title: Combined repeated dose and reproductive/developmental toxicity screening test of 4-methoxy-2-nitroaniline in rats.
abstract: 4-Methoxy-2-nitroaniline (4M2NA) is widely used as an intermediate for the synthesis of dyes, pigments and other chemical compounds. Since 4M2NA has amino-group and nitro-group on the benzene ring, it was expected that it induced obvious hemolytic anemia. We conducted a combined repeated dose and reproductive/developmental toxicity screening test according to Organisation for Economic Co-operation and Development (OECD) Test Guideline No. 422 (OECD TG 422) to enrich the toxic information and ensure the safety of 4M2NA. 4M2NA was administered to Crl:CD(SD) male and female rats by gavage at 0, 12.5, 75 or 450 mg/kg/day for 42 to maximum of 54 days through pre-mating, mating, pregnancy and lactation periods. An extramedullary hematopoiesis and congestion in spleen, and higher reticulocyte ratio were noted in only females at 450 mg/kg/day without decreased anemic parameters in the hematological examination. Hypertrophy of centrilobular hepatocytes in both sexes was observed with increased relative liver weight at 450 mg/kg/day. Furthermore, the diffuse follicular cell hypertrophy of the thyroid was observed in females at 450 mg/kg/day. No abnormalities were detected in the reproductive indices of copulation, delivery or fetal viability. We concluded the no-observed-adverse-effect level (NOAEL) for repeated-dose toxicity was 75 mg/kg/day based on the trace evidences of hemolytic anemia, and the NOAEL for reproductive/developmental toxicity as 450 mg/kg/day based on no toxicological concerns for reproductive endpoints. The hemolytic anemia was much milder than expected. Thus, we discussed the reason of this much less hemolytic effect from the point of view of the structural characteristics of 4M2NA.
authors.affiliation: a CERI Hita, Chemicals Evaluation and Research Institute , Japan, Ishii-machi , Hita-shi , Oita , Japan .
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tsubokura
authors.affiliation: a CERI Hita, Chemicals Evaluation and Research Institute , Japan, Ishii-machi , Hita-shi , Oita , Japan .
authors.forename: Sunao
authors.initials: S
authors.lastname: Aso
authors.affiliation: a CERI Hita, Chemicals Evaluation and Research Institute , Japan, Ishii-machi , Hita-shi , Oita , Japan .
authors.forename: Takayuki
authors.initials: T
authors.lastname: Koga
authors.affiliation: a CERI Hita, Chemicals Evaluation and Research Institute , Japan, Ishii-machi , Hita-shi , Oita , Japan .
authors.forename: Junichi
authors.initials: J
authors.lastname: Kikuchi
authors.affiliation: a CERI Hita, Chemicals Evaluation and Research Institute , Japan, Ishii-machi , Hita-shi , Oita , Japan .
authors.forename: Toshio
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: a CERI Hita, Chemicals Evaluation and Research Institute , Japan, Ishii-machi , Hita-shi , Oita , Japan .
authors.forename: Satsuki
authors.initials: S
authors.lastname: Hoshuyama
authors.affiliation: a CERI Hita, Chemicals Evaluation and Research Institute , Japan, Ishii-machi , Hita-shi , Oita , Japan .
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Oshima
authors.affiliation: a CERI Hita, Chemicals Evaluation and Research Institute , Japan, Ishii-machi , Hita-shi , Oita , Japan .
authors.forename: Katsumi
authors.initials: K
authors.lastname: Miyata
authors.affiliation: a CERI Hita, Chemicals Evaluation and Research Institute , Japan, Ishii-machi , Hita-shi , Oita , Japan .
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kusune
authors.affiliation: a CERI Hita, Chemicals Evaluation and Research Institute , Japan, Ishii-machi , Hita-shi , Oita , Japan .
authors.forename: Takako
authors.initials: T
authors.lastname: Muroi
authors.affiliation: b CERI Kurume, Chemicals Evaluation and Research Institute , Japan, Miyanojin , Kurume-shi , Fukuoka , Japan , and.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: c Chemical Biotesting Center, Chemicals Evaluation and Research Institute , Japan, Koraku, Bunkyo-ku , Tokyo , Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Hasegawa
authors.affiliation: a CERI Hita, Chemicals Evaluation and Research Institute , Japan, Ishii-machi , Hita-shi , Oita , Japan .
authors.forename: Shozo
authors.initials: S
authors.lastname: Ajimi
authors.affiliation: a CERI Hita, Chemicals Evaluation and Research Institute , Japan, Ishii-machi , Hita-shi , Oita , Japan .
authors.forename: Kotaro
authors.initials: K
authors.lastname: Furukawa
mesh_terms: D000743:Anemia, Hemolytic / Q000139:chemically induced*; D000814:Aniline Compounds / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D007774:Lactation; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects*; D012156:Reticulocytes / Q000187:drug effects / Q000378:metabolism; D012737:Sex Factors; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D018675:Toxicity Tests
chemical_list: D000814:Aniline Compounds; C000609082:4-methoxy-2-nitroaniline
keywords: Aniline; hemolytic anemia; nitrobenzene