Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 (2008)

The U.S. Navy requested that the committee review and recommend inhalation exposure guidance levels for oil mist, specifically turbine oil with military nomenclature 2190 TEP. However, no relevant health-effects data specific to 2190 TEP were located in the public literature. Therefore, to determine exposure guidance levels, the committee had to define a petroleum distillate that it could use as a surrogate for evaluating health effects. In the absence of relevant data on 2190 TEP, the committee reviewed and evaluated literature on highly and severely refined distillate base stocks—a broad category of petroleum distillates that includes the base stock used in 2190 TEP (The Petroleum High Production Volume Testing Group 2003; CONCAWE 1986)—that were also insoluble in water. In general, lubricating base oils fit that characterization, and some information on the lubricating oil base stock of 2190 TEP (CAS no. 64742-54-7) was available. Other literature sources were evaluated when deemed appropriate.

This chapter summarizes relevant epidemiologic and toxicologic studies of the selected petroleum distillates mentioned above. Chemical and physical properties, toxicokinetic and mechanistic data, and inhalation exposure levels from other agencies are also presented. The committee considered all that information in its evaluation of the Navy’s proposed 1-h, 24-h, and 90-day exposure guidance levels for oil mist. The committee’s recommendations for oil mist exposure levels are provided at the conclusion of the chapter with a discussion of the adequacy of the data for defining the levels and the research needed to fill remaining data gaps. The effects of specific additives possibly present in the final petroleum products, such as sulfur or phosphate additives, were considered to be outside the scope of this assessment. Additives are usually proprietary materials and are used to improve the physical properties of products (Mackerer 1989). However, one additive, 2,6-di-tert-butyl-4-nitrophenol, is discussed in Chapter 4 of this report.

2190 TEP is a hydrotreated heavy paraffinic distillate that may have been further refined by severe solvent extraction, severe hydrocracking, or severe hydrotreating (Chevron 2001). It is described as a clear colorless to pale yellow liquid. Few physical and chemical property data are available; however, Table 8-1 provides information from material-safety data sheets provided by Navy suppliers.

Mineral oil of inhalable particle size is called oil mist. The size of the particles depends on the process by which they are generated. Oil mists can potentially be generated in a variety of applications, which include metalworking, textile machinery, mist lubrication, and machining processes (ACGIH 2003; CONCAWE 1986). In submarines, generation of oil mist occurs primarily in the engine room. Inhalation and dermal contact are two possible exposure routes. The focus of this review is inhalation because adverse health effects resulting from dermal exposure are considered minimal provided that adequate personal-hygiene measures, such as wearing protective clothing and washing hands, are followed. Dermal toxicity of highly refined oils in humans is briefly summarized in CONCAWE (1986) and consists primarily of dermatitis and acne induced by oil.

A summary of the literature on occupational exposure to lubricating oil base stocks with and without additives is presented in Table 8-2. Animal data are summarized in Table 8-3. In addition, six articles (CONCAWE 1986; Mackerer 1989; Kenny et al. 1997; NRC 1997; NIOSH 1998; The Petroleum HPV Testing Group 2003) have summarized the available literature.

No relevant information on accidental exposures or experimental studies in humans was identified. However, occupational exposure to petroleum oil mists was associated primarily with effects on the respiratory system. Symptoms observed in automobile workers included coughing, wheezing, and phlegm, as reported by Kriebel et al. (1997), Greaves et al. (1997), and Ameille et al. (1995) at exposures (geometric means) of 0.19 mg/m³, 0.43 mg/m³, and 2.2 mg/m³, respectively. Effects on respiratory function—as measured by reductions in cross-shift response in forced expiratory volume in 1 sec (FEV₁)—were demonstrated by Kriebel et al. (1997) and Kennedy et al. (1989) at the exposures defined previously. Marine engineers exposed to oil mists demonstrated similar effects on the respiratory system at a time-weighted average (TWA) of 0.45 mg/m³ (Svendsen and Hilt 1997, 1999). A synergistic effect on respiratory function between inhaled tobacco smoke and oil mist has been suggested (Ameille et al. 1995).

