KC 400

Absorption, Distribution and Excretion
In experimental animals, the absorption of PCBs by the gastrointestinal tract is well documented; however, few studies provided quantitative estimates. In rats, individual congeners (mono- to hexachlorobiphenyls) were readily absorbed when administered by gavage (vehicle not reported) in doses between 5 and 100 mg/kg. Retention was > 90% of the administered dose over a 4 day period, and was apparently dose independent. No relationship between substitution pattern and degree of absorption could be established due to the low levels of excretion, although a later study reported that absorption efficiency decreased in rats as the number of chlorine atoms increased such that dichlorobiphenyls were absorbed with a 95% efficiency, whereas octachlorobiphenyls had an absorption efficiency of only 75%. Results similar to those obtained in rats were reported in monkeys administered a single dose of 1.5 or 3.0 g Aroclor 1248/kg by gavage and in ferrets given 0.05 mg (14)C-labeled Aroclor 1254 in the food on days 14 and 35 of gestation. Retention was estimated to be > 90% and 85.4% of the administered dose in the monkeys and ferrets, respectively. Over 90% of a single dose of 10 mg PCB 105 was absorbed by minks. In mice, absorption of a gavage dose of 8 mg/kg of PCB 52 /2,2',5,5'-tetrachlorobiphenyl/ or 100 mg/kg of PCB 77 /3,3',4,4'-tetrachlorobiphenyl/ was rapid, with serum concentrations increasing 4-7-fold in 30-60 minutes; peak serum concentrations were achieved 2 hours after dosing.
In monkeys, a single dose of 1.5 or 3.0 g/kg Aroclor 1248 resulted in a dose-dependent liver concentration of Aroclor 1248 (25 or 53 ug/g) 2 times higher than that found in the kidney (12 or 27 ug/g) and brain (17 or 28 ug/g) 4 days after dosing. This difference was greatly increased 14 days after treatment due to both a reduction in kidney and brain concentration and an increase in liver concentration. The blood levels of Aroclor 1254 increased rapidly in monkeys during 10 months of treatment (from approximately 1.2 ug/g at time zero to about 100 ug/g in the high-dose group) with doses between 20 and 80 ug/kg/day, but this increase leveled off during the remaining 27 months of treatment. A dose of 5 ug/kg/day induced only a slight increase in blood PCB levels during the total treatment period of 37 months. When the data were expressed as relative concentration, it appeared that absorption and bioaccumulation were dose-dependent. However, the concentration/dose levels were, to some extent, affected by background PCB levels of the control group, which would have a greater impact on the relative concentrations of the lowest dose groups rather than on the higher dose groups.
4 wk after ip injection of 1 g Aroclor 1248 into rats, adipose tissue contained 338 ug tetrachlorinated biphenyl (TCB) residues/g, and there was a shift to pentachlorobiphenyls and hexachlorobiphenyls (up to 63%) in chromatographic and spectrometric analysis patterns of residue. Only 5% of higher chlorinated components were present in the TCB admin.
Over 90% of a single oral dose (1.5 or 3.0 g/kg body weight) of Aroclor 1248 was absorbed from the gastrointestinal tract of monkeys as determined by chromatographic analysis of excreta. The major route was by biliary excretion into the gastrointestinal tract. By the 14th day after PCB administration, 5.6% of the original dose had been eliminated in the urine and feces.

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Metabolism / Metabolites
PCBs are absorbed via inhalation, oral, and dermal routes of exposure. They are transported in the blood, often bound to albumin. Due to their lipophilic nature they tend to accumulate in lipid-rich tissues, such as the liver, adipose, and skin. Metabolism of PCBs is very slow and varies based on the degree and position of chlorination. PCBs are metabolized by the microsomal monooxygenase system catalyzed by cytochrome P-450 enzymes to polar metabolites that can undergo conjugation with glutathione and glucuronic acid. The major metabolites are hydroxylated products which are excreted in the bile and faeces. The slow metabolism of PCBs means they tend to accumulate in body tissues. (L4, T6)

Toxicity Summary
The mechanism of action varies with the specific PCB. Dioxin-like PCBs bind to the aryl hydrocarbon receptor, which disrupts cell function by altering the transcription of genes, mainly be inducing the expression of hepatic Phase I and Phase II enzymes, especially of the cytochrome P450 family. Most of the toxic effects of PCBs are believed to be results of Ah receptor binding. Other PBCs are believed to interfere with calcium channels and/or change brain dopamine levels. PCBs can also cause endocrine disurption by altering the production of thyroid hormones and binding to estrogen receptors, which can stimulate the growth of certain cancer cells and produce other estrogenic effects, such as reproductive dysfunction. They will bioaccumulate by binding to receptor proteins such as uteroglobin. (A3, A4, A30, A66)

