Subacute Oral Toxicity Research Articles

Acute and sub-acute oral toxicity of aqueous whole leaf and green rind extracts of Aloe vera in Wistar rats

BackgroundSeveral local communities in Central, Western, Eastern, and Northern regions of Uganda have been using the whole leaf extracts of Aloe vera (L.) Burm. f. (Asphodelaceae) in the treatment of various ailments. Also, several commercial companies sell A. vera as soft drinks in Uganda. However, there are inadequate reports on the toxicities of such preparations. This paper reports the acute and sub-acute oral toxicity of aqueous extracts of whole leaf and green rind of A. vera in Wistar rats.MethodsAcute oral toxicity test was carried out in female Wistar rats at doses of 175, 550, 1750, and 5000 mg/kg, p.o. The animals were observed for signs of toxicity for 14 days. Similarly, a sub-acute oral toxicity test was performed in both sexes of rats at doses of 200, 400, and 800 mg/kg, p.o. daily for 28 days. All the groups of animals were monitored for behavioral, morphological, biochemical, and physiological changes, including mortality and compared with respective controls. Body weights were measured weekly while the animals’ relative organ weights, hematological, biochemical, gross, and microscopic pathology were examined on day 29.ResultsThere was no mortality or apparent behavioral changes at the doses tested in acute and sub-acute oral toxicity tests. Thus, the Median Lethal Dose (LD50) of green rind and whole leaf aqueous extracts was above 5000 mg/kg. Gross anatomy revealed that the rats’ relative spleen weight in green rind extract at 200 mg/kg significantly decreased compared to the control group. The creatinine levels in female rats that received green rind extract and the chloride ion levels in male rats administered whole leaf extract were significantly elevated. Conversely, Mean Corpuscular Hemoglobin Concentration (MCHC) levels significantly decreased at lower doses of the green rind extract compared to the control. Histopathology of the kidney revealed the renal interstitium’s inflammation at doses of 200 and 800 mg/kg of the whole leaf extract.ConclusionThe findings demonstrated that A. vera green rind and whole leaf extracts are non-toxic at relatively high doses when used for a short duration. Prolonged use of the aqueous whole leaf extract might be associated with kidney toxicity.

Toxicological Evaluation of Methanolic Extract of Vetiveria Zizanioides Roots in Male and Female

Vetiveria zizanioides roots were used from tradition in the treatment of various types of liver disorder. The objective of present study was to evaluate the oral acute and sub-acute toxicity (28 days) of the methanolic extract of Vetiveria zizanioides roots (MEVZ) in Wistar albino rats of both sexes. In the acute toxicity study, Wistar rats were treated orally with a single dose of 5 g/kg of body weight, and were observed for 14 days. Animals were monitored continuously for the first 4 h, for every 6 h for the next 24 h, upto 14 days. In the sub-acute toxicity study, MEVZ was administered orally at doses of 175, 550 and 1750 mg/kg daily for 28 days to Wistar albino rats. Treatment with MEVZ did not produce any toxic signs or deaths. Treatment with MEVZ did not alter either the body weight gain or the food and water consumption. The hematological and biochemical parameters did not show any significant differences in any of the parameters examined in both gender groups. Organ weight, necropsy and histopathological examination, did not reveal any remarkable treatment related changes. A no-observed adverse-effect level for MEVZ is 5 g/kg for rats in our study. Consumption of MEVZ for various medicinal purposes is safe.

Acute and subacute oral toxicity of artemisinin-hydroxychloroquine sulfate tablets in rats

Artemisinin-hydroxychloroquine sulfate tablets (AH) are considered a relatively inexpensive and novel combination therapy for treating all forms of malaria, especially aminoquinoline drugs-resistant strains of P.falciparum. We aim to carry out acute and subacute oral toxicity studies in rats to acquire preclinical data on the safety of AH. Acute toxicity was evaluated in Sprague-Dawley (SD) rats at a single dose of 1980, 2970, 4450, 6670, and 10000 mg/kg. A 14-days subacute toxicity was assessed in SD rats at doses of 0, 146, 219, 328, and 429 mg/kg. The median lethal dose (LD50) of acute oral administration of AH in rats is found to be 3119 mg/kg, and toxic symptoms include decreased spontaneous activity, dyspnea, bristling, soft feces, spasticity, and convulsion. Repeated doses of AH have toxic effects on the nervous system, skin, blood system, liver, kidney, and spleen in rats. The main toxic reactions include epilation, emaciation, mental irritability, decreased body weight gain and food consumption, changes in the hematological and biochemical parameters, especially pathological lesions in the liver, kidney, and spleen. The no-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) of AH are considered to be 219 mg/kg and 328 mg/kg, respectively.

