1 OCCUPATIONAL EXPOSURE LIMITS FOR CHEMICAL SUBSTANCES

Acetaldehyde [CAS No. 75–07–0] is an irritating colorless liquid (boiling point 20.2℃, vapor pressure 101 kPa (20℃)) that is used as an intermediate raw material in the manufacture of chemical materials, preservatives, organic solvents, reducing agents, and glues as a substitute of formaldehyde. The occupational exposure limit-Ceiling (OEL-C) was recommended at 50 ppm (90 mg/m3) for acetaldehyde in 1990, and acetaldehyde was assigned to carcinogenicity Group 2B in 1991. The Japanese Society for Occupational Health (JSOH) re-evaluated the OEL-C, and proposes 10 ppm as the OEL-C for acetaldehyde based on observed eye irritation in human at concentrations of 50 ppm for 15 min and 4 hours1 and the possibility of slight impairment of mucociliary transport in upper respiratory tract in rats2 at the concentrations of 150 ppm for 6 hours/day, 5 days/week for up to 65 exposure days (13 exposure weeks; No-observed-adverse-effect-level (NOAEL) 50 ppm). As the new OEL-C, 10 ppm is expected to prevent the observed effects on the eyes and upper respiratory tract in consideration of the higher sensitivity due to the lower metabolic rate for acetaldehyde on in approx. 40% of the Japanese population, which has the ALDH2*2 genotype.3 The carcinogenicity group remains the same.

Glyphosate [CAS No. 1071–83–6] is a white crystalline powder (melting point 184.5℃, vapor pressure 1.31×10−5 Pa (25℃)) that is used as liquid, powder, or mist pesticide for weeding. The JSOH proposes 1.5 mg/m3 as OEL-Mean (OEL-M) for glyphosate based on the results of animal experiment. The NOAEL in male and female rats was considered 10 mg/kg body weight per day based on observed pathological changes: an increased incidence of pronounced cellular alterations of parotid and mandibular grands at or above 100 mg/kg body weight per day in 104 weeks.4 Uncertainty factors for species and absorption rates were applied and weight, respiratory volume, and working hours were adjusted in the assessment. The proposed carcinogenicity classification for glyphosate is Group 2B based on limited epidemiological and insufficient experimental carcinogenicity evidence.

Zinc oxide nanoparticle [CAS No. 1314–13–2] is a white crystalline powder with particle size of 1–100 nm. It is used as a material in the manufacture of cosmetics, pharmaceuticals, household and sporting goods, paint, and ink. The JSOH proposed 0.5 mg/m3 as the OEL-M for zinc oxide nanoparticle based on the results of animal experiment. The NOAEL in male mice was considered 3.5 mg/m3 based on the absence of increases in inflammatory markers in the lung, e.g., neutrophils and cytokines other than macrophages in bronchoalveolar lavage fluid in a 13-week inhalation study.5 Uncertainty factors for species and exposure duration were applied in the assessment.

2-Bromopropane [CAS No. 75–26–3] is a nonflammable colorless liquid (melting point −90℃, boiling point 59.4℃, vapor pressure 315 hPa (25℃)). It is used as solvents and intermediates for pharmaceuticals, pesticides, and photosensitizers. The recommended OEL-M for this chemical is 1 ppm (5mg/m3), and a skin absorption notation was indicated in 1999. 2-Bromopropane was classified in Group 1 as a reproductive toxicant in 2014. The JSOH re-evaluated the chemical's OEL by examining subsequent reports. The JSOH now proposes 0.5 ppm (2.5 mg/m3) as the OEL-M for 2-bromopropane based on epidemiological and animal experimental studies. Hematological indices might be adversely suppressed in female workers exposed to approx. 6.5 ppm.6 The low-observed-adverse-effect-level (LOAEL) in male rats was considered 67 ppm based on the significant increase in the incidence of ear canal carcinoma,7 despite its rarity in humans. Uncertainty factors for species and absorption rates were applied and body weight, respiratory volume, and working hours were adjusted in the assessment. The proposed carcinogenicity classification is Group 2B based on the lack of epidemiological and sufficient experimental carcinogenicity evidence. The skin absorption notation and the classification as a reproductive toxicant (Group 1) remain the same.

