UPDATE OF THE HUMAN HEALTH RISK … · Web viewUPDATE OF THE RISK ASSESSMENT ADDENDUM OF BIS(PENTABROMOPHENYL) ETHER (DECABROMODIPHENYL ETHER) CAS Number: 1163-19-5 EINECS Number:

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UPDATE OF THE RISK ASSESSMENT ADDENDUMOF

BIS(PENTABROMOPHENYL) ETHER(DECABROMODIPHENYL ETHER)

CAS Number: 1163-19-5EINECS Number: 214-604-9

Human Health Draft

23rd of February 2005

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CONTENTS

CONTENTS................................................................................................................................20 OVERALL RESULTS OF THE RISK ASSESSMENT.....................................................44. HUMAN HEALTH............................................................................................................5

4.1.1.2 Occupational exposure...................................................................................54.1.1.3 Consumer exposure........................................................................................54.1.1.4 Humans exposed via the environment........................................................7

4.1.1.4.1 Discussions on the model..........................................................................84.1.1.4.2 Exposure routes to DBDPE......................................................................9

4.1.1.5 Exposure to infants via milk.........................................................................124.1.1.5.1 Exposure to infants via human breast milk.............................................134.1.1.5.2 Exposure to infants via cows’ milk...........................................................14

4.1.1.6 Combined exposure......................................................................................144.1.2 Effects assessment: Hazard identification and dose (concentration)-response (effect) assessment:...........................................................................................................15

4.1.2.1 Toxicokinetics, metabolism and distribution:...................................................154.1.2.1.1 Summary and discussion.........................................................................15

4.1.2.9 Toxicity for reproduction..................................................................................284.1.2.9.1 Developmental Neurotoxicity:.......................................................................28

4.1.3 Risk characterisation.........................................................................................334.1.3.2 Workers.............................................................................................................34

4.1.3.2.1 and 4.1.3.2.2. Repeated dose toxicity and carcinogenesis.........................344.1.3.2.3 Developmental neurotoxicity.................................................................34

4.1.3.3 Consumers....................................................................................................344.1.3.4 Humans exposed via the environment.........................................................35

4.1.3.4.1 Repeated dose toxicity / carcinogenicity................................................354.1.3.4.2 Developmental neurotoxicity..................................................................354.1.3.4.3 Infants exposed via milk.........................................................................35

5. RESULTS.....................................................................................................................376. REFERENCES.............................................................................................................387. OTHER PAPERS REVIEWED THAT DID NOT CONTAIN SIGNIFICANT NEW INFORMATION RELEVANT TO THE RISK ASSESSMENT.............................................438. OTHER PAPERS NOT YET REVIEWED:.....................................................................44

TABLES

Table 4.1.1.4A: Estimated total daily human intake for exposure of man via environmental routes for each scenario......................................................................................................7

Table 4.1.1.4B: Estimated daily human intake for exposure of man via environmental routes.7Table4.1.1.4.2A: Estimated daily human intake for exposure of man via environmental routes

for the generic production scenario (considering a maximum soil pore water concentration of 0.1 µg/L)................................................................................................10

Fig4.1.2.1.1A: Fecal and biliary metabolites formed and identified by mass spectrometry....18following dose of decabromodiphenyl ether in the rat (quoted in Hakk and Letcher, 2003).. .18Table 4.1.2.1.1.A: Summary of levels of decabromodiphenyl ether in human blood serum

collected in a general population (WWF 2003 and 2004 and Sjödin et al., 2001b) and in Swedish workers (Jakobsson et al., 2003)........................................................................26

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Table 4.1.2.1.1B Summary of levels of decabromodiphenyl ether in blood serum Swedish workers (Jakobsson et al., 2003).......................................................................................27

Table 4.1.2.9A: Summary of effects seen on spontaneous behaviour in mice (Viberg et al., 2003).................................................................................................................................30

Table 4.1.2.9B: Distribution of 14C-label in mice tissues (Viberg et al. 2003).........................31

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0 OVERALL RESULTS OF THE RISK ASSESSMENT

Cas N° : 1163-19-5EINECS N° : 214-604-9IUPAC name : Bis(pentabromodiphenyl)ether

Decabromodiphenyl ether

Human Health

Workers

Conclusion (i) : There is a need for further information and /or testing.

