Studies of hepatic toxicity in mice suggest that ingested 1,3-dichloropropene is biotransformed via cytochrome P-450, with metabolites inducing liver damage, and that glutathione plays an important role in the detoxification of 1,3-dichloropropene.
来源:Hazardous Substances Data Bank (HSDB)
代谢
给予大鼠1,3-二氯-2-丙烯的主要尿液代谢物是巯基尿酸。
The major urinary metabolite in rats given 1,3-dichloro-2-propene was a mercapturic acid.
(14)C-1,3-dichloropropene ((14)C-DCP) is rapidly absorbed and eliminated in both the male F344 rat and B6C3F1 mouse following oral administration of 1 or 50 mg/kg (rat) or 1 or 100 mg/kg (mouse). It is extensively metabolized in both species. Urinary excretion was the major route of elimination, accounting for 50.9-61.3 and 62.5-78.6% of the administered dose in rat and mouse, respectively. Urinary elimination half-lives ranged from 5 to 6 hr (rat) and from 7 to 10 hr (mouse). Elimination via feces or as (14)CO2 accounted for 14.5-20.5 and 13.7-17.6% of the administered dose, respectively. Metabolites arising from glutathione conjugation account for 36-55 and 48-50% of the administered dose in excreted from rats and mice, respectively. Hydrolysis of the 3-chloro moiety of DCP accounted for 24-37 and 29% of the dose administered to rats and mice, respectively. Two novel dimercapturic acid conjugates were also identified at low levels that might arise via initial hydrolysis of DCP or of epoxidation of DCP-glutathione conjugate or of DCP itself. Structural confirmation of these dimercapturates was obtained via analysis of deuterium retention from D4-DCP in the male F344 rat. Only quantitative differences are seen between the overall metabolic profile of DCP in these two species.
1,3-Dichloropropene (1,3-DCP) is used as a soil nematocide worldwide. Technical grade 1,3-DCP is genotoxic/mutagenic and carcinogenic. /A previous study/ reported that mutagenic activity is lost after purification of 1,3-DCP samples via silica gel column chromatography. We found that mutagenicity and SOS repair in Escherichia coli, strain PM 21, are strongly reduced after purification via silica gel and that mutagenicity and induction of SOS repair depend on oxidative impurities and secondary products. Both isomers (E and Z) of 1,3-DCP are oxidized to 1,3-dichloropropene epoxide (1,3-DCP-Ox). The epoxide is subjected to rapid internal rearrangement to 2,3-dichloropropanal (2,3-DCPA), which spontaneously eliminates HCl and forms the extremely mutagenic, genotoxic, and carcinogenic 2-chloroacrolein (alpha-chloroacrolein) alpha-ClA. Thus, the genotoxic/mutagenic effects of unpurified 1,3-DCP samples mainly depend on alpha-ClA. The underlying genotoxic and mutagenic mechanism is formation of promutagenic exocyclic 1,N(2)-propanodeoxyguanosine adducts of alpha-ClA. Pure 1,3-DCP samples have only a very low S(N)1 reactivity as measured in trifluoroacetic acid solvolysis reactions, hydrolysis, and computed reactivities but possess a moderate S(N)2 reactivity as determined in alkylation tests with the nucleophiles 4-(p-nitrobenzyl)pyridine (NBP) and N-methyl-mercaptoimidazole (MMI). Evidently, the low S(N)1 reactivity is not sufficient to form necessary amounts of O(6)-alkylguanine DNA adducts required for back-mutation in Salmonella typhimurium strain TA1535. The S(N)2 reactivity may, however, lead to other DNA adducts, e.g., N7-guanine adducts, which can induce error prone repair in S. typhimurium strain TA100 and thus lead to back-mutation in this strain. Application of 1,3-DCP samples in agriculture must be considered as a mutagenic risk because the samples can be oxidized and form the extremely mutagenic alpha-ClA. As a consequence, it is questionable whether any stabilizers can prevent oxidation during application.
