The effects of 4-week inhalation exposure to titanium nitride on lungs of Sprague–Dawley rats

Kim Yong-Soon,Cho Eun-Sang,Park Chan-Hyuck,Cha Hyo-Geun 한국독성학회 2023 Toxicological Research Vol.39 No.1

Titanium nitride (TiN) is a ceramic material with physical properties such as extreme hardness, high decomposition temperature, defect structure, and gold-yellow color. TiN is generally considered non-toxic and safe; however, hazards have not been identified, especially in workers after inhalation exposure. Here, we conducted a four-week inhalation toxicity study of TiN using a nose-only inhalation exposure system in Sprague–Dawley rats. Rats were exposed to TiN for 4 weeks (6 h a day, 5 days per week) at target concentrations of 45, 90, and 180 mg/m3. Clinical signs, mean body weight changes, hematology, blood biochemistry, necropsy, organ weight, bronchoalveolar lavage fluid analysis, and histopathological findings were observed. Analytical concentrations of the low, middle, and high-concentration groups were 45.55 ± 3.18 mg/m3, 90.69 ± 7.30 mg/m3, and 183.87 ± 15.21 mg/m3, respectively. The mass median aerodynamic diameter (MMAD) for the low, middle, and high-concentration groups were 1.44 ± 0.07 μm, 1.47 ± 0.18 μm, and 1.68 ± 0.16 μm, and the geometric standard deviation (GSD) was 2.24 ± 0.03, 2.31 ± 0.16, and 2.43 ± 0.11, respectively. No systemic adverse effects were observed after inhalation exposure to TiN; however, histopathological findings (increased phagocytic macrophages and alveolar/bronchiolar epithelial hyperplasia) and Bronchoalveolar Lavage Fluid (BALF) analysis (elevated lactate dehydrogenase and gammaglutamyltransferase values) showed adverse effects on the lungs in the middle and high-concentration groups. Based on these results, the no observed adverse effect concentration (NOAEC) is suggested to be 45 mg/m3.

DCS-HT®의 4주 반복투여 경피독성시험

이혜숙,황석연 한국피부과학연구원 2010 대한피부미용학회지 Vol.8 No.1

The purpose of this study was to investigate the four week repeated-dose toxicities of DCS-HT, a hair growth promoting agent which is composed of several plant extracts(β-sitosterol, moraceae, polygonum multiflorum thunberg, 3:1:1), in ICR mice. In the repeated dermal toxicity study, the test substances were administerd on the dermal of male and female ICR mice at dose levels of 10, 20, 40 %(in distilled water, 1㎖) for 28 days. The results showed that there were not significantly different from control group in body weight gain, food intake, water consumption, relative organ weights, hematology findings and serum biochemistry findings at dose levels of DCS 10, 20 %. Also we observed no death and abnormal clinical signs were observed during the experimental period. However, in 40 % DCS group, there were statistical significance in body weight gain, food intake, water consumption and relative organ weights. From these results, NOAEL(no-observed-adverse-effect level) of DCS-HT in ICR mice is estimated to be 20 %. 탈모예방과 양모효과를 나타내는 시험물질인 DCS(β-sitosterol, 하수오, 상백피, 3:1:1)의 반복투여에 의한 경피독성을 평가하고자 5주령의 암 ‧ 수 ICR 마우스의 체표면적 약 10 % 이상의 등 부위를 clipper로 제모한 후, DCS 시험물질을 멸균정제수에 농도별로 희석하여 28일간 피부에 도포하였을 경우 나타날 수 있는 독성을 평가하였다. 반복투여 경피독성시험은 시험물질인 DCS(10, 20 또는 40 %)를 반복도포 하면서 시험물질에 노출되었을 때 나타날 수 있는 경피독성을 28일간 관찰하였다. 그 결과, 동일한 농도로 각각 DCS 10, 20 %를 28일간 반복적으로 피부에 도포하였을 경우 사망동물은 물론 일반 증상, 체중변화, 부검 및 육안소견, 그리고 다른 장기의 중량에 있어 어떠한 이상소견도 발견되지 않음으로써 개략의 치사량을 산출할 수 없었다. 하지만 40 %의 고농도 도포 결과에서는 사망동물은 발생하지 않았으나, 암⋅수 모두에서 피부가 경화되면서 벗겨지는 일반증상과 체중변화, 사료 및 음수섭취량에서의 변화가 관찰되었고 부검 및 육안소견, 장기중량에서도 유의할만한 차이가 관찰됨으로 시험물질의 농도 중 DCS 40 % 농도 이하에서 최대내성용량(maximum tolerated dose, MTD)인 것으로 사료되어 무독성량(no observed adverse effects level, NOAEL)은 20 %인 것으로 관찰되었다.