A conclusion (i) applies to the human health part (section 4.1.2.10.5) because an appropriate NOAEL cannot be derived from the available neurotoxicity study. New data is consequently expected namely a developmental neurotoxicity study before this part of the risk characterisation can be filled.

Consumers

Conclusion (ii): There is at present no need for further information and/or testing and for risk reduction measures beyond those which are being applied already.

This conclusion was reached in the risk assessment report because consumer exposure was considered negligible. However, consumers may be exposed to DBDPE released from consumer products (electronic equipment and fabrics). Exposure is not yet quantified in this report but will be considered when further information about the neurotoxic developmental effects become available.

Humans exposed via the environment

Conclusion (i) applies to the risk characterisation for human exposed via the environment.

- Although no risk has currently been identified, additional information are needed on current concentrations of decabromodiphenyl ether in humans due to the remaining uncertainties on DecaBDPE exposure. Consequently, a suitable bio-monitoring programme, including breast milk, and a trend analysis over a certain time period, are required.

- In order to complete the risk assessment for developmental neurotoxicity an appropriate NOAEL should be derived for this endpoint. A developmental neurotoxicity study is consequently expected.

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4. HUMAN HEALTH

4.1.1.2 Occupational exposure

Updated information

Sjödin et al. (2001a) analysed BDE-209 in personal air samples from a plant recycling electronic goods. The sampling train was comprised of a 25-mm, binder-free borosilicate glass fiber filter followed by two 15-mm polyurethane foam plugs to trap the particulate and the semivolatile fractions, respectively. The sampling rate was 3.0 l/min, for a total volume of 1.5 cubic metre. Filters and plugs were analysed separately, after two successive extractions with methylene chloride in an ultrasonic bath and other sample preparation steps. The analytical conditions by gas chromatography were splitless injections with oven temperature programming from 80 °C (2 minutes) to 300 °C (at 10 °C/min, then holding 6 minutes at this temperature) on a DB-5 capillary column (30 m x 0.25 mm. i.d., 0,25 µm film thickness). DBDPE was identified through its retention time compared with that of an authentic sample, together with in-line mass spectrometry. On 12 samples, the mean and range of BDE-209 were 36 and 12-70 ng/m3, respectively; in two samples taken near the shredder, the concentrations were 150 and 200 ng/m3. The concentrations measured in other working environments (corrected for the background in blank samples) were much lower, namely 0.22 (mean; n = 6) and <0.04-0.32 (range) ng/m3 for the highest ones (assembly of circuit boards; maximum value of around 0.09 ng/m3 in other locations, <0.04 ng/m3 outdoors).

In recent studies (Jakobsson et al., 2002 and 2003) conducted in Swedish workers, decabromodiphenyl ether was found in blood / blood serum concentration in the range of <0.7g/kg lipid up to 278g/kg lipid in rubber wire producers (see section 4.1.2.1.1).

4.1.1.3 Consumer exposure

Updated information

Recent studies report decabromodiphenyl ether measurements in house dust:

- Santillo D et al., 2003 conducted a study about chemical contaminant in house dust, using samples of dust collected in 2002 from vacuum cleaners by 100 volunteer households in 10 regions across UK. In addition two dust samples from other countries were included for comparative purposes, namely 1 from Denmark and 1 from Finland. Quantitative analysis of brominated flame retardants was performed by GC-MS using ECNI by the Netherlands Institute for Fisheries Research. Limit of detection (dry weight basis) was 0.12-0.62 ppb (ng/g). Analysis of blank samples (background level of the laboratory) are not reported. Decabromodiphenyl ether was by far the most abundant PBDPE present in the UK samples. It was found in all samples at levels between 3,800 and 19,900 ppb with a mean of 9,820 ppb and a median of 7,100 ppb. Levels of decabromodiphenyl ether were much lower in non-UK samples (100 ppb in Finland and 260 ppb in Denmark). This difference deserves further investigation as they may well reflect existing regional differences within Europe regarding the extent of use of decabromodiphenyl ether.