Results of pulmonary exposure of laboratory animals to lubricating oils are similar to those observed in humans in occupational settings except that the animals were generally exposed at much higher concentrations. The target organ in animals was the respiratory tract. The most prevalent effect was the occurrence of foamy macrophages in the lungs. In general, the rat and the dog were the most sensitive species compared with rabbits, mice, and hamsters (Wagner et al. 1964). Acute exposures to metalworking fluids have been shown to be sensory and pulmonary irritants in mice (Schaper and Detwiler 1991). Straight oils caused sensory irritation that decreased within 1 h; pulmonary irritation was not observed until 2 h of exposure. The highest concentration tested was 2,816 mg/m³. That is consistent with the low toxicity (primarily mucous membrane irritation of the upper respiratory tract) observed after acute exposure to oil mists with profile characteristics outside those defined in the present review (CONCAWE 1986; Dalbey and Biles 2003). Four-and 13-week exposures to oil mists with the same CAS number as 2190 TEP resulted in lung pathology at concentrations of 50 mg/m³ and greater; pulmonary function was not affected at concentrations as great as 1,000 mg/m³ (Dalbey et al. 1991; Dalbey 2001). Dogs and rats exposed to oil mist for up to 26 months at 5.5-105.8 mg/m³ did not have an increase in tumor incidence (Stula and Kwon 1978; Wagner et al. 1964).

No relevant information was identified.

No relevant information was identified.

Fifteen studies of the general health effects of occupational exposure to lubricating oil mists were reviewed (see Table 8-2). In all cases, exposure was chronic, from at least 1 month to 35 years. No relevant studies of acute exposure to oil mists were identified. However, two studies (Kennedy et al. 1989; Kriebel et al. 1997) measured “acute pulmonary responses” (health effects measured on a single day) to metalworking fluid but after an exposure period of at least 1 month. Automobile workers (machine operators) exposed to aerosols of cutting oils and coolant fluids for at least 6 months demonstrated a significant drop in FEV₁ relative to assembly (control) workers (Kennedy et al. 1989); the response was associated with exposures greater than 0.20 mg/m³. In a study by Kriebel et al. (1997), workers exposed to mineral oil at 0.24 mg/m³ for at least 1 month, with respiratory effects being measured on a single day, provided some evidence of acute and chronic pulmonary respiratory symptoms. The results of Kriebel et al. (1997) are considered equivocal at best because nonmachinists (control population) demonstrated similar respiratory effects.

Most of the reviewed literature addressed chronic respiratory effects elicited after exposure of more than 1 year. Of the studies reviewed, only five (Ameille et al. 1995; Greaves et al. 1997; Eisen et al. 1997; Svendsen and Hilt 1997, 1999) were considered relevant for EEGL and CEGL development; of the five studies, three were specific to automobile workers, and two to marine engineers. In a study conducted by Ameille et al. (1995), automobile workers did not demonstrate an increased prevalence of respiratory symptoms when exposed to straight cutting oils at a geometric mean concentration of 2.2 mg/m³ for a duration of at least 1 year. However, a combined analysis of workers exposed to straight cutting oil or a mixture of straight cutting oil and soluble cutting oil did exhibit an increased prevalence in cough or phlegm. Respiratory function and pulmonary function were also impaired in straight-cutting-oil-exposed workers who smoked.

Results of Greaves et al. (1997) suggested an association of increased reporting of respiratory effects (cough, phlegm, and wheezing) with exposure to metal-working fluids (synthetic oils > straight oils > soluble oils) after exposure of at least 2 years. The average exposure concentration was 0.43 mg/m³. Eisen et al. (1997) reanalyzed those data to evaluate bias in the selection of asthmatics out of the work-

place. Their analysis demonstrated a slight increase in the rate ratio for asthma in workers exposed to straight metalworking fluid. As was observed in the Greaves et al. study (1997), the effects were greatest in the workers exposed to synthetic fluids.