Toxicological Study of Safflower Seeds by Thirteen-Week Repeated Oral Administration in F344 Rats

Euna Kwon,Hyung-Jun Choi,Yun Soon Kim,Sang-Koo Lee,Kook-Hyun Lee,Jin Ho Chung,Myung-Whun Sung,Byeong-Cheol Kang 한국실험동물학회 2008 Laboratory Animal Research Vol.24 No.4

Safflower seeds which contains large amounts of conjugated linoleic acid and glyceride, are known to have effect on osteoporosis, bone fracture, and cholesterol metabolism. In this study, the 13-week repeated oral dose toxicity study of Safflower seeds was performed using F344 rats. In 14-day repeated dose study to determine the adequate dosage of safflower seeds administration, no other important changes were observed except statistically significant decreases in the mean absolute weights of the liver and the mean liver weight relative to body weight. It was dose-related finding at groups higher than 0.015 g/㎏ body weight (B.W.) in males and 0.045 g/㎏ B.W. in females. Based on preliminary test, safflower seeds was orally administered five times per week, weekday only to 5 groups of 6-week-old 10 male and 10 female F344 rats at dosage levels of 0.003, 0.016, 0.08, 0.4 and 2 g/㎏/day. The control group, also consisting of 10 males and 10 females, received the vehicle, 1% methylcellulose (MC), on a comparable regimen. One male and a female in the 0.4 g/㎏/day group, and a female in the 2 g/㎏/day group were found dead but the death could not be related to test article toxicity. No test article-related effect was observed on clinical signs and water consumption. For the 2 g/㎏/day males, there were significant decrease in body weight changes and food consumption from 10th week to study termination. The statistically significant decreases in the mean absolute weights of liver and the mean liver weight relative to body weight of the 0.003, 0.016 and 2 g/㎏/day group males and 0.003, 0.016 and 0.08 g/㎏/day females showed no dose related pattern and considered not to be test article related. There were no dose-related changes in hematology, biochemistry parameters, sperm morphology and vaginal cytology of all animals treated with safflower seeds. Gross and histopathological findings revealed no evidence of specific toxicity related to safflower seeds. These results suggest that no-observed adverse-effect level (NOAEL) of the test substance was considered to be 2 g/㎏/day for male and female rats under the conditions in this study.

삼정환의 랫드를 이용한 90일 반복 경구투여 독성시험

김민지(Min-Jee Kim),이명종(Myeong-Jong Lee),김호준(Hojun Kim) 한방비만학회 2018 한방비만학회지 Vol.18 No.1

Objectives: The study is aimed at evaluating the possible toxicity in 90-day repeated oral administration of modified Samjung-hwan (mSJH) in Sprague-Dawley (SD) rats. This study was conducted to detect the no-observed adverse effect level (NOAEL). Methods: Modified SJH extract was administered orally in male and female SD rats at dose of 0, 1,000, 2,000, 4,000 mg/kg. Each group consisted of 10 rats of each gender. The modified SJH extract was given once a day for 90 days. We monitored the changes of mortalities, clinical signs, body weight changes, food consumption, ophthalmologic findings, urine analysis, hematology, serum biochemistry, necropsy findings, organ weights, histological markers of all animals treated with modified SJH extract during the study period. Results: There were no toxicologically significant changes in mortalities, clinical signs, body weight gains, food consumption, ophthalmologic findings, urine analysis, hematology, serum biochemistry, necropsy findings, organ weights, histological markers in any of rats tested. Conclusions: The NOAEL of the modified SJH extract in male rats and no observed effect level (NOEL) in female rats are considered 4,000 mg/kg.

Subacute oral toxicity and bacterial mutagenicity study of Korean Red Ginseng oil