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- As a follow-up of its breast milk study, the Environmental Working Group (EWG) asked ten women in the U.S. to collect samples of dust from their vacuum cleaners. PBDPEs levels in the samples averaged 4,629 ppb, ranging from 614 to 16,366 ppb. DBDPO was the dominant congener found, with average level of 2,394 ppb and a concentration range from < 400 to 7,510 ppb. Analytical details are not available (Sharp R and Lunder S, 2004).

- To evaluate the potential for electronic equipment to be a source of exposure to brominated flame retardants, the Computer Take Back Campaign and Clean Production Action gathered 16 wipe samples of dust from surface of computer monitors in public facilities across the U.S, including University, State House, school, children museum. Deca-, Octa-, Nona-BDPE and tetrabromobisphenol A (TBBPA) were found in every sample. The highest levels were found for decabromodiphenyl ether with concentrations ranging 2.09 to213.00 pg/cm2 (McPherson A. et al, 2004).

Whether decabromodiphenyl ether migrates out of products and finds its way in dust or comes from the breakdown of the product matrix itself is not clear. However these studies show that inhalation of dust particles containing DBDPE should be considered as a potential pathway of consumer exposure. Particles that lay on the ground or on furniture may also be a source of dermal and oral exposure for children. The results could be used for exposure assessment by taking commonly accepted dust uptake data. This could be considered in a further update.

Hays et al., 2003 have specifically dealt with the exposure of infants and children to decabromodiphenyl ether, which was included in the U.S. EPA voluntary children's chemical evaluation program (VCCEP). A child-specific assessment of decabromodiphenyl ether was performed following the VCCEP guidance for a tier 1 exposure assessment (e.g., screening-level assessment using currently available data and conservative assumptions). Exposure pathways that were considered included general environmental exposures, breast milk exposures, inhalation of decabromodiphenyl ether particulates in air, and mouthing decabromodiphenyl ether -containing consumer products. For each exposure scenario, a mid-range estimate and an upper estimate of intake were calculated. The highest exposure was for the infant (manufacturer scenario) with 0.76 mg/kg/day and the lowest exposure estimated for the child’s exposure with 0.0012 mg/kg/day. Despite the uncertainties, results indicate that the aggregate exposures for children to decabromodiphenyl ether for each scenario evaluated were at least an order of magnitude (most being several orders of magnitude) below the National Academy of Sciences reference dose for decabromodiphenyl ether (4 mg/kg-day), whose evaluation relies on more recent and more appropriate data than that of the USEPA's Integrated Risk Information System (IRIS). The authors conclude that, using the available data, current levels of decabromodiphenyl ether in the U.S. are not likely to represent an adverse health risk for children1.

In recent studies (see section 4.1.2.1.1), decabromodiphenyl ether was found in blood serum samples in human population in a biomonitoring study by WWF, 2003 at a median concentration of 83 g/kg. lipid and maximum concentration of 241 g/kg. Lipid. In a second survey (WWF, 2004), decabromodiphenyl ether was found at a median concentration of 53 g/kg. lipid and maximum concentration of 2,400 g/kg. lipidWhereas in blood serum samples collected from blood donors in the United States, decabromodiphenyl ether was 1 In this study, the doses used in risk calculation were based on an ingested dose rather than an absorbed dose and thereby no consideration was taken to the differences in bioavailability between the experimental animal toxicity studies and the bioavailability in the human exposure scenarios.

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found at a median concentration <0.96 g/kg lipid and in a range <0.96 – 33.6 g/kg lipid. However, the representativeness of the population studies compared with the general population is not assured and potential occupational exposure of the population studied is difficult to appreciate. Moreover, rather limited information is available on the sources of exposure.

4.1.1.4 Humans exposed via the environment

The exposure to man via environmental routes has been estimated using EUSES (see Appendix B). The results are reported in Table 4.1.1.4A and Table 4.1.1.4B. Calculations of the daily doses have been performed using the following values for absorption: 2% for dermal route, 26% for the oral route (except for the scenario exposure to infants via human breast milk where a value of 100% has been used considering that all decaBDPE in breast milk is in a bioavailable form) and 100% for the inhalation route.