Manganese and its compounds (as Mn except for organic manganese compounds) [CAS No. 7439–96–5] is a red-gray or silver metal (melting point 1,245℃, boiling point 2,150℃, specific gravity 7.43), and is an essential trace element contained in water, soil, and food. Manganese is used as raw material for manganese-containing alloys, reagents, fungicides, bleach, gunpowder, and pharmaceuticals. The recommended OEL-M was set at 0.2 mg/m3 in 2008, and manganese and its compounds were categorized in Group 2 as a reproductive toxicant in 2014. The JSOH re-evaluated the OEL and reproductive toxicant class by examining subsequent reports, and proposed the OEL-M values of 0.1 mg/m3 and 0.02 mg/m3 for the total and respirable particulate matters for manganese and its compounds, respectively, based on the results of epidemiological studies in which the cumulative exposure concentrations were converted to annual average concentrations for 25 years. The LOAELs for total particulate matters were 0.143 mg/m3,8 0.225 mg/m3,9 and 0.301 mg/m3.10 A dose-dependent functional decrease on the finger-tapping test was observed in three groups of workers exposed to 0.031, 0.137, and 0.423 mg/m3 of total particulate matters, respectively, and the functional decrease among workers exposed to 0.423 mg/m3 was significantly low compared to that in workers exposed to 0.031 mg/m3.11 The NOAEL has been set at 0.060 mg/m312 of total particulate matters based on several neurobehavioral tests. The LOAELs of respirable particulate matters were 0.029 mg/m3,8 0.035 mg/m3,9 0.036 mg/m3,10 and 0.01–0.04 mg/m3,13 and the NOAEL was set at 0.021 mg/m3 based on observed effects on the nervous system.12 The class of reproductive toxicant (Group 2) remains the same.

Ethylbenzene [CAS No. 100–41–4] is a colorless liquid (boiling point 136.2 ℃, vapor pressure 1.27 kPa (25 ℃)) that is used as a raw material in the manufacture of stylene monomer, plastic, and rubber, and it is a component of mixed xylene. The JSOH proposed 150 mg/g･creatinine (Cr) of mandelic acid (MA) at the end of a work shift, 200 mg/g･Cr of MA plus phenylglycoxylic acid (PGA) at the end of the shift at the end of a work-week, and 15 µg/l of ethylbenzene at the end of a work shift in the urine for ethylbenzene as OEL based on biological monitoring (OEL-B) obtained in human studies. The estimated values of MA, MA+PGA, and ethylbenzene were 152 mg/g･Cr,14-17 205 mg/g･Cr,14, 17 and 13 µg/l15, 18 in urine corresponding to the OEL-M of 20 ppm for ethylbenzene.

Cadmium and its compounds [CAS No. 7440–43–9] are a soft bluish silver white metal (melting point 321℃, boiling point 765℃) that are used as raw materials for cadmium-containing alloys, pigments, and batteries. The LOAELs were 10 µg/l in blood and 10 µg/g･Cr in urine based on renal tubular effects in human study,19 and no effects were observed in workers whose cadmium concentrations were less than 5 µg/l in blood and 5 µg/g･Cr in urine.20 The OEL-Bs of 5 µg/l in blood and 5 µg/g･Cr in urine of cadmium are expected to prevent critical effects on renal function.

2 CARCINOGENICITY CLASSIFICATIONS

Both ultraviolet (UV) radiation from welding and welding fumes are proposed to be group 1 carcinogens. Proposed group 2B carcinogens are 2-bromopropane, CI direct blue 218, crotonaldehyde, glyphosate, and N-nitroso-N-phenylhydroxylamine ammonium salt (cupferron).

3 OTHER CLASSIFICATIONS

Group 1 is proposed as the respiratory and skin occupational sensitizer classifications for ortho-phthalaldehyde. Group 2 is proposed as the skin occupational sensitizer classification for ethylene glycol dimethacrylate and 1,6-hexanediol diacrylate. Group 3 is proposed as the reproductive toxicants classification for glyphosate.

