Comparative Toxicity Study of 3-Aminophenol in Newborn and Young Rats

Koizumi, Mutsuko; Nishimura, Nobuo; Enami, Tomonori; Sunaga, Masao; Horikawa, Hironao; Kamata, Eiichi; Hasegawa, Ryuichi

doi:10.2131/jts.27.411

Cited by 13 publications

(12 citation statements)

References 19 publications

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“…Therefore, it could be predicted that chemicals directly exerting adverse effects might show stronger toxicity in the newborn than in young/adult rats. As expected, our previous comparative studies demonstrated that the susceptibility to four chemicals (4-nitrophenol, 2,4-dinitorophenol, 3-aminophenol, 3-methylphenol), which may exert toxicity without metabolic activation, was 2 to 4 times greater in the newborn than in young rats (Koizumi et al, 2001(Koizumi et al, , 2002(Koizumi et al, , 2003.…”

Section: Discussionsupporting

confidence: 81%

“…In order to estimate more appropriate NOAELs and unequivocally toxic levels than those depending on the dosages of main studies, the results of dose-finding studies for each case were incorporated. Earlier, we reported analytical results for five chemicals (4-nitrophenol, 2,4-dinitrophenol, 3-aminophenol, 3-methylphenol, tetrabromobisphenol A) (Koizumi et al, 2001(Koizumi et al, , 2002(Koizumi et al, , 2003Fukuda et al, 2004). The susceptibility of newborn rats to the toxicity of the first four was 2 to 4 times higher than that of their young counterparts, although these chemicals had no impact on development in the newborn period and showed similar toxicity profiles in both age groups (mainly effects on the central nervous system).…”

Section: Introductionmentioning

confidence: 91%

“…Cytoplasmic vacuolization of hepatocytes was observed in these rats. We have conducted the newborn rat studies on DBP and TBE and evaluated the results in comparison with published findings in young rats (MHLW, 2003a(MHLW, , 2003b, in the same manner as for the five chemicals already documented (Koizumi et al, 2001(Koizumi et al, , 2002(Koizumi et al, , 2003. CAS No.…”

Section: Introductionmentioning

confidence: 99%

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Susceptibility of Newborn Rats to Hepatotoxicity of 1,3-Dibromopropane and 1,1,2,2-Tetrabromoethane, Compared With Young Rats

et al. 2005

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-Newborn rat studies were conducted with oral administration of 1,3-dibromopropane (DBP) and 1,1,2,2-tetrabromoethane (TBE) from postnatal Days 4 to 21 to allow comparison of NOAELs and unequivocally toxic levels with those from 28-day young rat studies starting at 5-6 weeks of age. The unequivocally toxic level was estimated by our specified criteria, requiring simultaneous change of organ weights, histopathology, some biochemical parameters and body weights, because in this study only hypertrophy of hepatocytes was observed as a major histopathological change. DBP caused centrilobular hypertrophy of hepatocytes with alteration in biochemical parameters, as well as lowering of body weights, regardless of sex, in both newborn and young rats. NOAELs and unequivocally toxic levels were considered to be 50 and 150 mg/kg/day in newborn rats and 10 and 250 mg/kg/day in young rats, respectively. In the newborn rat study of TBE, some hepatic effects observed at the top dose of 50 mg/kg were not considered adverse because of the lack of histopathological changes. Significant lowering of body weight was noted at 200 mg/kg in the dose-finding study but histopathological data were not available. In the young rat study, there was no definite toxicity at 6 mg/kg and hypertrophic changes in liver and thyroids without body weight change occurred at 200 mg/kg. There were no clear sex differences in both the newborn and young rat studies. NOAELs were considered to be 50 and 6 mg/kg/day in newborn and young rats, respectively, but unequivocally toxic levels for both rats could not be estimated. Abnormalities of external and sexual development and reflex ontogeny in the newborn were not observed with either chemical. Based on these results, it can be concluded that the target organ of DBP and TBE is the liver in both newborn and young rats, and that while the doses at which toxic signs began to appear are higher in newborn rats, those causing clear toxicity may be paradoxically lower in the newborn case.

