D4 octamethylcyclotetrasiloxaan

Siloxanen zijn verbindingen met silicium en zuurstof-atomen. In implantaten zijn eveneens vloeibare vluchtige siloxanen aangetroffen, zoals 

D4 octamethylcyclotetrasiloxaan en D5 decamethylcyclopentasiloxaan.

Bij het van de markt halen van de implantaten door de FDA – in 1992 - werden D4 en D5 onveilig genoemd. Bij het weer op de markt brengen van de implantaten in 2006 werd bepaald dat deze stoffen verminderd moesten worden. Dat betekent wel dat vrouwen met oudere implantaten langdurig zijn blootgesteld aan een veel te hoge dosering D4 en D5.

Bij wetenschappelijke onderzoeken wordt vaak gezegd dat er geen data voorhanden is bij blootstelling aan mensen. Maar de wetenschappers (en overheden) hadden in onderstaande onderzoeken kunnen lezen dat er patiënten waren die blootgesteld werden aan siliconen implantaten met grote hoeveelheden D4/D5 van plusminus 1600ppm.

Volgens wetenschappelijke onderzoeken zijn de risico’s van D4 en D5:

• auto-immuunreacties

• D4 aangetoond in hersenen, longen, klieren, vetweefsel

• fenobarbitalachtige reacties in lever van ratten 

• zwak oestrogene werking

• veranderingen vrouwelijke voortplantingsorganen van ratten

• siloxanen en platina lekken in omliggend weefsel

We vonden het opvallend dat de wetenschappers van deze onderzoeken vaak banden met de industrie hadden

Geneesmiddelen interactie Phenobarbital; zie onderaan deze pagina

Bijwerkingen Phenobarbital >>

Ziekte interacties Phenobarbital >>

Voedselinteracties

• Vermijd alcohol

• Vermijd grote hoeveelheden koffie of thee (cafeïne) 

• Verhoog de inname van magnesium, foliumzuur, vit. B6, B12 en/of overweeg om multivitaminen te nemen 

• Op een lege maag innemen voor een snellere opname 

Bijsluiter Depakine (anti-epileptica)>> 

Zeer zelden komen ernstige sufheid en slaperigheid voor, soms overgaand in tijdelijke bewusteloosheid. Dit ging soms gepaard met een toename in aanvallen. Dit komt meestal voor als het samen met Depakine Chrono Phenobarbital is ingenomen of als de dosering van Depakine Chrono plotseling is verhoogd. >>  

Depakene inhibits certain liver enzymes and can cause the levels of Felbatol (felbamate), Lamictal (lamotrigine), Mysoline (primidone), and phenobarbital to increase markedly—in some cases, more than double. If a person taking phenobarbital is also given Depakene, a rapid rise in phenobarbital levels can lead to extreme tiredness, slurred speech, and other signs of intoxication.

In implants with a gel fluid number molecular weight of 13,840 g/ mol, gel fluid diffusion averaged a number molecular weight of 11,630 g/ mol (less than 0.05% low molecular weight cyclic siloxanes, D4-D 6) or 6,194 g/mol (less than 0.4% low molecular weight cyclics, molecular weight of D4 = 296) depending on the absence or presence, respectively, of a barrier coat (IOM Scientific Workshop, 1998). A minority percentage of higher molecular weight siloxanes, up to 400,000, was also reported in diffusate from implants without barrier coats, possibly from uncross-linked shell silicones (Varaprath, 1991Varaprath, 1992). 