서휘원,서재현,소승호,경종수,김용순,한창균 고려인삼학회 2017 Journal of Ginseng Research Vol.41 No.4

Background: Red ginseng oil (RGO) is produced by supercritical CO2 extraction of secondary products derived from Korean Red Ginseng extract. As the use of RGO has increased, product safety concerns have become more important. Methods: In the present study, the subacute oral toxicity and bacterial reverse mutagenicity of RGO were evaluated. SpragueeDawley rats were orally administered with RGO for 28 d by gavage. Daily RGO dose concentrations were 0 mg/kg body weight (bw), 500 mg/kg bw, 1,000 mg/kg bw, or 2,000 mg/kg bw per day. Bacterial reverse mutation tests included five bacterial strains (Escherichia coli WP2 and Salmonella typhimurium TA98, TA100, TA1535, and TA1537), which were used in the presence or absence of metabolic activation. The plated incorporation method for mutation test was used with RGO concentrations ranging from 312.5 mg to 5,000 mg per plate. Results: The subacute oral toxicity test results did not reveal any marked changes in clinical characteristics. There were no toxicological changes related to RGO administration in hematological and serum biochemical characteristics in either control or treatment animals. Furthermore, no gross or histopathological changes related to RGO treatment were observed. The bacterial reverse mutation test results did not reveal, at any RGO concentration level and in all bacterial strains, any increase in the number of revertant colonies in the RGO treatment group compared to that in the negative control group. Conclusion: The no-observed-adverse-effect level of RGO is greater than 2,000 mg/kg bw and RGO did not induce genotoxicity related to bacterial reverse mutations.

Thirteen-week inhalation toxicity study of 1-methylnaphthalene in F344 rats

Yong-Soon Kim,Mi-Ju Lee,Dong-Suk Seo,Tae-Hyun Kim,Min-Ha Kim,Cheol-Hong Lim 한국독성학회 2020 Toxicological Research Vol.36 No.1

1-Methylnaphthalene is generally utilized in solvents, as an intermediate in organic synthesis, a dye carrier, in resins, and others. There are some toxicological studies of 1-methylnaphthalene; however, inhalation toxicity studies are rare. Each of 10 male and female F344 rats was exposed to vapors of 1-methylnaphthalene for 13 weeks (6 h a day, 5 days per week) at concentrations of 0, 0.5, 4, and 30 ppm in a whole-body inhalation chamber system. The exposure concentrations were 0.52 ± 0.05, 4.08 ± 0.25, and 30.83 ± 1.28 ppm for the low-, middle-, and high-dose group, respectively. Body weight changes were not affected by exposure to 1-methylnaphthalene. Blood prothrombin time was delayed at 30 ppm in male and female groups, and activated partial thromboplastin time was also delayed at 30 ppm in the male group. Values of alanine aminotransferase in the serum were decreased and those of albumin were increased at 30 ppm in the male group. Differential cell counts and levels of lactate dehydrogenase in the bronchoalveolar lavage fluid were not affected. However, mucous cell hyperplasia in the nasopharyngeal tissues was found and the severity was correlated to exposure concentrations. In conclusion, 1-methylnaphthalene mainly affects the upper respiratory system and the no-observed-adverse-effect level is suggested to be 4 ppm on the basis of histopathological findings.

Subacute (28 day) Toxicity of Surfactin C, a Lipopeptide Produced by <i>Bacillus subtilis</i>, in Rats

Hwang, Youn-Hwan,Kim, Myoung-Seok,Song, In-Bae,Park, Byung-Kwon,Lim, Jong-Hwan,Park, Seung-Chun,Yun, Hyo-In The Pharmaceutical Society of Japan 2009 Journal of Health Science Vol.55 No.3

<P>Surfactin C, produced by <I>acillus subtilis</I> isolated from Korean soybean paste, was given to Sprague-Dawley rats of both sexes at dose of 500, 1000 or 2000 mg/kg for 28 days. There were no surfactin C-related toxicities in survival, clinical signs, and hematological parameters in the experimental period. The highest dose of surfactin C showed the decrease in body weight gain despite normal food and water consumptions and the increase in relative liver weight. alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) levels were increased in animals administered with surfactin C of 1000 or 2000 mg/kg. Zonal necrosis of hepatocyte around the hepatic vein was observed after administration of the same doses in a dose-dependent manner. In the present study, the no-observed-adverse-effect level (NOAEL) of surfactin C was 500 mg/kg following oral administration in rats.</P>

Subacute oral toxicity and bacterial mutagenicity study of Korean Red Ginseng oil

Seo, Hwi Won,Suh, Jae Hyun,So, Seung-Ho,Kyung, Jong-Soo,Kim, Yong-Soon,Han, Chang-Kyun The Korean Society of Ginseng 2017 Journal of Ginseng Research Vol.41 No.4