Acute, subacute oral toxicity and Ames test of Py-mulin: an antibacterial drug candidate

BackgroundPy-mulin is a new pleuromutilin derivative with potent antibacterial activities in vitro and in vivo, suggesting this compound may lead to a promising antibacterial drug after further development. The present study is aimed to evaluate the acute and subacute oral toxicity, and the genotoxicity with the standard Ames test according to standard protocols.MethodsAcute oral toxicity of Py-mulin was determined using Kunming mice. The 28-day repeated dose oral toxicity study in SD rats was performed according to OECD guideline No. 407. The bacterial reverse mutation (Ames test) was carried out using four Salmonella typhimurium (S. typhimurium) strains TA97, TA98, TA100 and TA1535 with and without S9 metabolic activation.ResultsThe LD50 values in acute oral toxicity were 2973 mg/kg (female mice) and 3891 mg/kg (male mice) calculated by the Bliss method. In subacute toxicity study, 50 mg/kg Py-mulin did not induce any abnormality in body weight, food consumption, clinical sign, hematology, clinical chemistry, organ weight, and histopathology in all of the treatment groups. However, high doses of Py-mulin (100 and 300 mg/kg) displayed slightly hepatotoxicity to female rats. Furthermore, Py-mulin did not significantly increase the number of revertant colonies of four standard S. typhimurium strains with the doses of 0.16–1000 μg/plate in the Ames study.ConclusionsBased on our findings, our study provides some information for the safety profile of Py-mulin.

Effect of a methanolic extract of Salvadora oleoides Decne. on LPS-activated J774 macrophages, its in vitro and in vivo toxicity study and dereplication of its chemical constituents

Salvadora oleoides is used in Pakistani traditional medicine to treat inflammatory conditions, piles, boils, and ulcers. To evaluate the anti-inflammatory potential of S. oleoides (a mixture of aerial branches, leaves, and stem bark), we prepared crude extracts in Soxhlet apparatus by successively using different solvents and found the methanolic extract (OLM) to significantly inhibit the LPS-induced expression of pro-inflammatory cytokines and enzymes in J774 macrophages, at 50 µg/mL concentration. We also analysed the chemical constituents of OLM by dereplication, performed by HPLC-MS/MS and molecular networking. The major detected constituents were flavonoids and phenolic acids glycosides, most of them identified for the first time in S. oleoides. We also evaluated the toxicity of OLM against five cell lines, namely Caco-2, HepG2, HeLa, J774, and WI-38 by MTT assay. The IC50 was found to be higher than 100 µg/mL against these five cell lines after 72 h treatment. Furthermore, OLM was tested in mice for acute and sub-acute oral toxicity according to the guidelines of the Organisation for Economic Co-operation and Development (OECD). OLM was found non-toxic, except for some fibrosis observed in the spleens of treated mice in the sub-acute oral toxicity test. Our results confirm the anti-inflammatory potential of OLM and that it could be tested in in vivo inflammatory models, but its effect on the spleen should be considered before designing the experiments.

Safety Assessment of Canola Oil Extracted by Aid of Pulsed Electric Field: Genetic, Acute and Subacute Toxicity

Pulsed electric field (PEF) is a nonthermal technology resulting in the rupture of cell membranes and increasing the electrical conductivity and the permeability of intracellular material. There was little work about the safety of food treated by PEF. The acute, subacute oral, and genetic toxicities were investigated to explore the safety of canola oil extracted by aid of PEF treatment (PTCO). The results showed that no negative consequences were caused by PEF. PTCO was regarded as practically non-toxic with a LD50 higher than 40 g/kg bw. No oil intake-related mortality, clinical, weight gain and organ coefficient abnormalities were observed. The histopathological symptoms indicated a mild load but not obvious toxicities on liver and kidney. The 28-day subacute toxicity test confirmed that less than 10 g/kg·d bw of oil intake did not exhibit any intake-related changes in physical, physiological, biochemical, hematological, and histopathological signs. The less than 4 of atherosclerosis index suggested that no risk of cardiovascular disease caused by PTCO intake. It was speculated that the PEF treatment would not cause any safety issues to food products.