A silicone gel implant is said to contain about 855 parts per million (ppm) of D4, or about 256 mg in an average-size (300-cc) gel implant 

(T.H. Lane and J.J. Kennan, personal communication, 1998). Using different methods, others have reported 1 mg per day of low molecular weight cyclic diffusion into surrounding hydrophilic media in vitro (Lykissa et al., 1997; E.D. Lykissa, personal communication, July 29, 1998). This figure seems high given the measurements cited above for total diffusion and the percentage of these compounds in the gel fluid. Presumably if this were to continue, the entire amount of D4 in an implant would diffuse out in a year, which seems unlikely

Information from Mentor Corporation indicates the current potential amount of D4 in a whole device is 0.47 ug/g or 785 ug of D5 per two devices, for an estimated reasonable worst-case daily exposure of 26 ug D4. As discussed earlier, a NOAEL of 0.75 mg/kg/day D4 has been established based on the most sensitive toxic endpoint of reversible liver weight increases, based on a 2%day inhalation study in rats. This NOAEL is equivalent to a dose of 45,000 ug/day for a 60 kg human adult. Thus, this NOAEL is 1,700 higher than the estimated worst-case daily exposure from Mentor silicone gel-filled implants (i.e., assuming bioavailability of all of the D4 present in two implants), demonstrating a wide margin of safety.

Information from Mentor Corporation indicates the current potential amount of D5 in a whole device is 2.47 ug/g or 4,125 ug of D5 per two devices, for an estimated reasonable worst-case daily exposure of 138 ug D5.~ As discussed earlier, a NOAEL of 5.4 mg/kg/day D5 has been established for the most sensitive toxic endpoint of endometrial tumors, based on the chronic toxicity/oncogenicity inhalation study in rats, This NOAEL is equivalent to a dose of 324,000ug/day for a 60 kg human adult. Thus, this NOAEL is

2,300 higher than the estimated worst-case daily exposure from Mentor silicone gel-filled implants (i.e., assuming bioavailability of all of the D5 present in two implants),demonstrating a wide margin of safety.

Omrekentabel >> 

D4 Conversion factor: 1 ppm = 12 mg/m3; 1 mg/m3 = 0.0835 ppm

D5 Conversion factor: 1 ppm = 15.1 mg/m3; 1 mg/m3 = 0.0645 ppm

hoeveelheden in  PIP-implantaten

D4 136 (0-261) ppm          = 1632mg/m3                = 3132mg/m3                                                                         

D5 434 (0-710) ppm          = 6553,4mg/m3             = 15175,5mg/m3

D6 474 (0-1005)ppm    

Uitgaande dat 1ppm = 1000ppb, dan is 1000 parts per billion gelijk aan 1 part per million 

De implantaten van na 2006 bevatten veel minder D4/D5 dan de implantaten daarvoor, nl. ca. 69 ppm in plaats van 850 ppm in een implantaat van 300 cc. 

PIP bevatte max. 740ppm = 740,000ug 

D4 136 (0-261)

D5 434 (0-710)

D6 474 (0-1005)

Past biomonitoring studies: The national survey of human adipose tissue conducted in 1982

analyzed 46 composite samples and qualitatively found D4 in 21 samples (U.S. EPA. 1987). 

Flassbeck et al. (2001) analyzed plasma and blood of women exposed to silicone gel filled implants (n = 14) and found that many years after the removal of ruptured silicone implants, D4 was present in the range of 14-50 ng/mL in plasma and 79-92 nanograms/milliliter (ng/mL) in  blood. D4 was not detectable in plasma or blood of women without implants. In 3 women with silicone gel-filled implants, D4 was the most abundant siloxane found and was present at levels ranging from 11.9 - 1,300 nanograms/gram (ng/g) depending on the woman and the type of tissue sampled; no siloxanes were detected in control breast tissue samples (Flassbeck et al.2003)  >> 

Interacties Phenobarbital   

Therefore, D4 can be described as a "PB-like" (Phenobarbital -like) inducer of hepatic microsomal enzymes in the Fischer 344 rat. Phenobarbital is in a group of drugs called barbiturates (bar-BIT-chur-ates). Phenobarbital slows the activity of your brain and nervous system. Phenobarbital is used to treat or prevent seizures. It is also used short-term to treat insomnia, or as a sedative before surgery. Phenobarbital may also be...  >>

Overzicht van alle onderzoeken NBCI  (spreadsheat)

Octamethylcyclotetrasiloxane D4 en decamethylcyclopentasiloxane D5 

The PIP scandal: an analysis of the process of quality control that failed to safeguard women from the health risks >>

