Identification of structural alerts for liver and kidney toxicity using repeated dose toxicity data

Abstract A focal point in the safety evaluation of cosmetic ingredients includes oral repeated dose toxicity testing, which is intended to address the most complex human endpoints. Seven years after the full implementation of the animal testing ban for cosmetic ingredients in the EU, there are still no alternative methods available capable of fully replacing oral repeated dose toxicity testing. Until this issue is resolved, the development of new cosmetic ingredients remains seriously hampered. The present paper describes a thorough screening of the oral repeated dose toxicity data included in safety evaluation reports of cosmetic ingredients addressed in the Annexes of the Cosmetics Regulation (EC) No 1223/2009, issued by the Scientific Committee on Consumer Safety between 2009 and 2019. The liver and the haematological system were identified as the potentially most frequently affected organs upon oral administration of cosmetic ingredients to animals. Evaluation of altered biochemical, morphological, and histopathological parameters related to hepatotoxicity indicated that the most recurrent events are liver weight changes, elevated liver enzymes, and alterations in serum cholesterol and bilirubin levels. Combined listing of affected parameters associated with steatosis and cholestasis indicated the possible occurrence of cholestasis, provoked by a limited number of cosmetic ingredients. The most frequently affected parameters related to the haematological system were indicative of anaemia. An in-depth analysis allowed characterisation of both regenerative and non-regenerative anaemia, pointing to direct and indirect haematotoxicity, respectively. The results presented in this study call for prioritisation of research targeted towards the development of new approach methodologies fit for animal-free repeated dose toxicity evaluation of cosmetic ingredients.

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Prediction of the Carcinogenic Potential of Human Pharmaceuticals Using Repeated Dose Toxicity Data and Their Pharmacological Properties

Frontiers in Medicine ◽

10.3389/fmed.2016.00045 ◽

2016 ◽

Vol 3 ◽

Cited By ~ 11

Author(s):

Jan Willem van der Laan ◽

Wenny H. W. Buitenhuis ◽

Laura Wagenaar ◽

Ans E. M. F. Soffers ◽

Eugene P. van Someren ◽

...

Keyword(s):

Repeated Dose ◽

Pharmacological Properties ◽

Toxicity Data ◽

Carcinogenic Potential ◽

Repeated Dose Toxicity

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Single-dose and 4-week repeated dose Toxicity of Aconitum Sinomontanum Nakai Pharmacopuncture: An Experimental Study

Journal of Acupuncture Research ◽

10.13045/jar.2020.00332 ◽

2021 ◽

Vol 38 (1) ◽

pp. 47-59

Author(s):

Sang Ha Woo ◽

Jung Hee Lee ◽

Cho-in Lee ◽

Yun Kyu Lee ◽

Hyun-Jong Lee ◽

...

Keyword(s):

Single Dose ◽

Normal Saline ◽

Repeated Dose ◽

Control Group ◽

Weight Changes ◽

Significant Toxicity ◽

Repeated Dose Toxicity ◽

Adverse Effect Level ◽

Liver And Kidney ◽

Effect Level

Background: This study aimed to assess the toxicity of Aconitum sinomontanum Nakai (ASN) pharmacopuncture.Methods: To investigate the toxicity of ASN pharmacopuncture, single and 4-week repeated dose toxicity experiments were conducted on BALB/c mice. In the single-dose toxicity experiment, mice were assigned 1 of 4 groups (5 males, 5 females per group). Then, 31.25, 62.5, and 125 mg/kg of ASN pharmacopuncture were administered to the mice in the experimental groups at acupoint ST36, while 0.2 mL of normal saline was administered to the control group at ST36. After a 4-week repeated dose regimen, the mice were assigned into 4 groups (5 males, 5 females per group). Then, 15.625, 31.25, and 62.5 mg/kg of ASN pharmacopuncture at ST36 were administered to the mice in the experimental groups, while 0.2 mL of normal saline was administered to the control group at ST36. Mortality, morbidity, general body and organ weight changes (after 4 weeks repeated dose), serum hematological and biochemical values, and histopathological changes in the liver and kidney were observed.Results: In both single and 4-week repeated dose toxicity experiments, no deaths or symptoms occurred in any of the groups. There were no significant differences between groups in terms of body and organ weights, serum hematological and biochemical values, and specific organ histopathological changes.Conclusion: ASN pharmacopuncture injection did not demonstrate significant toxicity in BALB/c mice compared with the control group, with a no-observed-adverse-effect level for a single dose of >125 mg/kg, and for 4 weeks repeated dose it was more than 62.5 mg/kg/day

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Repeated-Dose Toxicity in Mouse Liver and Kidney after Skin Exposure to Silver Nanoparticles

JOURNAL FOR CLINICAL AND DIAGNOSTIC RESEARCH ◽

10.7860/jcdr/2018/28535.11114 ◽

2018 ◽

Author(s):

Parastoo Yarmohammadi Samani ◽

Parisa Yarmohammadi Samani ◽

Mehran Arabi ◽

Mohammad Shadkhast ◽

Peyman Yarmohammadi Samani ◽

...

Keyword(s):

Silver Nanoparticles ◽

Mouse Liver ◽

Repeated Dose ◽

Skin Exposure ◽

Repeated Dose Toxicity ◽

Liver And Kidney

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In Vivo Evaluation of the Oral Toxicity of the Chlorobutanol

Toxics ◽

10.3390/toxics10010024 ◽

2022 ◽

Vol 10 (1) ◽

pp. 24

Author(s):

Dahye Jeong ◽

Hyosook Shin ◽

Jinhee Lee ◽

Junyoung Yang ◽

Kikyung Jung ◽

...

Keyword(s):

Body Weight ◽

Single Dose ◽

Toxicity Study ◽

Male Rats ◽

Repeated Dose ◽

High Dose ◽

Oral Toxicity ◽

Single Dose Study ◽

Repeated Dose Toxicity ◽

Liver And Kidney

Chlorobutanol (CB) is used as a preservative in cosmetics and has antibacterial activity. This study investigated the single- and repeated-dose 28-day oral toxicity of a CB solvent in Sprague Dawley (SD) rats. For the single-dose oral toxicity study, a dose of 62.5, 125, or 250 mg per kg of body weight (mg/kg b.w.) of CB was given once orally via gavage. For the repeated-dose 28-day toxicity study, the high dose was set as 100 mg/kg b.w./day, and the middle, middle-low, and low doses were set to 50, 25, and 12.5 mg/kg b.w./day, respectively. Body weight was not significantly changed in the repeated-dose toxicity study. Relative liver and kidney weights were significantly increased in both sexes of the 100 mg/kg b.w./day treatment group. However, there were histopathological changes in liver and kidney for females and males, respectively. These data suggested that the approximate lethal dose (ALD) of CB was over 250 mg/kg b.w./day in the single-dose study, and the no adverse effect level (NOAEL) for CB was over 50 and 12.5 mg/kg b.w./day for female and male rats in the repeated-dose toxicity study.

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