Efficacy and Safety of Combination Therapy of Zinc and Silver Oxide Nanoparticles in Streptozotocin-Induced Diabetic Rats

In the present study, Zinc oxide nanoparticles andSilver Oxide nanoparticles were evaluated for their in vivo and in vitro antidiabetic activity. The resulting ZnO, Ag2O were characterized via various methods like UV, XRD, FTIR, PSA and SEM, TEM, and ICP-OES. The synthesized NPs were tested sub-acute oral toxicity model by abiding by the OECD425 guidelines. The male Wistar rats with a weight ranging from 180-200 g were grouped as follows: normal control: those that didn’t received any trea

Amelioration of DMH-induced colon cancer by eupafolin through the reprogramming of apoptosis-associated p53/Bcl2/Bax signaling in rats

Introduction: Colorectal cancer is the third most common malignancy and the second most deadly cancer worldwide. In this present study, the effects of eupafolin on DMH-induced colon cancer in rats were assessed. Methods: The acute and sub-acute oral toxicity study in the balb/c mice was performed to evaluate the LD50 dose and the chemotherapeutic doses of eupafolin. The colon cancer was induced in the animals through a single intraperitoneal injection (i.p) of 30 mg/kg of dimethylhydrazine followed by 2% DSS for 7 days in the drinking water in male Wistar rats. The rats were treated with eupafolin (50, 100, and 200 mg/kg) through oral route for 18 weeks. The animals were sacrificed and colon tissues were subsequently investigated for aberrant crypt foci (ACF), in vivo antioxidant studies, histology and immunohistochemical analysis, and apoptosis by TUNNEL technique after 18 weeks of eupafolin therapy. Results: The acute oral toxicity data represented the LD50 dose of eupafolin which was found to be 500 mg/kg body weight. Along with that, the sub-acute toxicity study suggested the chemotherapeutic doses of eupafolin, that is, 50, 100, and 200 mg/kg body weight. Eupafolin therapy inhibits ACF development in rat colon mucosa efficiently. Additionally, eupafolin has improved the colonic lesions and the structural integrity of the colonic mucosa. Eupafolin therapy causes anti-oxidant enzymes such as superoxide dismutase, catalase, and glutathione to increase as well. Increased levels of P53, BAX, and PCNA and a simultaneous decrease in Bcl2 and IL-6 expressions show eupafolin therapy successfully regulated these biological markers in colorectal cancer. Eupafolin also induced apoptosis efficiently in the rat colon mucous membrane. Conclusion: These results show that eupafolin can improve colon cancer by modulating the p53, Bcl2, BAX, and IL-6 pathways in rats.

Evaluation of Skin Irritation and Acute and Subacute Oral Toxicity Assessment of the Hydroethanolic Extract of Randia Aculeata L. (Rubiaceae) Seed in Rats

Evaluation of Skin Irritation and Acute and Subacute Oral Toxicity Assessment of the Hydroethanolic Extract of Randia Aculeata L. (Rubiaceae) Seed in Rats

Evaluation of Anti Ulcerogenic Potential of Plant Extract of Morinda tinctoria

M. tinctoria plant has many therapeutic uses in traditional Indian medicine. M. tinctoria has Antibacterial, Antifungal, Hepatoprotective, Antioxidant, Wound Healing, Dye Yielding and Larvicidal properties. The study is employ to the anti- ulcerogenic potential of M. tinctoria extract. The plant extraction was done with 50% ethanol and 50% water (hydro-alcoholic). OECD guidelines were used for acute- toxicity (14 days) and Sub-acute toxicity (28 days). The study was carried by ligation (pylorus) and drug-induced ulcer models in Wistar rats. The anti-ulcer activity of M. tinctoria was compared with the standard drugs to perceive the anti-ulcerogenic potential. The Pharmacognostic analysis was performed according to the Indian pharmacopoeia. A preliminary Phytochemical test of the aerial part of M.tinctoria was performed which showed the presence of carbohydrates, amino acid, glycosides, flavonoids, alkaloids in the hydro-alcoholic extract. Acute-oral toxicity (14 days) and Sub-acute oral toxicity (28 days) were performed and doesn’t show any effect on body weight as well as organ weight and was non-toxic. M. tinctoria extract (MTE) effectively prevents the gastric mucosa from the threat of ulcers caused by pylorus ligation and aspirin-induced ulcers. MTE demonstrated a substantial reduction in the ulcer index developed by all 2 experimental models comparable to the standard drug Omeprazole. Current evidence shows that aerial parts of MTE have substantial antiulcer action.