A significant increase in mucous membrane irritation and dyspnea (Svendsen and Hilt 1997) and a decrease in respiratory function (Svendsen and Hilt 1999) were observed in marine engineers exposed to mist oil at a TWA of 0.45 mg/m³ for more than 5 years. The engineers also had previous potential exposure to asbestos, welding fumes, and other irritating gases. The authors concluded that the findings of the respiratory-function evaluation were weak and that additional investigational work was needed.

Schaper and Detwiler (1991) exposed Swiss-Webster mice to different aerosolized metalworking fluids obtained from three General Motors plants. Mice were exposed to straight (new or “neat” and used), soluble, or synthetic oils; only the results with straight oil are discussed here. Exposure concentrations ranged from about 200 to 2,492 mg/m³ and from about 400 to 2,816 mg/m³ for the neat and used metalworking fluid, respectively. For both neat and used oils, six concentrations were tested at 3-h exposure periods with four mice per exposure. Sensory irritation, as defined in Table 8-3, was observed immediately on exposure to both oils at all concentrations tested, but the irritation decreased within 1 h or less. Pulmonary irritation was apparent at 2 h on exposure to all oil mists. Mild interstitial pneumonia was observed after exposure to both the neat and used straight oils at the highest concentration tested.

As a follow-up to occupational-exposure studies of cable-plant workers exposed to mists and vapors of mineral oil and kerosene (Skyberg et al. 1986), Skyberg and co-workers (1990) exposed Wistar rats to two mineral oil mists derived from a mildly refined naphthenic crude oil for 7 h/day, 5 days/week for 2 weeks. One of the oils was representative of an oil used as an impregnation fluid (mineral oil A), and the other was used in cable splicing (mineral oil B/C). Exposure concentrations ranged from 126 to 770 mg/m³ for mineral oil A and 75 to 748 mg/m³ for mineral oil B/C. A significantly reduced necropsy body weight was observed in the high-dose group exposed to mineral oil A. Increased liver and lung weights were observed, but statistical significance was not achieved. Macroscopic changes were not observed in the lungs of any of the exposed groups. Mineral oil B/C induced significant increases in the number of alveolar macrophages (at 748 mg/m³) and the degree of vacuolization (at greater than 75 mg/m³). Damage to the bronchial mucosa (including ciliary loss), increased number of goblet cells, and cellular disorien-

tation were observed after exposure to all oils, except mineral oil A, at 748 mg/m³. Liver pathology was noted as slight fatty liver degeneration (mineral oil A, 770 mg/m³) and sinusoidal dilatation (mineral oil B/C, ≥75 mg/m³). Mineral oil A was detected in the fat tissue of exposed animals and was retained 2 weeks after the completion of exposure.

Several inhalation studies of oil mists, with the characteristic profile outlined by the committee, were conducted by Dalbey et al. (1991) and Dalbey (2001). Two of the petroleum distillates tested, including one hydrotreated base stock and one gear oil, had the same lubricating base stock as 2190 TEP (CAS no. 64742-54-7). In a standard 4-week toxicity study, whole-body exposure to hydrotreated base oil at 50, 210, and 1,000 mg/m³ for 6 h/day, 5 days/week, only lung and associated lymph node changes were observed (Dalbey et al. 1991). The main histologic changes observed at 210 and 1,000 mg/m³ were accumulation of foamy macrophages in alveoli, infiltration of neutrophils and lymphocytes associated with the foamy macrophages, and a slight thickening of the alveolar wall; concentration dependence was demonstrated. Similar pathology of the lung and slight hyperplasia of alveolar epithelial cells were observed on exposure to gear oil (CAS no. 64742-54-7 and 64742-57-0) for 13 weeks at 60, 150, and 520 mg/m³ (Dalbey 2001). Additional changes included an increase in lung weight and a shift in the white-blood-cell (WBC) differential (≥150 mg/m³). Pulmonary function was not affected in any treatment group.