Induction of type II collagen arthritis in the DA rat using silicone gels and oils as adjuvant.>>

Building a Tiered Approach to In Vitro Predictive Toxicity Screening: A Focus on Assays with In Vivo Relevance  >>

The effect of molecular weight and gel preparation on humoral adjuvancy of silicone oils and silicone gel.>>

The adjuvancy of silicones: dependency on compartmentalization >>

Silicone gel and octamethylcyclotetrasiloxane potentiate antibody production to bovine serum albumin in mice >>

Cytotoxicity and membrane damage in vitro by inclusion complexes between gamma-cyclodextrin and siloxanes >> ­­

Silicone gel and octamethylcyclotetrasiloxane (D4) enhances antibody production to bovine serum albumin in mice. >>

Protein denaturation induced by cyclic silicone >>

Extraction of octamethylcyclotetrasiloxane and its metabolites from biological matrices >>

Low molecular weight silicones are widely distributed after a single subcutaneous  injection in mice. >>

Evaluation of octamethylcyclotetrasiloxane (D4) as an inducer of rat hepatic microsomal cytochrome P450, >>

UDP-glucuronosyltransferase, and epoxide hydrolase: a 28-day inhalation study. >>

Quantitative exposure of humans to an octamethylcyclotetrasiloxane (D4) vapor >>

Repeated inhalation exposure to octamethylcyclotetrasiloxane produces hepatomegaly, transient hepatic hyperplasia, and sustained hypertrophy in female Fischer 344 rats in a manner similar to phenobarbital. >>

Potential estrogenic and antiestrogenic activity of the cyclic siloxane octamethylcyclotetrasiloxane (D4) >> 

Bioavailability of octamethylcyclotetrasiloxane (D(4)) after exposure to silicones by inhalation and implantation >>

Inhalation toxicology of octamethylcyclotetrasiloxane (D4) following a 3-month nose-only exposure in Fischer 344 rats. >>

The effect of cyclic swelling (octamethylcyclotetrasiloxane) on the physical properties of silicone breast implant shells. >>

Dose-response modeling of cytochrome p450 induction in rats by octamethylcyclotetrasiloxane. >>

Percutaneous absorption studies of octamethylcyclotetrasiloxane using the human skin/nude mouse model.>>

Bioavailability of D4 after inhalation and implantation exposure to silicones.>>

Further Comments on the Bioavailability of D4 >>

Route-specific differences in distribution characteristics of octamethylcyclotetrasiloxane  in rats: analysis using PBPK models >>

Determination of siloxanes, silicon, and platinum in tissues of women with silicone gel-filled implants. >>

In vitro and in vivo evaluation of the estrogenic, androgenic, and progestagenic potential of two cyclic siloxanes. >>

Silicone gel and octamethylcyclotetrasiloxane (D4) enhances antibody production to bovine serum albumin in mice. >>

Physiologically based pharmacokinetic modeling of the disposition of octamethylcyclotetrasiloxane (D4) migration from implants in humans. >>

Determination of siloxanes in silicone products and potential migration to milk, formula and liquid simulants. >>

The transport of octamethylcyclotetrasiloxane (D4) and polydimethylsiloxane (PDMS) in lightly cross-linked silicone rubber. >>

Silicone gel and octamethylcyclotetrasiloxane potentiate antibody production to bovine serum albumin in mice. >>

D4(H)/D4(V) silicone: a replica material with several advantages for nanoimprint lithography and capillary force lithography. >>

Induction of type II collagen arthritis in the DA rat using silicone gels and oils as adjuvant. >>

Concentration-Dependent Effects of Silicone Oil Components on Corneal Endothelial Permeability >>

Toxicology and humoral immunity assessment of octamethylcyclotetrasiloxane (D4) following a 28-day whole body vapor inhalation exposure in Fischer 344 rats. >>

Determination of siloxanes, silicon, and platinum in tissues of women with silicone gel-filled implants. >>