ANTI-INFLAMMATORY AND ORAL TOXICITY ASSESSMENT OF R-38TM: A TRADITIONAL HERBAL SUPPLEMENT FOR ARTHRITIS

R-38TM is a traditional herbal supplement for treating arthritis-related conditions. High-performance liquid chromatography (HPLC) analysis was performed for identification and quantification of rosmarinic acid in the R-38TM water extract. The anti-arthritic potential of the R-38TM water extract was investigated by measuring the production of IL-6 and TNF-α in inflamed cells. Xanthine oxidase (XO) and cyclooxygenase-2 (COX-2) inhibition assays were also conducted. The cytotoxic effect of R-38TM water extract was investigated on HSF1184 cell line. Acute and subacute oral toxicity studies were conducted on female Sprague-Dawley (SD) rats. The rosmarinic acid was identified at 1.208 min (3.61 %w/w). The inflamed cells showed a decrease in the production of IL-6 (55.9%) and TNF-α (52.13%). The COX-2 and XO enzymes were moderately inhibited by R-38TM water extract. The cytotoxicity analysis showed no cytotoxic effect on the cell. The acute and subacute oral toxicity studies revealed no mortality and normal body weight at all doses. There were no significant differences (p > 0.05) in organ weight, hematological and biochemical parameters, and histology of liver and kidneys with the control group. In conclusion, R-38TM water extract exhibited no toxic effect orally and may possess potential therapeutic properties against pro-inflammatory diseases including arthritis.

Acute and Sub-Acute Oral Toxicity Profile of Purified Tomato Extract on the Liver and Kidney Functions of Male Wistar Rats

a peer-reviewed, open access online international journal which publishes original research papers. The journal welcomes submission from scholars and experts for possible publication from all over the world. The scope of the journal includes: Pharmaceutical research, chemistry and biochemistry of naturally occurring compounds, biological evaluation of crude extracts, ethnomedicine, traditional and complementary medicine, ethnopharmacology, biomedical research, Biotechnology, Evaluation of natural substances of land and sea and of plants, microbes and animals, pharmacognosy, bioavailability, clinical, pharmacological, toxicological studies and pharmacokinetics of phytochemicals, Isolation and characterization of compounds, structure elucidation, synthesis and experimental biosynthesis of natural Product as well as developments of methods in these areas are welcomed in the journal.

Acute and subacute repeated oral toxicity study of fragmented microplastics in Sprague-Dawley rats

Polypropylene (PP) is the second most highly produced plastic worldwide, and its microplastic forms are found in water and food matrices. However, the effects of PP microplastics on human health remain largely unknown. Here, we prepared 85.2 µm-sized weathered PP (w-PP) microplastics by sieving the microplastic particles after fragmentation and accelerated weathering processes. The prepared particles are irregular in shape and no chemical additives including phthalates and bisphenol A were not released in simulated body fluids. Then, the w-PP samples were gavaged to rats for acute and subacute toxicity testing in accordance to the Organization for Economic Co-operation and Development (OECD) test guidelines under good laboratory practice regulations. The highest dose for gavaging to rats was 25 mg/kg bw/day, which was the maximum feasible dose based on the dispersibility of microplastics. Both toxicity testings for w-PP microplastics showed no adverse effects and mutagenicity. Thus, the no observed adverse effect level (NOAEL) of w-PP microplastics is higher than 25 mg/kg bw/day. Furthermore, the w-PP microplastics did not show any skin or eye irritation potentials in the 3-dimensional reconstructed human skin or corneal culture model. The dose of 25 mg/kg of w-PP microplastics is roughly equal to 2.82 × 105 particles/kg, which suggests that human exposure to w-PP microplastics in a real-life situation may not have any adverse effects.

Acute and sub-acute oral toxicity Lagerstroemia speciosa in Sprague-Dawley rats

Through the boost of the natural medicinal market, individuals began to use a variety of organic materials in the marketed herbal preparation. Lagerstroemia speciosa (LS) leaves are known as banaba. People have been using a decoction of LS leaves as antidiabetic. The study aimed to investigate the acute and sub-acute oral toxicity of LS in Sprague-Dawley rats. The acute toxicity was determined by a single oral dose of LS (2000 mg/kg). Therein animal behaviour and mortality rate were observed for 14 days. The LS (200 mg/kg) was given for 28 days daily in the sub-acute study. The body weight, organ weight, food, water intake, biochemical, haematological parameters, and histopathology were studied. The findings of this study showed no mortality or morbidity was found in acute and sub-acute toxicity studies in rats.Additionally, no significant variations were found in the respective weight of organ, haematological and biochemical parameters of treated groups with reference to the control group. Moreover, no visible histological changes were detected in the liver of treated groups with reference to the control. In conclusion, the oral administration of LS did not fabricate any major toxic effect in rats. No toxic consequences were reported during acute and sub-acute toxicity investigations. Overall, LS is a safe, natural bio-actives as studied. Further investigations of cytotoxicity and genotoxicity of the above drug(s) or their combinations may be executed for appreciative safety.