IDENTIFICATION AND USE: 1,3-Dichloropropene is a colorless to amber colored liquid with a penetrating, irritating, chloroform-like odor. It has been widely used in agriculture as a pre-plant soil fumigant for the control of nematodes in vegetables, potatoes, and tobacco. It often appears as part of a mixture also including 1,2-dichloropropane. Application is primarily by soil injection. HUMAN EXPOSURE AND TOXICITY: Irritation of the eyes and the upper respiratory mucosa appears promptly after exposure. Dermal exposure caused severe skin irritations. Inhalation may result in serious signs and symptoms of poisoning with lower exposures resulting in depression of the central nervous system and irritation of the respiratory system. Some poisoning incidents have occurred in which persons were hospitalized with signs and symptoms of irritation of the mucous membrane, chest discomfort, headache, nausea, vomiting, dizziness and, occasionally, loss of consciousness and decreased libido. The fertility status of workers employed in the production of chlorinated three-carbon compounds was compared with a control group. There was no indication of an association between decreased fertility and exposure. ANIMAL STUDIES: The acute oral toxicity of 1,3-dichloropropene in animals is moderate to high. Acute dermal exposure is moderately toxic. Acute intoxication showed central nervous and respiratory system involvement. Severe reactions were seen in rabbit skin and eye irritation tests. Degeneration of the olfactory epithelium and hyperplasia were seen in inhalation studies with mice and rats. Cis- and trans-1,3-dichloropropene and mixtures were mutagenic in bacteria with, and without, metabolic activation. In mice, increased incidences of hyperplasia of the urinary bladder, the forestomach, and the nasal mucosa were observed. There was an increase in the incidence of benign lung tumors. Some toxic changes in the olfactory mucosa of the nasal cavity were also seen in rats, but no increase in tumor incidence. ECOTOXICITY STUDIES: The acute toxicity of 1,3-dichloropropene to saltwater aquatic life occurs at concn as low as 790 mg/L. In a test conducted on a mixed assemblage of emerald shiners and fathead minnows exposed to 1,3-dichloropropene, 100% of the fish survived 3 days at 1,000 ug/L, and none survived at 10,000 ug/L. 1,3-Dichloropropene at 20 ug/mL of air, killed 100% of microsclerotia after incubation for 30 hr, and at 100 ug/g of soil moisture after incubation for 3 days. Higher temperatures increased the toxicity.
Evaluation: No epidemiological data relevant to the carcinogenicity of 1,3-dichloropropene were available. There is sufficient evidence in experimental animals for the carcinogenicity of mixed isomers of 1,3-dichloropropene (technical grade). Overall evaluation: 1,3-Dichloropropene (technical grade) is possibly carcinogenic to humans (Group 2B).
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌性证据
癌症分类：B2组可能的人类致癌物
Cancer Classification: Group B2 Probable Human Carcinogen
WEIGHT-OF-EVIDENCE CHARACTERIZATION: Human data are inadequate for assessment of the potential human carcinogenicity of 1,3-dichloropropene because the only human data available are case studies. In chronic animal bioassays, 1,3-dichloropropene produced tumors in F344 rats (forestomach, liver) and B6C3F1 mice (forestomach, urinary bladder, and lung) at high gavage doses, liver tumor in F344 rats at lower dietary doses, and benign lung tumors in male mice exposed via inhalation. Although 1,3-dichloropropene elicited a positive response for mutagenicity in bacterial assays with the addition of S9, the most compelling evidence for mutagenicity is the isolation of mutagenic epoxide metabolites from mouse liver at high (~LD50) doses. Thus, under the current Risk Assessment Guidelines (USEPA, 1987), 1,3-dichloropropene is a B2, probable human carcinogen, because of the lack of data in humans and sufficient evidence of carcinogenicity in animals. Although the available human data are inadequate, 1,3-dichloropropene is characterized as "likely" to be a human carcinogen in accordance with the Proposed Guidelines for Carcinogen Risk Assessment (USEPA, 1996). This characterization is based on tumors observed in chronic animal bioassays for both inhalation and oral routes of exposure. Although the chronic dietary and inhalation bioassays suggest that tumors may not occur at low doses, a nonlinear mechanism of tumor formation is not supported by the available mechanistic data. In fact, the mutagenic properties of 1,3-dichloropropene suggest a genotoxic mechanism of action. The mutagenic properties and the absence of data to support a nonlinear mechanism of tumor formation require that the quantitative assessment default to a linear model. HUMAN CARCINOGENICITY DATA: Inadequate. ANIMAL CARCINOGENICITY DATA: Sufficient.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌性证据
A3；已确认对动物有致癌性，但对人类的相关性未知。
A3; Confirmed animal carcinogen with unknown relevance to humans.
