapor. Rats were affected at 0.85 mg/liter (170 ppm), but this concentration as well as 1.7 mg/liter (350 ppm) was well tolerated by human volunteers in sensory threshold studies. The LC50 for rats that inhaled the vapor for 4 hr was 24 (22–30) mg/liter or 4900 (4500–6100) ppm. Half this concentration caused loss of coordination, but 3.4 mg/liter (690 ppm) caused no visible response. Similar responses occurred in beagles at 9.5 mg/liter (1900 ppm) and 4.0 mg/liter (820 ppm). Cats died within 4 hr at 20 mg/liter (4100 ppm). The rat Lt50 was 150 min at 38.0 mg/liter (7700 ppm). There were slight increases in liver and kidney weights of beagles on the 5.7- and 2.8-mg/liter levels after 65 exposures (6 hr/day) with no other findings statistically significant. Dilated kidney tubules and pink homogeneous material at the cortico-medullary junction were found in rats that had inhaled 5.7, 2.8, and 1.4 mg/liter (1200, 570, and 290 ppm, respectively), for 13 weeks. In an extension of this study with rats only at 0.85, 0.44, and 0.20 mg/liter (170, 90, and 41 ppm, respectively), there was a statistically significant increased frequency of moderate kidney tubular regeneration and, in our opinion, an unrelated decrease in blood urea nitrogen after 13 weeks of inhalation of 0.85 mg/liter. The odor threshold, as determined by 6 people, was approximately 0.01 mg/liter (2 ppm). Based upon 15-min inhalation periods by humans and the animal findings, the concentration judged acceptable for 8 hr/day, 5 days/week of inhalation was 0.44 mg/liter (90 ppm).

Petroleum hydrocarbon toxicity studies: VII. Animal and human response to vapors of “70 Solvent”

Abstract The suggested hygienic standard for human inhalation of “70 Solvent”, based upon the results of inhalation studies with rats and dogs and the sensory response of human subjects, is 0.32 mg/liter (59 ppm). Inhalation of 4.4 mg/liter (810 ppm) for 8 hr caused lacrimation, loss of coordination, and fine tremors but no deaths among 10 rats. During the 4-hr inhalation of 5 mg/liter (930 ppm), a beagle had convulsions in 2 hr and died 1.5 hr subsequent to the exposure. Four cats that inhaled 2.0 mg/liter (370 ppm) for 6 hr had signs indicative of central nervous system effect. At a concentration of 2.2 mg/liter (410 ppm) body weights of rats and dogs were slightly depressed only after the 13 th week of inhalation. The adjacent level, 1.1 mg/liter (200 ppm), was considered the no-ill-effect level for both species. The odor threshold, as determined by a sniff test involving six human subjects, is approximately 0.004 mg/liter (0.7 ppm). Only minimal responses were elicited by the six subjects during a 15-min period in 0.32 mg/liter (59 ppm) while, at 0.95 mg/liter (180 ppm), ocular and nasal irritation was reported by five and three subjects, respectively. Therefore, a concentration of 0.32 mg/liter (59 ppm) should be tolerated by most individuals.

Comparative effect of carbarylon rat reproduction and guinea pig teratology when fed either in the diet or by stomach intubation

Abstract A 3-generation rat reproduction study, terminating with teratologic and mutagenetic studies included groups receiving carbaryl in the diet at maximum daily doses of 200 mg/kg while other groups concurrently received daily po intubation of carbaryl in doses as high as 100 mg/kg. A guinea pig teratology study was also run with maximum levels of carbaryl of 300 mg/kg in the diet or 200 mg/kg po. Previous publications of repeated po intubation reported rat reproduction effects from carbaryl at 2 mg/kg and guinea pig teratology at a maternal toxic level of 300 mg/kg. The concurrent study of administration of carbaryl by daily po administration or by dietary inclusion resulted in neither rat teratology or mutagenesis nor guinea pig teratology in the animals that received the maximum dosage levels. However, the maximum po groups had severe toxic effects in both studies as contrasted to little or no effect at the maximum dietary levels for rat or guinea pigs and no effect at 25 mg/kg po to rats or 100 mg/kg po to guinea pigs. These studies verify the differences that result by deviation from certain proposed guidelines for experimental design. There-fore, the importance of mode of administration was demonstrated, thus verifying that dosage-related responses must be considered if results are to be used to predict safety for man.

Petroleum hydrocarbon toxicity studies. XIII. Animal and human response to vapors of toluene concentrate.

Abstract The suggested hygienic standard for human inhalation of Toluene Concentrate, based upon results of these inhalation studies with rats and dogs and the sensory response of human subjects, is 1.9 mg/liter (480 ppm). The LC50 for rats that inhaled Toluene Concentrate for 4 hr was 35 (31 to 38) mg/liter or 8800 (7800 to 9600) ppm. Rats tolerated 6.8 mg/liter (1700 ppm) for 4 hr and dogs 3.0 mg/liter (760 ppm) for 6 hr without any signs of discomfort. Four cats that inhaled 31 mg/liter (7800 ppm) for 6 hr developed signs suggestive of central nervous system effects, including mydriasis, mild tremors, prostration in 80 min, and light anesthesia after 2 hr. One of four died as a result of pneumonic infection within 14 days. Rats and dogs that inhaled 3.9, 1.9, or 0.95 mg/liter of Toluene Concentrate for 13 weeks, 6 hr/day, were not statistically significantly different from their air-exposed controls in any of the criteria of injury that were monitored including hematology, clinical chemistry, and micropathology. The odor threshold as determined by a sniff test involving two trials with six human subjects is approximately 0.01 mg/liter (2.5 ppm). Six of six people indicated their willingness to work in a concentration of 1.9 mg/liter (480 ppm) which is equivalent to 0.87 mg/liter or 220 ppm of contained toluene, the limiting concentration recommended for the hygienic standard. Only the response of people in the workplace can determine whether the toxic and irritative effects of the components of this mixture are additive or less than additive, as the evidence presented suggests to us that they are not greater than additive.

Petroleum hydrocarbon toxicity studies: XI. Animal and human response to vapors of Deodorized Kerosene☆☆☆

The suggested hygienic standard for human inhalation of Deodorized Kerosene, based upon the results of inhalation studies with rats and dogs and the sensory responses of human subjects is 0.10 mg/liter (14 ppm). Air saturated at 25°C with these vapors produced no signs of discomfort, nor any mortality in rats, dogs, or cats during 8-hr inhalation periods. Aerosols caused only skin irritation of extremities of rats after 6 hr/day for 4 days at a mean concentration of 7.5 mg/liter. Cats were not affected by 6.5 mg/liter after 6 hr in a similarly generated aerosol. Air at 25°C substantially saturated with the vapors caused no statistically significant deviations from control groups in any of the monitored criteria of effect when inhaled 6 hr/day, 5 days/week, for 67 and 68 days by rats and dogs, repectively. The most probable odor threshold as determined by a sniff test conducted with six human subjects is 0.0006 mg/liter (0.09 ppm). Substantially saturated vapor at room temperature ca. 0.10 mg/liter (14 ppm) should be well tolerated in the workroom atmosphere for continuous 8 hr/day inhalation.