Table 4.1.1.4A: Estimated total daily human intake for exposure of man via environmental routes for each scenario

Scenario Estimated total daily dose (mg/kg bw/day)

Local - Production (generic)a 2.2x10-1

Local – Production (site specific)a b 2.0x10-3

Local – Polymer and rubber processing 2.610-4

Local – Textiles (formulation of back coatings) 1.0x10-3

Local – Textiles (application of back coatings) 1.0x10-3

Local – Textiles (combined compounding and application site) 2.0x10-3

Local – Polymers recycling of electronic equipment – particulate loss 4.510-5

Regional 5.210-5

Note: a) Production no longer occurs in the EU.

b) At the production site, no application of sewage sludge to agricultural soil occurred.

Table 4.1.1.4B: Estimated daily human intake for exposure of man via environmental routes

Scenario Route Predicted concentration Estimated daily dose (mg/kg bw/day)

Local - Production (generic)a Wet fish 6.810-3 mg/kg 1.110-5

Root tissue of plants 3.9x101 mg/kg 2.1x10-1

Leaves of plants 1.210-3 mg/kg 2.110-5

Drinking water 3.010-3 mg/L 8.610-5

Meat 7.5x10-1 mg/kg 3.210-3

Milk 2.4x10-1 mg/kg 1.910-3

Air 1.710-6 mg/m3 1.910-6

Total local daily dose 0.22

Local Wet fish 3.8x10-5 mg/kg 6.2x10-8

Polymer and rubber processing Root tissue of plants 2.0x10-2 mg/kg 1.1x10-4

Leaves of plants 3.7x10-3 mg/kg 6.3x10-5

Drinking water 2.4x10-6 mg/L 6.8x10-8

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Meat 1.2x10-2 mg/kg 5.2x10-5

Milk 3.8x10-3 mg/kg 3.1x10-5

Air 5.9x10-6 mg/m3 6.4x10-6

Total local daily dose 2.6x10-4

Local – Textiles Wet fish 2.1710-4 mg/kg 3.610-7

(combined compounding and Root tissue of plants 3.6x10-1mg/kg 2.0x10-3

application site) Leaves of plants 6. 610-4 mg/kg 1.110-5


Meat 9.2x10-3 mg/kg 3.910-5

Milk 2.9x10-3 mg/kg 2.310-5

Air 1.110-6 mg/m3 2.210-7


Local Wet fish 3.1x10-5 mg/kg 5.1x10-8

Polymers recycling of electronic Root tissue of plants 5.0x10-3 mg/kg 2.7x10-5

equipment – particulate loss Leaves of plants 3.9x10-4 mg/kg 6.7x10-6


Meat 1.5x10-3 mg/kg 6.3x10-6

Milk 4.7x10-4 mg/kg 3.7x10-6

Air 6.2x10-7 mg/m3 6.8x10-7


Regional Wet fish 3.1x10-5 mg/kg 5.1x10-8

Root tissue of plants 6.5x10-3 mg/kg 3.6x10-5

Leaves of plants 3.4x10-4 mg/kg 5.8x10-6


Meat 1.4x10-3 mg/kg 6.0x10-6

Milk 4.4x10-4 mg/kg 3.5x10-6

Air 5.5x10-7 mg/m3 6.0x10-7


Note: a) Production no longer occurs in the EU.

4.1.1.4.1 Discussions on the model

There is considerable uncertainty inherent in the approach taken by EUSES (and the Technical Guidance Document) - E.C., 1996 and E.C., 2003.