4 DATA AVAILABILITY STATEMENT

Data openly available in a public repository that issues datasets with DOIs.

5 MEMBERS OF THE COMMITTEE FOR RECOMMENDATION OF OCCUPATIONAL EXPOSURE LIMITS, JAPAN SOCIETY FOR OCCUPATIONAL HEALTH

Atsuko Araki1, Kenichi Azuma2, Ginji Endo3, Yoko Endo4, Tetsuhito Fukushima5, Kunio Hara6, Kouji Harada7, Hajime Hori6, Seichi Horie6, Hyogo Horiguchi8, Masayoshi Ichiba9, Gaku Ichihara10, Tatsuya Ishitake11, Akiyoshi Ito12, Yuki Ito13, Satoko Iwasawa14, Takeyasu Kakamu5, Michihiro Kamijima13, Kanae Karita15, Toshio Kawai16, Toshihiro Kawamoto3, Reiko Kishi1, Shinji Kumagai, Akiko Matsumoto9, Muneyuki Miyagawa17, Hiroyuki Miyauchi6, Yasuo Morimoto6, Kasuke Nagano18, Hisao Naito19, Tamie Nakajima20, Makiko Nakano21, Tetsuo Nomiyama22, Hirokazu Okuda23, Masayuki Okuda24, Kazuyuki Omae21, Kazuhiro Sato25, Tomotaka Sobue26, Yasushi Suwazono27, Toru Takebayashi21, Tatsuya Takeshita28, Akito Takeuchi3, Ayano Takeuchi21, Shigeru Tanaka29, Mayumi Tsuji6, Teruomi Tsukahara22, Susumu Ueno6, Jun Ueyama30, Yumi Umeda23, Kenya Yamamoto12, Yuko Yamano31, Takenori Yamauchi31 and Eiji Yano17.

1Hokkaido University, 2Kindai University, 3Japan Industrial Safety and Health Association, 4Endo Occupational Health Consultant Office, 5Fukushima Medical University, 6University of Occupational and Environmental Health, Japan, 7Kyoto University, 8Kitasato University, 9Saga University, 10Tokyo University of Science, 11Kurume University, 12National Institute of Occupational Safety and Health, Japan, 13Nagoya City University, 14National Defense Medical College, 15Kyorin University, 16Kansai Technical Center for Occupational Medicine, 17Teikyo University, 18Nagano Toxicologic-Pathology Consulting, 19Kinjo Gakuin University, 20Chubu University, 21Keio University, 22Shinshu University, 23Japan Bioassay Research Center, 24Yamaguchi University, 25University of Fukui, 26Osaka University, 27Chiba University, 28Wakayama Medical University, 29Jumonji University, 30Nagoya University, 31Showa University.

DISCLOSURE

Approval of the research protocol: N/A. Informed consent: N/A. Registry and the registration no. of the study/trial: N/A. Animal studies: N/A. Conflict of interest: The authors declare that there is no conflict of interest.

AUTHOR CONTRIBUTIONS

All the authors contributed draft preparation and deliberation of the proposals in the committee. The corresponding author (TN) developed and finalized the article based on the comments from all other authors’ feedback.