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Toxicity Data
LD50: 11 g/kg (Oral, Rat) (T14)
LD50: 880 mg/kg (Intraperitoneal, Mouse) (T14)

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Interactions
Acute parenteral administration of several commercial PCB mixtures (Aroclors 1242, 1248, 1254, and 1260) and a synthetic mixture of PCB congeners reflective of PCBs detected in human milk antagonized 2,3,7,8-TCDD /2,3,7,8-tetrachlorodibenzodioxin/-induced impairment of the immune response to SRBC /sheep red blood cells/ in mice at PCB:TCDD dose ratios > 1000:1 Aroclor 1232 had no effect on TCDD-induced immunotoxicity in these studies. Aroclor doses that antagonized the acute immunotoxicity of single doses of 0.0012 or 0.0036 mg/kg 2,3,7,8-TCDD ranged from about 1 to 50 mg/kg/day. Among seven individual PCB congeners examined for their ability to influence this immunotoxic action of single intraperitoneal doses of 0.0012 ug/kg 2,3,7,8-TCDD in mice (six hexachlorobiphenyls and one pentachlorobiphenyl with different chlorine substitution patterns), three were antagonistic (the 2,3,3',4,5,5'-, 2,3,3',4,5'- and 2,2',4,4',5,5'-congeners), and 4 showed no influence (the 2,3,3',4,4',5' -, 2,3',4,4',5',6-, 2,2',4,4',5,6'-, and 2,2',4,4',6,6'-congeners ). In these studies, doses of individual PCB congeners ranged from about 1 to 100 - 300 mg/kg. Oral co-exposure of pregnant mice to 244 mg/kg Aroclor 1254 and 0.020 mg/kg 2,3,7,8-TCDD, at an Aroclor:TCDD dose ratio of 12,200:1, completely antagonized TCDD-induced cleft palate formation in offspring. The complexity of interactions between PCBs and TCDD-induced developmental toxicity is illustrated by observations that, among one tetrachlorobiphenyl and two hexachlorobiphenyl congeners examined, one (the 2,3,3',4,4',5-congener) potentiated TCDD-induced cleft palate formation and the other two (the 2,2',4,4'- and 2,2',4,4',5,5'-congeners) antagonized TCDD's actions. Antagonism of TCDD-induced cleft palate formation in mouse offspring by 2,2',4,4'-tetraCB and 2,2',4,4',5,5'-hexaCB showed complex (i.e., inverted U-shape) relationships with dose. For example, no antagonistic effect (against a TCDD dose of 0.0015 ug/kg) was produced by 10-20 mg/kg doses of 2,2',4,4',5,5'-hexaCB, but antagonism increased with increasing 2,2',4,4',5,5'-hexaCB dose to a maximum (500 mg/kg), and then declined to no antagonism at 1,000 mg/kg 2,2',4,4',5,5'-hexaCB. 2,2',4,4',5,5'- HexaCB also antagonized TCDD-induced hydronephrosis in mouse offspring showing a similar inverted U-shape relationship with dose. In contrast, combined exposure of pregnant mice to 2,3,3',4,4',5-hexaCB and 2,3,4,7,8-pentachlorodibenzofuran appeared to additively produce hydronephrosis and cleft palate in the offspring. Several 13-week oral exposure studies have examined possible binary interactions between three PCB congeners (at several dietary concentrations delivering daily doses ranging from about 0.1 to 10 mg/kg/day) and 2,3,7,8-TCDD (at several dietary concentrations delivering daily doses ranging from about 0.00003 to 0.3 mg/kg/day) in influencing several end points in rats. The PCB:TCDD concentration ratios administered in these studies were selected to reflect relative concentrations in samples of human milk and fat. 2,2',4,4',5,5'-HexaCB and 2,3,7,8-TCDD showed joint additive action in decreasing thyroid hormone levels at 4 weeks, but synergistic action at 13 weeks, whereas 2,3,3',4,4',5-hexaCB and 3,3',4,4',5-pentaCB showed less-than-additive joint action with 2,3,7,8-TCDD in decreasing thyroid hormone levels. 2,2',4,4',5-Hexachlorobiphenyl did not influence TCDD-induced effects on body weight and thymus weight, and additively increased relative liver weight with TCDD, whereas 2,3,3',4,4',5-hexaCB and 3,3',4,4',5-pentaCB showed less-than-additive joint action with TCDD on these end points. 2,2',4,4',5,5'-hexaCB and 2,3,7,8-TCDD showed a distinct synergism in increasing hepatic porphyrin levels, but 2,3,3',4,4',5-hexaCB and 3,3',4,4',5-pentaCB showed no such synergism with 2,3,7,8-TCDD. All three of these congeners individually decreased hepatic levels of retinol and retinylpalmitate. In combination with TCDD, less-than-additive joint actions were noted, but TCDD doses used in these studies produced a near maximal response in decreasing retinoid levels