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Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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Susceptibility of Newborn Rats to Hepatotoxicity of 1,3-Dibromopropane and 1,1,2,2-Tetrabromoethane, Compared With Young Rats

et al. 2005

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“…2001), 2,4‐dinitrophenol (Koizumi et al . 2001), 3‐aminophenol(Koizumi et al . 2002), and 3‐methylphenol (Koizumi et al .…”

Section: Introductionmentioning

confidence: 99%

Comparative toxicity study of 2,4,6‐trinitrophenol (picric acid) in newborn and young rats

Takahashi

Ogata²,

Hayashi³

et al. 2004

Congenital Anomalies

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The toxicity of oral 2,4,6-trinitrophenol (TNP) was determined in newborn rats, and compared with that in young rats. In newborn rats, males and females were given TNP at 0, 16.3, 81.4 or 407 mg/kg per day on postnatal days (PND) 4-17 for the dose-finding study, and at 0, 4.1, 16.3 or 65.1 mg/kg per day on PND 4-21 for the main study. Deaths, lower body weight (BW) and behavioral changes were found at 81.4 and 407 mg/kg per day in the dose-finding study, and lower BW was observed in males at 65.1 mg/kg per day during the dosing period of the main study. In young rats, 5-week-old males and females were given TNP at 0, 20, 100 or 500 mg/kg per day for 14 days as the dose-finding study and at 0, 4, 20 or 100 mg/kg per day for 28 days as the main study. Deaths were observed at 500 mg/kg per day in the dose-finding study. Deaths or changes in BW were not found at 100 mg/kg per day or less. At 100 mg/kg per day, hemolytic anemia and testicular toxicity were found. In conclusion, toxicity profiles induced by TNP were markedly different between newborn and young rats.

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“…We have also conducted infant toxicity studies on 18 chemicals to compare toxicity levels and profiles between infants and young animals. We have already reported outcomes of detailed evaluation of data for four chemicals (Koizumi et al . 2001a, 2002a, 2003) and are now processing the other data that has been obtained.…”

Section: Introductionmentioning

confidence: 99%

Principles of risk assessment for determining the safety of chemicals: Recent assessment of residual solvents in drugs and di(2‐ethylhexyl) phthalate

Hasegawa¹,

Koizumi²,

Hirose

2004

Congenital Anomalies

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Risk assessment of chemicals is essential for the estimation of chemical safety, and animal toxicity data are typically used in the evaluation process, which consists of hazard identification, dose-response assessment, exposure assessment, and risk characterization. Hazard identification entails the collection of all available toxicity data and assessment of toxicity endpoints based on findings for repeated dose toxicity, carcinogenicity or genotoxicity and species-specificity. Once a review is compiled, the allowable lifetime exposure level of a chemical is estimated from a dose-response assessment based on several measures. For non-carcinogens and non-genotoxic carcinogens, the no-observed-adverse-effect-level (NOAEL) is divided by uncertainty factors (e.g. with environmental pollutants) or safety factors (e.g. with food additives) to derive a tolerable daily intake (TDI) or acceptable daily intake (ADI), respectively. These factors include interspecies and individual differences, duration of exposure, quality of data, and nature of toxicity such as carcinogenicity or neurotoxicity. For genotoxic carcinogens, low dose extrapolation is accomplished with mathematical modeling (e.g. linearized multistage model) from the point of departure to obtain exposure levels that will be associated with an excess lifetime cancer risk of a certain level. Data for levels of chemicals in food, water and air, are routinely used for exposure assessment. Finally, risk characterization is performed to ensure that the established 'safe' level of exposure exceeds the estimated level of actual exposure. These principles have led to the evaluation of several existing chemicals. To establish a guideline for residual solvents in medicine, the permitted daily exposure (PDE), equivalent to TDI, of N,N-dimethylformamide was derived on the basis of developmental toxicity (malformation) and of N-methylpyrrolidone on the basis of the developmental neurotoxicity. A TDI for di(2-ethylhexyl)phthalate was derived from assessment of testicular toxicity.

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Comparative Toxicity Study of 3-Aminophenol in Newborn and Young Rats

Cited by 13 publications

References 19 publications

Susceptibility of Newborn Rats to Hepatotoxicity of 1,3-Dibromopropane and 1,1,2,2-Tetrabromoethane, Compared With Young Rats

Susceptibility of Newborn Rats to Hepatotoxicity of 1,3-Dibromopropane and 1,1,2,2-Tetrabromoethane, Compared With Young Rats

Comparative toxicity study of 2,4,6‐trinitrophenol (picric acid) in newborn and young rats

Principles of risk assessment for determining the safety of chemicals: Recent assessment of residual solvents in drugs and di(2‐ethylhexyl) phthalate

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