Determination of low molecular weight silicones in plasma and blood of women after exposure to silicone breast implants by GC/MS. >>

Surface reaction of particulate silica with polydimethylsiloxanes >>

The effect of cyclic swelling (octamethylcyclotetrasiloxane) on the physical properties of silicone breast implant shells. >>

Amino acid and peptide chemistry on silicones >>

Use of plasm a polymerization for preparing silicone-coated membranes for possible use in blood oxygenators >>

A Flash Point Behavior of Dimethyl Silicone Liquids >> 

Über Silicone LI >>

PBPK modeling advances understanding of D4 pharmacokinetics >>

Physiological modeling of inhalation kinetics of octamethylcyclotetrasiloxane in humans  during rest and exercise. >>

Octamethylcyclotetrasiloxane exhibits estrogenic activity in mice via ERalpha. >>

In vitro and in vivo evaluation of the estrogenic, androgenic, and progestagenic potential of two cyclic siloxanes. >>

A two-generation reproductive toxicity study of octamethylcyclotetrasiloxane (D4) in rats  exposed by whole-body vapor inhalation. >>

It should be noted that D4 is classified as a reprotoxic substance, category 3 [ECB 2006]. The NOAEL for systemic toxicity (150 ppm) used for this risk assessment also covers reprotoxic effects (NOAEL = 300 ppm).   >>

First, it is clear that the silicone products sold in bulk by Union Carbide to McGhan Medical (and later to NuSil for processing and resale to McGhan Medical) were not inherently defective or unreasonably dangerous to consumers. These same materials were sold to other companies in a variety of industries, where they were safely incorporated into various products, including waxes and polishes, brake fluids, cosmetics, insulation, lubricants, food additives, stomach medicine, and electronic equipment. These silicone compounds became potentially harmful, if at all, only in particular applications—here, according to plaintiffs, when incorporated into breast implants. Even for such applications, the rat D4 inhalation studies can hardly be viewed as sufficient to create material issues regarding the safety of the raw materials for incorporation into implants.  

Het volledige document >> 

5 HUMAN HEALTH HAZARD ASSESSMENT   >>

A review of information related to human health is included in EA (2009) and a more recent evaluation by the Scientific Committee on Consumer Safety is also available (SCCS, 2010).  The currently agreed classification under Directive 67/548/EEC of D4 for health hazard is as follows. 

• Repro. Cat 3. 

• R62: Possible risk of impaired fertility. 

• The equivalent classification under Regulation (EC) No. 1272/2008 is as follows. 

• Hazard class and category: Repr. 2. 

• Hazard statement: H361f: Suspected of damaging fertility. 

In an in vivo toxicokinetics study in humans (reliability score 1), male volunteers (24 - 52 years old) inhaled 10 ppm C14-labeled D4 via a mouthpiece for one hour. Metabolites were far more persistent in blood and plasma than parent D4 and were still present at 24 hours post-exposure. Approximately 25-30 % of the D4 uptake was found in urine when the C14 activity of the metabolites was expressed in D4 equivalents. One urinary metabolite tentatively identified as trimethyldisiloxane-1,3,3-triol, which has not been identified in rats.

In an in vitro study (reliability score 1) that investigated the metabolism of D4 by human liver microsomes, 14C-D4 was converted by liver microsomes from the phenobarbital-treated rats to at least eight metabolites, designated M1 through M8, based on their retention times. M8 was the major metabolite formed in incubations with human liver microsomes and also in liver microsomes from saline-treated rats, suggesting a similarity in the metabolism of D4 for rats and humans

A Union Carbide 1980 sales brochure, entitled "Union Carbide Silicones for the Drug and Pharmaceutical Industry," stated that certain of its silicone products "are chemically inert under most conditions [and] may be of specific value in the formulation of certain ointment bases and medical devices," and "[are] of extreme value in the manufacture of silicone rubber implants and other medical devices." It cautioned, however, that "nothing in this booklet is to be taken as a warranty or representation" and that "no chemical should be used in a food, feed, drug, or cosmetic, or in a product or process in which it may contact a food, feed, drug, or cosmetic, until you have determined the safety and legality of the use." In this brochure, Union Carbide's A-40—its brand name for a dimethysiloxane D4 chemical that was sold to McGhan Medical and many others—was represented as being of particular value in the manufacture of silicone rubber implants and other medical devices.