Wagner et al. (1964) exposed five species—dogs, rabbits, mice (CF No. 1 strain and CAF1/Jax strain), rats, and hamsters—to two concentrations of light mineral oil (naphthenic base) for 1 year (5 mg/m³) to 26 months (100 mg/m³). CF No. 1 mice were used to determine responses to exposures both histologically and physiologically and were used to assess longevity. CAF1 mice, which were used as a model to evaluate tumorigenic potential, were exposed only at 100 mg/m³. No significant changes in body weight or hematologic characteristics were observed in any of the test species. Respiratory function was not affected in the rabbits, the only species tested this way. Basic alkaline phosphatase (BAP) and magnesium-activated alkaline phosphatase (MgAP) were monitored in all species. No significant differences from control animals were observed in rabbits (5 and 100 mg/m³) or in dogs, rats, and hamsters (5 mg/m³). In general, BAP and MgAP were increased in dogs, rats, and hamsters at 100 mg/m³ as early as 6 months of exposure. No pathologic response was evident in the lung tissue of mineral-oil-exposed rabbits and mice. Pathologic responses (as evidenced by foamy macrophages and oil-droplet formation) were observed in dogs and rats. Those effects were apparent at 12 months of exposure in dogs (5 mg/m³). Significant pulmonary alveolar and hilar lymph node oil deposition and granuloma formation were also observed at 12 months but only at 100 mg/m³. In rats, pulmonary tissue alterations were of significance only at 100 mg/m³.

Stula and Kwon (1978) evaluated the chronic toxicity of a complex mineral oil containing adjuvants and acetone in dogs, rats, mice, and gerbils. The primary objective was to determine whether the toxicity profile observed with pure mineral oil mist (Wagner et al. 1964) would be altered by the addition of adjuvants and acetone. The animals were exposed to the complex mixture for 12-24 months 6 h/day, 5 days/week at 5 and 100 mg/m³ in combination with 1,000-ppm acetone. Relative to the results of Wagner et al. (1964), inhalation toxicity was not significantly altered by the addition of adjuvants and acetone. Oil mist was detectable in lung macrophages of all species tested at both concentrations. Oil microgranulomas were observed in rats and dogs only at the higher concentration. The data were not considered relevant to the present analysis, because of the composition of the test material. However, the data do confirm the results of Wagner et al. (1964).

Sperm morphology and counts were not adversely affected in male rats exposed to hydrotreated base oil at 1,000 mg/m³ 6 h/day for 4 weeks (Dalbey et al. 1991).

No relevant information was identified.

Solvent-refined hydrotreated heavy paraffinic distillate was negative in the modified salmonella mutagenicity assay (Blackburn et al. 1986).

Four studies of the carcinogenic potential of mineral oil in humans were reviewed (Waldron 1975; Decoufle 1978; Jarvholm et al. 1981; Eisen et al. 1994). Results are detailed in Table 8-2. Although it has been reported that workers exposed to mist oils have an increased risk of cancer, contamination of the mineral oils with polycyclic aromatic hydrocarbons (PAH, some known to be carcinogenic) confounds interpretation of the observed results. Metalworking fluids, such as 2190 TEP, that are highly or severely refined have low concentrations of PAHs when “unused” and are classified as A4 (not classifiable as a human carcinogen).

Severe processing can significantly reduce or eliminate the carcinogenic potential of crude oils, as has been demonstrated in mouse-skin painting studies (Kane et al. 1984). On the basis of the results of a modified salmonella mutagenicity assay (Blackburn et al. 1986), solvent-refined hydrotreated heavy paraffinic distillate was not predicted to be carcinogenic.

As discussed above, Wagner et al. (1964) exposed dogs, rabbits, mice (CF No. 1 strain and CAF1/Jax strain), rats, and hamsters to two concentrations of light mineral oil (naphthenic base) daily for 1 year (5 mg/m³) to 26 months (100 mg/m³). Significant pulmonary alveolar and hilar lymph node oil deposition or lipid granuloma formation were observed after 12 months in the dog. Although Stula and Kwon (1978) evaluated whether the toxicity profile observed with pure mineral oil mist would be altered by the addition of adjuvants and acetone, their results discussed above support those of Wagner et al. (1964).