First, in the indirect exposure assessed at the local scale, all food products are derived from the vicinity of one point source. In reality, people do not consume 100% of their food products from the immediate vicinity of a point source. Therefore, the local assessment represents a situation which does not exist in reality. Besides, for each food product, the

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highest country-averaged consumption rate from the Member States is used. Therefore, the total food basket is unrealistic.Secondly, there is also a high uncertainty in estimating the concentrations of substances with high log Kow values in various parts of the food chain. For instance, the concentrations in drinking water are high, frequently close to or above the water solubility of the substance, and are sometimes higher than the concentrations predicted/found in surface waters. The reason for this is that within EUSES the drinking water concentrations are related to the soil pore water concentrations. For poorly soluble substances like decabromodiphenyl ether, very high concentrations in soil are predicted due to application of sewage sludge containing the substance. This then leads to high values for the estimated soil pore water concentrations (and hence drinking water concentrations), which in turn leads to very high concentrations in plant roots, and hence other parts of the food chain e.g. leaves, meat and milk.The partition coefficients for the various parts of the food chain depend crucially on the log Kow value of the substance (for decabromodiphenyl ether only a measured fish bioconcentration value was available, all other partition coefficients were estimated from log Kow), but it is not known if the assumptions/methods used in EUSES are valid for substances with very high log Kow values. This may be a particular problem for decabromodiphenyl ether since the available bioconcentration and uptake data indicate that the actual uptake by freshwater aquatic organisms is very much less than would be predicted from the log Kow value.The predicted daily human intake figures for decabromodiphenyl ether are 220 µg/kg bw/day for production, 0.26 µg/kg bw/day for polymer and rubber processing, 2 µg/kg for textiles (combined formulation/application), 0.04 µg/kg for polymers recycling of electronic equipment and 0.05 µg/kg at the regional level. It should be reminded that production of DBDPE in the EU has now ceased. Therefore, calculations for the production site is only for information. The second highest intake (combined formulation and application in textiles), is still 100 fold lower than intake through exposure to the generic production site.In all cases, uptake from root crops is predicted to account for the vast majority (≥90%) of the daily dose.

4.1.1.4.2 Exposure routes to DBDPE

There could be a high uncertainty on the fate and behaviour of decabromodiphenyl ether through trophic chains. For example, the actual uptake by terrestrial and marine mammals could be significant but seems to occur if the organisms are exposed to decabromodiphenyl ether in a form that optimises uptake. Then, a possible metabolisation of decabromodiphenyl ether to form lower brominated diphenyl ether congeners is still not certain.

Exposure due to uptake of contaminated water

As mentioned above, there are considerable uncertainties in the predictions of the water concentrations, particularly regarding the soil pore water concentrations and whether decabromodiphenyl ether in soil pore water is actually taken up by plant roots.

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If it is assumed that the maximum soil pore water concentration is 0.1 µg/L (i.e. the upper limit for the water solubility of decabromodiphenyl ether), then the resulting maximum concentration in plant roots can be estimated using the following equation:

CrootK C

RHOplantplant water porewater

plant

where Crootplant = concentration in root tissueKplant-water = partition coefficient between plant tissue and water = 9,050 m3/m3 for a log Kow value of 6.27.RHOplant = bulk density of plant tissue = 700 kg/m3

Cporewater = concentration in soil pore water

Using a soil pore water concentration of 0.1 mg/m3 (i.e. 0.1 µg/L), the resulting concentration in plant roots is 1.29 mg/kg. This results in a daily human intake of 7 µg/kg bw/day, assuming an adult body weight of 70 kg and a daily consumption of 0.384 kg of root crops. This figure is the maximum possible intake from this source as it is based on the soil pore water being saturated with decabromodiphenyl ether, and assuming that the uptake from water can be estimated based on the log Kow value.Calculations using EUSES with the same release estimates as used for Table 4.1.1.4A, but where the soil pore water and drinking water concentrations are set to a maximum value of 0.1 µg/L, indicate that the maximum total daily human dose from all sources is around 12 µg/kg bw/day for production, 0.26 µg/kg bw/day for polymer processing, 1.06 µg/kg bw/day for textile (compounding), 1.06 µg/kg bw/day for textile (application), 0.044 µg/kg bw/day for recycling of electronic equipment, and 0.05 µg/kg bw/day at a regional level. Again, the majority of the dose is predicted to come from root crops. Details of predicted concentrations and estimated daily doses for the generic production site are exposed in Table 4.1.1.4.2A (only the generic local production scenario has been recalculated as the calculations for the other scenarios remain the same):

Table 4.1.1.4.2A: Estimated daily human intake for exposure of man via environmental routes for the generic production scenario (considering a maximum soil pore water concentration of 0.1 µg/L)