Union Carbide does not appear to have conducted its own tests on A-40. Instead, it apparently relied on information regarding D4 publicly available or obtained by it through the Silicones Health Council9 and the Global Silicone Producers Association.10 At the April 1988 meeting of the GSPA, members received a report on the status of D4 studies, one item being a 28-day D4 inhalation study performed on rats by a Japanese company. The members agreed that the study should be submitted to the EPA, which had earlier requested environmental effect studies on D4. At an October 1988 meeting, the GSPA decided to conduct a 90-day inhalation study. This study, when completed, showed a biological response—increased liver weights—after D4 inhalation.

In February 1991, Dr. Bryan Ballantyne, Union Carbide's Director of Applied Toxicology, circulated an internal memorandum about the implications of recent studies on D4. Ballantyne recommended that Union Carbide label its D4 product "May Cause Liver Injury," and he proposed amendments to the company's Medical Safety Data Sheets. That same month, Union Carbide sent a letter to its customers whose products contained one percent or more of D4 or D5, informing them of three toxicology studies showing liver damage after exposure to D4 or D5. In the following month, Union Carbide's Material Safety Data Sheets were amended to indicate the potential for increased liver weight after exposures to D4.

Also during 1991, Union Carbide personnel engaged in a series of discussions and analyses arising from particular concerns as to the safety of silicone breast implants. In September 1991, Union Carbide completed an "Analysis of Breast Implants for McGhan NuSil and McGhan Medical Corporation," which analyzed compounds extracted from implant gel and envelope materials. In March 1992 Union Carbide ceased all sales of A-40 to customers intending to use the product in manufacturing breast implant devices. 

Bron: Rechtszaak Union Carbide - McGhan/Nusil  

D4 und in geringerem Maße D5 führen zu adaptiven Prozessen in der Leber. 

Diese zeigen sich bei niedrigen Konzentrationen als Induktion von Leberenzymen, gefolgt von einer zentrilobulären.Hypertrophie der Leberzellen und einer Lebergewichtszunahme bei relativ hohen Konzentrationen (8400 mg D4/m3). Der europäische Wissenschaftliche Ausschuss für Verbraucherprodukte sieht für diesen Endpunkt 1800 mg D4/m3 als NOAEL an [5]. Auch nach Ansicht der kanadischen Umwelt- und Gesundheitsbehörde sollte die Induktion von Leberenzymen nicht als adverse Wirkung angesehen werden; ob die Zunahme des Lebergewichts als advers gelten kann, erscheint ihr unsicher

To protect public health the German Work­ing Group on Indoor Guidelines of the Fed­eral Environment Agency and the States´ Supreme Health Authorities is issuing in­door air guide values. 

For health evaluation of indoor air cyclic siloxanes no appropriate human data is available. Based on animal studies airway inflammation has been iden­tified as crucial adverse effect following inhalative exposure to cyclic siloxanes. Sig­nificant inflammatory lesions of nasal epi­thelium have been seen in F344 rats chroni­cally exposed to D5 (LOAEL = 600 mg/m3). The lowest adverse effect level for continu­ous exposure is assessed by the Working Group as 107 mg D5/m3. By applying an in­terspecies factor of 2.5 and an intraspecies factor of 10 a so-called health hazard guide value of 4 mg D5/m3 indoor air is obtained. Regarding the limited data on inhalation toxicity of volatile cyclic siloxanes D3 to D6 a health hazard guide value of 4 mg/m3 in­door air for the sum of cyclic siloxanes D3 to D6 is recommended. Additionally, a so-called health precaution guide value of 0.4 mg cyclic siloxanes D3–D6/m3 indoor is recommended.   >>