Wagner et al. (1964) evaluated the tumorigenic potential of light mineral oil in a lung-tumor-sensitive strain of mice (CAF1/Jax). Mice were exposed to light mineral oil at 100 mg/m³ 6 h/day, 5 days/week. Animals were sacrificed monthly from 7 months to 13 months of exposures, and the lungs were processed for histologic evaluation. The collective results of the studies were equivocal. Percentage differences in tumor incidences of 20% and 15% were observed in oil-exposed mice compared with control mice at 10 and 11 months, respectively. However, at 12 and 13 months, the percentage difference was 10% and 13%, respectively; and control mice exhibited more tumors than the oil-exposed mice.

The negative results of the mutagenicity study and rodent carcinogenicity studies support the view that there is no carcinogenic potential in animals. The material-safety data sheet provided by the supplier states that 2190 TEP is not classified as a carcinogen by the National Toxicology Program or by the International Agency for Research on Cancer (Chevron 2001).

Although there is recent concern about the cardiac and pulmonary toxicity of respirable particulate matter from ambient air pollution, mechanistic understanding is insufficient to implicate oil mist particles as a health hazard for otherwise healthy adults. On the basis of animal studies, 2190 TEP would be expected initially to cause an inflammatory reaction if inhaled into the alveolar (deep) region of the lung. Deposition in the deep lung will depend to some extent on the size of the droplets; that is, if smaller than 3-5 µm, they can be expected to reach this area. Furthermore, “fine” oils, such as 2190 TEP, can spread over the surface of the airways and alveoli, depending on the dose. Oil deposited in the airways can be expected to be removed from the lung within a few days by normal physiologic mechanisms, such as the mucoescalator apparatus. However, oil deposited in the alveolar region cannot be removed from the lung to any substantial extent. In that region, the oil will first induce an inflammatory reaction whose extent will be directly dose-dependent. Initially, as demonstrated in animal studies (Skyberg et al. 1990), the oil is taken up (phagocytized) by alveolar macrophages. After a period of weeks, the oil can be found in macrophages of the draining lymph nodes, where it is essentially inert (it causes little reaction at this site). If the dose is large enough in the lung, the macrophages can coalesce and form foreign-body giant cells (Dalbey 2001). If the lung reaction is severe enough, the chronic inflammation can result in

interstitial pneumonitis and fibrosis (Wagner et al. 1964). Because the oil cannot be metabolized what reaches the deep lung can be expected to remain there or in the draining lymph nodes for long periods. However, there is no evidence that the lesions are progressive or that they will result in cancer in either the lung or lymph nodes.

There are no inhalation exposure levels for 2190 TEP oil mist. However, there are a few occupational standards for mineral oil mist, and they are listed in Table 8-4.

The committee’s recommendations for EEGL and CEGL values for oil mist are summarized in Table 8-5. The proposed U.S. Navy values are provided for comparison.

Because of the lack of human data on the health effects of short-term exposure to oil mist, data from animal studies were used. The point of departure for estimating the 1-h EEGL was 200 mg/m³, which is the lowest observed-adverse-effect level from Schaper and Detwiler (1991). The committee concluded that that concentration would not affect task completion by a submariner. At that concentration for 3 h, aerosolized metalworking fluid produced sensory irritation

in mice that decreased in 1 h or less and became more pronounced at 3 h. Interstitial pneumonitis was observed at 24 h but not 14 days after exposure. The effect was reversible after exposure ended. Pulmonary irritation was not observed until 2 h of exposure. An uncertainty factor of 3 to account for interspecies differences was applied because animal species and humans respond similarly regarding pulmonary effects. A database uncertainty factor of 3 was applied to account for the lack of data specific to 2190 oil mist and the need to use data on surrogate oils to derive an exposure guidance level. No intraspecies uncertainty factor was applied, because the submariner population would be expected to react similarly to the pulmonary effects. Application of the interspecies and database uncertainty factors results in a 1-h EEGL of 20 mg/m³. That estimate is considered to be protective because it is based on a response after a 3-h exposure.