Assessment of the toxicological profile of Chlorella (C. vulgaris) powder by performing acute and sub-acute oral toxicity studies in mice

Assessment of the toxicological profile of Chlorella (C. vulgaris) powder by performing acute and sub-acute oral toxicity studies in mice

Brazilian Cerrado plant (arnica) Lychnophora ericoides Mart. (Asteraceae) toxicity characterization in mice

BackgroundLychnophora ericoides Mart. (Asteraceae) is a Brazilian plant commonly used in folk medicine to treat pain and inflammation by topical administration. In recent years, this medicine has begun to be used orally. However, no study concerning its toxicity profile has been reported. ObjectiveThe study evaluates the potential toxicity of the ethanolic extract from leaves of the Lychnophora ericoides, through the methods of acute and sub-acute oral administration in mice. MethodAn acute toxicity study was performed according to the Organization for Economic Cooperation and Development protocol (OECD 423). A single extract dose of 50, 300, and 2000 mg/kg (n = 3/group) was administered orally to female Swiss mice. For subacute toxicity, the protocol OECD 407 was followed. Doses of 50, 300, and 500 mg/kg (n = 10/group) of the extract were administered daily to Swiss mice of both sexes for 28 days. Abnormal behavior, muscle strength, toxic symptoms, weight, and death were observed when assessing toxicity. Biochemical analysis, hematological analysis, macroscopic examination, and histopathological examination of several organs were conducted at the end of the treatment period. ResultsIn acute and subacute toxicity, the extract did not produce mortality. The acute toxicity study revealed alterations in the behavioral test and histopathological changes in the liver, kidney, lung, and spleen. The subacute oral toxicity test showed changes in hematologic and biochemical parameters. Histopathological examination of liver, kidney, spleen, lung, and heart indicated degenerative characteristics with inflammatory infiltrates focus. ConclusionThe study results suggest that oral use of Lychnophora ericoides leaves extract should be performed with caution in low doses in both single and repeated administrations.

Aloe vera and artemisia vulgaris hydrogels: exploring the toxic effects of structural transformation of the biocompatible materials

Objectives This study was aimed to evaluate the toxicity profile of hydrogels of plant-derived mucilage from Aloe vera and Artemisia vulgaris used for various drug delivery applications, yet no such toxicity study has been reported for the toxicity evaluation of 3 D structures. New Drug carriers should be harmless for drug delivery applications. Methods Acute and sub-acute (repeated dose) oral toxicity studies were conducted following OECD 407 and 425 guidelines. In vitro toxicity through hemolysis and MTT assay were checked against RBC’s and human macrophages respectively. Results The hemolysis and MTT assay showed good compatibility of hydrogels with blood components. Mutagenicity testing showed no genotoxic effects of hydrogels. In vivo toxicity evaluation was done in female albino rats and rabbits. General behavior, adverse effects, clinical signs and symptoms, and mortality were recorded for 14 days post-treatment which showed no significant (p < 005) abnormality. Hematological and biochemical parameters including LFTs and RFTs appeared to be normal with slight variations in the treated groups. The normal architecture of kidney, liver, heart and intestine was evident upon histopathological analyses. Conclusion Hence, the results suggested that the 3 D structure of Aloe vera and Artemisia vulgaris based hydrogels are safe upon ingestion and can be used for drug delivery science being cheap, natural and biocompatible.

Phenolic fraction concentrate of Phoenix dactylifera L. seeds: A promising antioxidant and glucose regulator