REFERENCES

1Silverman L, Schulte HF, First MW. Further studies on sensory response to certain industrial solvent vapors. J Ind Hyg Toxicol. 1946; 28: 262- 266. 2Muttray A, Gosepath J, Brieger J, et al. No acute effects of an exposure to 50 ppm acetaldehyde on the upper airways. Int Arch Occup Environ Health. 2009; 82: 481- 488. 3Takao A, Shimoda T, Kohno S, Asai S, Harada S. Correlation between alcohol-induced asthma and acetaldehyde dehydrogenase-2 genotype. J Allergy Clin Immunol. 1998; 101: 576- 580. 4Atkinson C, Strutt AV, Henderson W, Finch J, Hudson P. Glyphosate: 104 week combined chronic feeding/oncogenicity study in rats with 52 week interim kill (results after 104 weeks). Unpublished report No. 7867, IRI project No. 438623, dated 7 April 1993, from Inveresk Research International, Tranent, Scotland. Submitted to WHO by Cheminova A/S, Lemvig, Denmark. (as cited in Joint FAO/WHO Meeting on Pesticide Residues, Pesticide residues in food–2004 and EPA, Evaluation of the carcinogenic potential of glyphosate, final report, 2015) 5Adamcakova-Dodd A, Stebounova LV, Kim JS, et al. Toxicity assessment of zinc oxide nanoparticles using sub-acute and sub-chronic murine inhalation models. Part Fibre Toxicol. 2014; 11: 15. doi:10.1186/1743-8977-11-15 6Ichihara G, Ding X, Yu X, et al. Occupational health survey on workers exposed to 2-bromopropane at low concentrations. Am J Ind Med. 1999; 35: 523- 531. 7Zhao LX, Kim EK, Lim HT, et al. Synthesis, characterization and in vtro identification of N7-guanine adduct of 2-bromopropane. Arch Pharm Res. 2002; 25: 39- 44. 8Roels HA, Ghyselen P, Buchet JP, et al. Assessment of the permissible exposure level to manganese in workers exposed to manganese dioxide dust. Br J Ind Med. 1992; 49: 25- 34. 9Mergler D, Huel G, Bowler R, et al. Nervous system dysfunction among workers with long-term exposure to manganese. Environ Res. 1994; 64: 151- 180. 10Bast-Pettersen R, Ellingsen DG, Hetland SM, et al. Neuropsychological function in manganese alloy plant workers. Int Arch Occup Environ Health. 2004; 77: 277- 287. 11Ellingsen DG, Konstantinov R, Bast-Pettersen R, et al. A neurobehavioral study of current and former welders exposed to manganese. Neurotoxicology. 2008; 29: 48- 59. 12Gibbs JP, Crump KS, Houck DP, et al. Focused medical surveillance: a search for subclinical movement disorders in a cohort of U.S. workers exposed to low levels of manganese dust. Neurotoxicology. 1999; 20: 299- 313. 13Young T, Myers JE, Thompson ML. The nervous system effects of occupational exposure to manganese—measured as respirable dust—in a South African manganese smelter. Neurotoxicology. 2005; 26: 993- 1000. 14Knecht U, Reske A, Woitowitz HJ. Biological monitoring of standardized exposure to ethylbenzene: evaluation of a biological tolerance (BAT) value. Arch Toxicol. 2000; 73: 632- 640. 15Janasik B, Jakubowski M, Jałowiecki P. Excretion of unchanged volatile organic compounds (toluene, ethylbenzene, xylene and mesitylene) in urine as result of experimental human volunteer exposure. Int Arch Occup Environ Health. 2008; 81: 443- 449. 16Jang JY, Droz PO, Kim S. Biological monitoring of workers exposed to ethylbenzene and co-exposed to xylene. Int Arch Occup Environ Health. 2001; 74: 31- 37. 17Korn M, Gfrörer W, Herz R, et al. Stereometabolism of ethylbenzene in man: gas chromatographic determination of urinary excreted mandelic acid enantiomers and phenylglyoxylic acid and their relation to the height of occupational exposure. Int Arch Occup Environ Health. 1992; 64: 75- 78. 18Kawai T, Sakurai H, Ikeda M. Biological monitoring of occupational ethylbenzene exposure by means of urinalysis for un-metabolized ethylbenzene. Ind Health. 2019; 57: 525- 529. 19Alessio L, Apostoli P, Forni A, Toffoletto F. Biological monitoring of cadmium exposure—an Italian experience. Scand J Work Environ Health. 1993; 19(Suppl 1): 27- 33. 20Roels HA, Lauwerys RR, Bernard AM, Buchet JP, Vos A, Oversteyns M. Assessment of the filtration reserve capacity of the kidney in workers exposed to cadmium. Br J Ind Med. 1991; 48: 365- 374.