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Non-Human Toxicity Values
LD50 Rat oral 11000 mg/kg
LD50 Rabbit skin 11.0 g/kg

Pcb-1248 is a viscous oily liquid. (NTP, 1992)
3,3',5,5'-tetrachlorobiphenyl is a tetrachlorobiphenyl that is biphenyl in which both phenyl groups are substituted by chlorines at positions 3 and 5. It is a tetrachlorobiphenyl and a dichlorobenzene.
Aroclor 1248 is a commercial mixture of PCBs with an average chlorine content of 48%. It is composed of mono- to heptachlorinated homologs. Polychlorinated biphenyls (PCBs) are a group of 209 synthetic organic compounds with 1-10 chlorine atoms attached to biphenyl. PCBs were manufactured as commercial mixtures but banned in the 1970's because they were found to bioaccumulate in the environment and cause harmful health effects. However, PCBs do not break down readily and are still found in the environment. (L4)
See also: Polychlorinated Biphenyls (component of).

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Mechanism of Action
One proposed molecular target for PCB disruption of calcium homeostasis that may be involved in neurological and neurodevelopmental effects is ryanodine-sensitive Ca+2 channels. Commercial PCB mixtures with intermediate to high degrees of chlorination (Aroclors 1248, 1254, and 1260) enhanced ryanodine binding to calcium release channels in sarcoplasmic reticulum membranes from skeletal or cardiac rabbit muscles, and mixtures with lower (Aroclors 1221, 1232) or higher (Aroclor 1268) chlorination showed little enhancement. Examination of selected pentachlorobiphenyls indicated that ortho substitution favored activity; 2,2',3,5',6-pentaCB induced the greatest enhancement of ryanodine binding, whereas the 3,3',4,4',5-isomer did not enhance binding. The 2,2',4,6,6'-isomer with full substitution at the ortho positions produced less enhancement than the 2,2',3,5',6-isomer, indicating that some degree of rotation about the biphenyl bond may be important for full activity. Results from studies with hippocampal slices from freshly dissected rat brains indicated that perfusion with a tri-ortho congener (2,2',3,5',6-pentaCB) enhanced ryanodine binding and inhibited electrophysiological responses to electrical pulse stimulations, but a mono-ortho congener (2,3',4,4'-tetraCB) showed no enhancement of ryanodine binding and no inhibition of electrophysiological responses to stimulation. Offspring of rats exposed to gavage doses of 8 or 32 mg/kg/day 2,2',3,5',6-pentaCB on gestation days 10-16 displayed neurobehavioral changes as adults (depressed open field locomotor activity, faster acquisition on a working memory task, and no changes in a delayed spatial alternation task) and changes in ryanodine binding to calcium channels in specific regions of the brain (e.g., decreased in hippocampus and increased in cerebral cortex). Although it is not understood how these changes in ryanodine binding are specifically related to the observed neurobehavioral changes, the results from this series of studies emphasize the potential importance of Ah receptor independent mechanisms in PCB-induced neurological and neurodevelopmental effects.

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Drug Warnings
Food and Environmental Agents: Reported Sign or Symptom in Infant or Effect on Lactation: Polychlorinated biphenyls and polybrominated biphenyls: Lack of endurance, hypotonia, sullen, expressionless facies. /From Table 7/

C12H6CL4

291.988039493561

289.92

12737-87-0

36400

Colorless mobile oil
Lower chlorinated Aroclors (1221, 1232, 1016, 1242, and 1248) are colorless mobile oils. Increasing chlorine content results in mixtures taking on the consistency of viscous liquids (Aroclor 1254) or sticky resins (Aroclors 1260 and 1262). Arclors 1268 and 1270 are white powders.

340-375 °C

6.1

0

0

0

1

16

189

0

UTMWFJSRHLYRPY-UHFFFAOYSA-N

InChI=1S/C12H6Cl4/c13-9-1-7(2-10(14)5-9)8-3-11(15)6-12(16)4-8/h1-6H

1,3-dichloro-5-(3,5-dichlorophenyl)benzene

KC-400; KC400; KC 400

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。