Inhalation studies with both humans and rats have shown that dichloropropene (DCP) is readily absorbed, conjugated with glutathione (GSH) via glutathione S-transferase (GST), and rapidly excreted in the urine as N-acetyl-S-(cis-3-chloroprop-2-enyl)-cysteine (3CNAC), a mercapturic acid metabolite. A study of six male volunteers exposed at 1 ppm commercial Telone II (50.6% cis-isomer, 45.2% trans-isomer) for 6 hours found the absorption of cis-DCP was 72% to 80%, while the absorption of trans-DCP was 77% to 82%. A similar percent absorption was found in rats exposed at 136 mg/cu m DCP for 3 hours. DCP does not bioaccumulate in the body. Half-lives were similar for both rats and humans for removal from the blood and for excretion of mercapturic acid metabolites. /A study/ found that the concentration of DCP in expired air and concentration in blood plateaued in the first hour of exposure and declined rapidly postexposure to nondetectable levels in less than an hour. A urinary excretion half-life of approximately 5.5 hours for DCP in rats and mice was calculated. Radio-labeled DCP, when dosed orally in rats, yielded 82% to 84% of the radioactivity in the urine within 24 hours after treatment. Most of this (14)C (92%) was present as N-acetyl-S-((Z), 3-chloroprop-2-enyl) cysteine (Z)-DCP mercapturic acid). Within 4 days, about 1% of the dose of each isomer was found in the carcass.
... /Some/ studies have concluded that urine collection during and after exposure may be representative of exposure to dichloropropene (DCP). Urinary excretion of thioethers was measured in 12 applicators occupationally exposed to DCP and was compared to excretion of the mercapturic acid metabolites. The 8-hour time weighted average exposures to the Z-isomer and the E-isomer of DCP ranged from 0.3 to 18.9 mg/cu m over 1- to 11-hour shifts. Cumulative urinary thioether excretions and urinary postshift levels minus preshift levels correlated well with DCP exposures. Mean urinary thioether concentrations were 1.38-fold greater than the mean DCP mercapturic acid metabolite concentration, suggesting the presence of an unidentified thioether metabolite. The thioether assay correlated well with relatively high DCP exposures.
Studies conducted on occupational and non-occupational exposure to dichloropropene (DCP) in the Dutch flower bulb culture industry found a strong correlation between inhalation exposure and the complete cumulative urinary excretion of the mercapturic acids of DCP. A possible subclinical nephrotoxic effect of subchronic DCP exposure was noted. There was a notable decrease of glutathione and GST activity in blood, suggesting that DCP exposure may affect the glutathione conjugating capacity.
In /a/ personal air monitoring study of 15 applicators of dichloropropene (DCP), excretion of the DCP metabolite, 3CNAC, and excretion of the renal tubular enzyme, NAG [N-acetyl glucosaminidase], were studied. Four workers had clinically elevated NAG in all of their urine collections after baseline. Nine workers showed greater than 25% increases in NAG excretion when compared to baseline. Dichloropropene air exposure products of >700 mg/min/cu m or excretion of >1.5 mg 3CNAC/day distinguished abnormally high daily excretion of NAG. These data indicate a positive relationship between air exposure and internal exposure and a possible subclinical nephrotoxic effect in workers. In a subsequent study using these same urine samples collected during five consecutive 6- to 8-hour intervals and stored frozen for 4 years, /the authors/ analyzed the samples for albumin and retinal binding protein (RBP). Urinary excretion of albumin and RBP during the second through fifth collection intervals was not significantly increased relative to the baseline period after correction for creatinine. Within each interval, excretion of albumin and RBP was significantly correlated with each other and the 3CNAC concentrations. NAG excretion was slightly increased in nine subjects. When the 3CNAC excretion data were dichotomized into subjects excreting less than and more than 1.5 mg/day, which corresponded to low and high DCP exposures, urinary excretion of NAG and RBP was significantly lower in the low exposure than in the high exposure group. Urinary albumin excretion was similar in both groups. Urinary excretion of RBP and albumin during the baseline period correlated best with 24 hours cumulative excretion of these proteins as indicated by logistic regression analysis. Excretion of NAG during the afternoon shift correlated best with 24-hour cumulative NAG excretion. Urinary 3CNAC excretion during the next morning correlated best with its 24-hour cumulative excretion. The conclusion made was that under the conditions used by pesticide applicators, DCP has only a slight effect on the kidney.