Context: The beneficial effects of natural polyphenolic compounds are increasingly emerging as powerful antioxidants and digestive boosters. Phoenix dactylifera seeds are recently identified as a healthy functional food with rich amounts of phenolic compounds. Aims: To analyzing the phenolic profile obtained from Moroccan variety of date seeds and evaluating the inhibitory capacity against digestive enzymes and the antioxidant potential of phenolic fraction concentrate (PFC) of date seeds as a promising antihyperglycemic agent. Methods: Lineweaver–Burk plot analysis was performed to evaluate PFC inhibitory effect against digestive enzyme activity in the presence of different doses of a substrate. Wistar rats were recruited to determine the acute and sub-acute oral toxicity of PFC. Finally, the optimal dose of PFC was selected and its effects on metabolic, hematological and biochemical parameters were determined. Results: High-performance liquid chromatography (HPLC) analysis revealed that PFC contains abundant amounts of phenolic acid: Caffeic acid, chlorogenic acid, 3,4-dihydroxybenzoic acid, p-hydroxybenzoic acid, and 3-hydroxybenzoic acid. PFC showed powerful antioxidant activity as determined by scavenging and reducing assays. PFC significantly inhibited alpha-amylase and alpha-glucosidase enzymes by 87.3% and 78.7%, respectively, via mixed manipulation of Km and Vmax. Acute toxicity examinations revealed PFC to be practically non-toxic with LD50 &gt; 5000mg PFC/kg for both sexes of rats. The no-observed-adverse-effect-level (NOAEL) and lowest observed adverse effect level (LOAEL) for oral administration of PFC were 1000 and 2500 mg/kg for both sexes. Finally, the sub-acute study showed that a PFC dose of 50 mg/kg did not cause any changes in metabolic, biochemical and hematological parameters and was considered to be the optimal healthy dose for rats. Consequently, it induces improvement in glucose concentration in rats. Conclusions: The rational use of phenolic date seeds fraction presents powerful antioxidant and blood glucose regulating nutraceutical that could aid in diabetes mellitus management.

Acute and subacute toxicity studies of a new herbal formula induced apoptosis in the highly metastatic MDA-MB-231 cells

Breast cancer is one of the major causes of cancer deaths worldwide, and survival rate remains low even with the advancement of screening and treatment methods. Polyherbal medicines have been widely used for cancer treatment. CBBh and SNH are two new polyherbal formulations that showed anticancer effects.MDA-MB-231 and MCF-7 cells were used for in vitro investigation. After treatments with CBBh and SNH, the proliferation and apoptosis of cells were detected by MTT assay, fluorescent microscopy, and Muse cell analyzer. The acute and subacute toxicities were studied following Organization for Economic Cooperation and Development (OECD) guidelines. Gas chromatography-mass spectrometry (GC–MS) was applied for analysis of chemical constituents of the extract.CBBh extract inhibited proliferation of MCF-7 (IC50: 109.7 μg/mL) and MDA-MB-231 (IC50: 71.1 μg/mL) cancer cells, whereas the IC50value for SNH was higher than 400 μg/mL against both cancer cell lines. The percentages of apoptotic cells following treatment with 200 and 300 μg/mL for 24 h were 38.9 ± 2.8% and 76.2 ± 2.1% MDA-MB231 cells respectively, versus 0.07% and 5.21% respectively in vehicle-treated cells. No acute or subacute oral toxicity was observed. CBBh extract was tolerated in concentrations up to 2000 mg/kg. Acute and subacute histopathological examination of the liver and kidneys revealed no abnormalities in their architecture.The new polyherbal formula CBBh could suppress breast cancer through apoptosis. Therefore, our findings could provide a novel herbal formula for the treatment of breast cancer.

An assessment of mutagenicity, genotoxicity, acute-, subacute and subchronic oral toxicity of paraxanthine (1,7-dimethylxanthine)

Paraxanthine or 1,7-dimethylxanthine is a natural dietary component and the main metabolite of caffeine in humans. A battery of toxicological studies was conducted in accordance with international guidelines to investigate mutagenicity, genotoxicity and acute and repeated-dose oral toxicity in rats of synthetic paraxanthine (ENFINITY™, Ingenious Ingredients, L.P., >99% purity). There was no evidence of mutagenicity in a bacterial reverse mutation as well as in an in vitro mammalian chromosomal aberration test. There was no evidence of genotoxicity in an in vivo mammalian erythrocyte micronucleus test as well as in an in vitro mammalian cell gene mutation test. An acute oral toxicity test resulted in a LD50 value of 1601 mg/kg bw/d. Paraxanthine did not cause mortality or toxic effects in a subacute 28-day repeated-dose oral toxicity study at daily doses of 75, 150, or 300 mg/kg bw/d (each group n = 10 per sex), administered by gavage. Paraxanthine also did not cause mortality or toxic effects in a subchronic 90-day repeated-dose oral toxicity study at daily doses of 75, 150, or 300 mg/kg bw/d (each group n = 10 per sex), administered by gavage. The no observed adverse effect level (NOAEL) determined from the 90-day study was greater than or equal to 300 mg/kg bw/d, the highest dose tested, for both male and female Wistar rats.