Background: Red ginseng oil (RGO) is produced by supercritical $CO_2$ extraction of secondary products derived from Korean Red Ginseng extract. As the use of RGO has increased, product safety concerns have become more important. Methods: In the present study, the subacute oral toxicity and bacterial reverse mutagenicity of RGO were evaluated. Sprague-Dawley rats were orally administered with RGO for 28 d by gavage. Daily RGO dose concentrations were 0 mg/kg body weight (bw), 500 mg/kg bw, 1,000 mg/kg bw, or 2,000 mg/kg bw per day. Bacterial reverse mutation tests included five bacterial strains (Escherichia coli WP2 and Salmonella typhimurium TA98, TA100, TA1535, and TA1537), which were used in the presence or absence of metabolic activation. The plated incorporation method for mutation test was used with RGO concentrations ranging from $312.5{\mu}g$ to $5,000{\mu}g$ per plate. Results: The subacute oral toxicity test results did not reveal any marked changes in clinical characteristics. There were no toxicological changes related to RGO administration in hematological and serum biochemical characteristics in either control or treatment animals. Furthermore, no gross or histopathological changes related to RGO treatment were observed. The bacterial reverse mutation test results did not reveal, at any RGO concentration level and in all bacterial strains, any increase in the number of revertant colonies in the RGO treatment group compared to that in the negative control group. Conclusion: The no-observed-adverse-effect level of RGO is greater than 2,000 mg/kg bw and RGO did not induce genotoxicity related to bacterial reverse mutations.

Four-week inhalation toxicity study of 1-propanol in F344 rats

Kim Yong-Soon,Cho Eun-Sang,Park Ka-Young,Lim Cheol-Hong 한국독성학회 2020 Toxicological Research Vol.36 No.4

1-Propanol is used as a solvent for waxes, vegetable oils, resins, cellulose esters, and ethers, and is not considered harmful to humans by food and non-occupational exposures. However, workers are potentially exposed to 1-propanol by inhalation when it is used in the workplace. Thus, inhalation toxicity data are needed to assess the hazard of 1-propanol for workers safety. Five male and five female F344 rats were exposed to 1-propanol vapor for 4-weeks (6 h/day, 5 days/week) at concentrations of 0, 100, 400, and 1600 ppm in a whole-body inhalation chamber system. The actual exposure concentrations were 100.11 ± 5.10, 403.19 ± 12.31, and 1598.08 ± 139.58 ppm for the low, middle, and high dose groups, respectively. No clinical signs, significant mean body weight changes, significant changes of hematology or blood biochemistry results, or histopathological abnormalities were seen related to exposure to the test substance. Under the conditions of this study, the no-observed-adverse-effect level of 1-propanol was over 1600 ppm.

Toxicity of a novel antifungal agent (ATB1651 gel) in Yucatan minipigs (Sus scrofa) following 4 weeks of daily dermal administration

Kim Hyung-Sun,Kang Goo-Hwa,Yang Mi-Jin,Joo Yun-Jeong,Lee Dong-Gi,Lee Han-Seung,Lee Jong-Seung,Hwang Jeong Ho 한국독성학회 2024 Toxicological Research Vol.40 No.2

ATB1651 gel is an antifungal drug candidate that enhances antifungal activity through substitution of several aryl rings, alkyl chains, and methyl groups. To ensure safety of use of ATB1651 gel, assessment of its potentially toxic side effects is necessary. In this study, we examined the repeated-dose toxicity of ATB1651 gel to Yucatan minipigs (Sus scrofa) in accordance with the Good Laboratory Practice guidelines. Five doses of ATB1651 gel (0%, 0.2%, 0.5%, 1.0%, 3.0%) were administered dermally to the left and right flanks of 38 minipigs daily for 4 weeks. Mortality, clinical symptoms, dermal scores, body weights, and physiological, biochemical, pathological, and toxicokinetic analyses were performed after the treatment period. No systemic toxicological damage was observed in either male or female minipigs regardless of dose; however, dermal application of ATB1651 gel caused some skin alterations at the application sites. Specifically, erythema and eschar formation, edema, and scabs or raise spots were observed at the application site(s) in males in the 3.0% ATB1651 gel treatment group and in females at ATB1651 gel concentrations ≥ 1.0%, with dermal scores ranging from grade 1 to 2. Additionally, histopathological assay indicated infiltration of different types of inflammatory cells and the presence of pustule/crust at the application site(s) in both males and females at ATB1651 gel concentrations ≥ 0.5%. However, these changes were reversible after a 2-week recovery period and were considered a local irritation effect of ATB1651 gel. The no-observed-adverse-effect level of ATB1651 gel was 3.0% with regard to topical and systemic toxicity in both male and female minipigs. Collectively, our results imply that ATB1651 gel is a safe candidate for clinical development as an antifungal drug with a wide therapeutic window.