[EN] CONJUGATES FOR TREATING DISEASES<br/>[FR] CONJUGUÉS POUR LE TRAITEMENT DE MALADIES
申请人：ENDOCYTE INC
公开号：WO2016148674A1
公开（公告）日：2016-09-22
The present disclosure relates to pyrrolobenzodiazepine (PBD) prodrugs and conjugates thereof. The present disclosure also relates to pharmaceutical compositions of the conjugates described herein, methods of making and methods of using the same.
[EN] PYRAZOLE COMPOUNDS AND USE THEREOF IN NOXIOUS ARTHROPOD PESTS CONTROLLING COMPOSITION<br/>[FR] COMPOSES DERIVES DU PYRAZOLE ET LEUR UTILISATION DANS UNE COMPOSITION DE LUTTE CONTRE LES ARTHROPODES NUISIBLES
申请人：SUMITOMO CHEMICAL CO
公开号：WO2005075433A1
公开（公告）日：2005-08-18
The present invention provides a pyrazole compound of formula (a): ;a noxious arthropod pests controlling composition containing the compound shown by the formula (a) as an active ingredient; and a method for controlling noxious arthropod pests comprising applying an effective amount of the compound shown by the formula (a).
A Mild and Convenient Barbier-Type Allylation of Aldehydes to Homoallylic Alcohols via Iodide Ion Promoted Stannylation of Allylic Bromides and Chlorides with Tin(II) Chloride
作者：Toshiro Imai、Shinya Nishida
DOI：10.1055/s-1993-25871
日期：——
Barbier-type allylation of aldehydes with allylic bromides and tin(II) chloride dihydrate is largely accelerated by adding stoichiometric or substoichiometric amounts of sodium iodide. This method has some merits such as lower temperature, shorter reaction time and/or more choices of solvents for the reaction. Moreover, the activation by the iodide ion enables the use of relatively unreactive allylic chlorides of various structural types (e.g., 3-chloro-2-chloromethylpropene as an isobutene dianion equivalent) and, thus, expands synthetic applicability of this reaction. The major role of the iodide salt is attributed to the in situ generation of the corresponding allylic iodide.
A simple, stereoselective, room-temperature synthesis of cis vinyloxiranes and trans 1-phenyl-1,3-butadiene
作者：Jacques Auge、Serge David
DOI：10.1016/s0040-4039(00)88249-0
日期：1983.1
The organotin reagent from 1-chloro-3-iodoprop-1-ene and SnCl2 in dimethylformamide reacted with aldehydes by ite chlorine-substituted carbon atom. Treatment with NaOMe then gave vinyloxiranes with good stereo-selectivity. benzaldehyde and 1-bromo-3-iodoprop-1-ene in the presence of two equivalents of SnCl2 gave exclusively -1-phenyl-1,3-butadiene.
SYNTHESIS OF β, γ-UNSATURATE CARBOXYLIC ACID DERIVATIVES BY THE NOVEL Ni (CO)<sub>4</sub>-INDUCED RING-OPENING CARBONYLATION REACTION OF 1,1-DIBROMO-2-CHLOROCYCLOPROPANES
作者：Toshikazu Hirao、Shinichiro Nagata、Toshio Agawa
DOI：10.1246/cl.1985.1625
日期：1985.11.5
1,1-Dibromo-2-chlorocyclopropanes underwent the Ni (CO)4-induced ring-opening carbonylation reaction with alcohol or amine giving the β, γ,-unsaturated carboxylic acid and dicarboxylic acid derivatives. Use of N,N-dimethyltrimethylsilylamine as an initial nucleophile in the presence of benzaldehyde led to a dienecarboxamide presumably via codensation of the nickel enolate intermediate.