No relevant human information was available for determining the 24-h EEGL value. The committee considered the publication by Skyberg et al. (1986) but decided that the composition of the petroleum distillate was too dissimilar from 2190 TEP and lubricating oils. Therefore, the point of departure for estimating the 24-h EEGL was the recommended 1-h EEGL, 20 mg/m³. Because the animals were exposed to the test metalworking fluid for 3 h, a time-duration adjustment factor of 8—(24 h)/(3 h) = 8—was applied to the 1-h EEGL, resulting in a 24-h EEGL of 2.5 mg/m³.

To determine the 90-day CEGL, the committee considered two studies of petroleum distillates with the same lubricating base stock as 2190 TEP (CAS no.

64742-54-7) tested on rats (Dalbey 2001; Dalbey et al. 1991). In a standard 4-week inhalation-toxicity study, whole-body exposure to hydrotreated base oil at 50, 210, and 1,000 mg/m³ resulted in lung and associated lymph node changes (Dalbey et al. 1991). The no-observed-adverse-effect level (NOAEL) was 50 mg/m³. The main histologic changes observed were accumulation of foamy macrophages in alveoli, infiltration of neutophils and lymphocytes associated with the foamy macrophages, and a slight thickening of the alveolar wall. Those effects were considered minimal. Similar pathology of the lung and slight hyperplasia of alveolar epithelial cells were observed on inhalation exposure of rats to gear oil (combination of CAS no. 64742-54-7 and 64742-57-0) for 13 weeks at 60, 150, and 520 mg/m³ (Dalbey 2001). Additional changes included an increase in lung weight and a shift in the WBC differential (≥150 mg/m³). Pulmonary function was not affected. Because the latter study combined two lubricating base stocks, the committee used the first study (NOAEL, 50 mg/m³) as the initial point of departure. In a study conducted by Ameille et al. (1995), automobile workers did not demonstrate an increased prevalence of respiratory symptoms when exposed to straight cutting oils at a geometric mean concentration of 2.2 mg/m³ for at least 1 year. However, a combined analysis of workers exposed to straight cutting oil or a mixture of straight cutting oil and soluble cutting oil did exhibit an increased prevalence in cough or phlegm. Respiratory function and pulmonary function were also impaired in straight-cutting-oil-exposed workers who smoked. In humans, exposures to metalworking fluids at 0.243 mg/m³ for at least 1 month (Kriebel et al. 1997) and 0.20 mg/m³ for at least 6 months (Kennedy et al. 1989) resulted in similar respiratory responses (significant drop in FEV₁ response). Because exposure data in humans are not as well controlled as in the animal studies and the oils were different from 2190 TEP, the rat studies were considered more appropriate for setting the 90-day CEGL. Starting with 50 mg/m³ as the initial point of departure, an uncertainty factor of 3 was applied to account for interspecies differences because animals and humans demonstrate similar respiratory symptoms on exposure to oil mist. A duration adjustment factor of 16.8—(7/5 [days])(24/6 [h])(3/1 [months])—was applied. A database uncertainty factor of 3 was also applied to account for the lack of data specific to 2190 oil mist and the need to use data on surrogate oils to derive an exposure guidance level. No intraspecies uncertainty factor was applied, because the submariner population would be expected to react similarly to the pulmonary effects. Application of the uncertainty and duration-adjustment factors results in a 90-day CEGL of 0.3 mg/m³.

The committee recommends analysis of the oil mist to which the submariners are exposed. That mist oil should then be evaluated in animals for potential adverse health effects. If the Navy does not agree with the approach taken by the committee to estimate exposure guidance levels in this profile, acute and 90-day animal studies should be conducted with 2190 TEP. The committee recommends that used 2190

TEP (used in the same manner as in a submarine) be characterized to determine the aromatic components present.

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