Local - Production (generic)a Wet fish 6.810-3 mg/kg 1.110-5

Considering maximum soil pore Root tissue of plants 1.29 mg/kg 7.110-3

water concentration of 0.1 µg/l Leaves of plants 1.0610-3 mg/kg 1.810-5


Meat 0.74 mg/kg 3.210-3

Milk 0.23 mg/kg 1.910-3

Air 1.710-6 mg/m3 1.910-6

Total local daily dose 0.012

Some of the other estimated concentrations in food are also sensitive (indirectly) to the soil pore water concentration (i.e. the concentration in plant roots affects the estimated concentration in plant leaves and hence the concentration in meat and so the concentration in milk) but the interrelation between the various media is complex.

Exposure due to ingestion of fish

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In most studies from the 80’s and the 90’s dealing with PBDE in biota, decabromodiphenyl ether was hardly ever found in fish and invertebrates collected in EU freshwater and marine samples. In more recent studies, an increasing incidence of decabromodiphenyl ether was found but this could be partly explained by the increased efficiency of the analytical methods.In these studies, decabromodiphenyl ether could be detected at the highest in half of the samples with highest concentrations around 37 µg/kg lipid (muscle samples from breams collected from the river Elbe, Germany), Lepom et al., 2002 and 480 µg/kg lipid (samples from blue mussels collected along the Dutch coast and depurated for 24 hours), Booij et al., 2000. The highest measured concentration in whole fish was detected in eels collected from the Scheldt basin : 0.6 µg/kg wet weight (de Boer et al., 2002a). This measured concentration is 10% the predicted concentration in wet fish in the local production scenario (generic) : 6.8 µg/kg wet weight. Although it could not be assumed that the measured concentration in eels is representative of a local scenario, the Scheldt basin is known to be polluted. Therefore, the results could be considered as characteristic of a polluted area. Then, the figures in Table 4.1.1.4A are likely to overestimate the actual daily human intake via fish ingestion and could be considered as a precautionary approach.Levels of PBDPE were investigated in Polar Bear samples in recent studies (SFT, 2004a and 2004b; Skaare and Jensen, 2004, see updated information part of point 3.1.4.2.2. Levels in terrestrial biota in the update of the environmental risk assessment). Decabromodiphenyl ether was found to be present at low but detectable concentrations in all of the samples (detection limit was 0.02 µg/kg wet weight). The actual source of exposure of these mammals is unknown but most probable routes include exposure through the air and through food (fish diet for polar bears).Fish were identified has containing the highest overall PBDE levels in a study by Schecter et al., in press. DBDPE was detected has the major PBDE congener, accounting for slightly 50% of all PBDEs, in the catfish (freshwater) fillet particularly. A concentration of 1,27 µg/kg wet weight was determined (lipid percent = 11.1).

Exposure due to ingestion of meat and milk

Decabromodiphenyl ether has been recently found quite widely in a variety of predatory birds tissues in UK. The proportion of predatory birds contaminated with decabromodiphenyl ether has increased for the last two decades but although levels found are clearly higher than 20 years ago no progressive time trend is observed. The highest median concentration was found in the Peregrine Falcon eggs (2 – 5 µg/kg wet weight), Herzke et al., 2003. In a recent study, decabromodiphenyl ether was also found in Lynx samples up to 4 µg/kg lipid, Mariussen et al., 2004.These measured concentrations are still negligible in comparison with the predicted concentration in meat derived by EUSES calculation for the generic production scenario : 740 µg/kg wet weight. Although both results are not comparable as the measured concentrations are referring to remote areas whereas the predicted concentrations are calculated at a local scale, it should be reminded that the human diet is prepared from various sources of food. Therefore, the EUSES calculations could still be considered as worst case situation.Then, it appears that terrestrial predators could be affected and contamination of the whole trophic chain (until Human) should not be excluded. Possible routes of exposure include exposure through food, through water and inhalation (including absorption of particulates).Several meat products coming from US supermarkets were also analysed for PBDEs (Schecter et al., in press). DBDPE was particularly found in ground turkey, duck, calf liver, chicken breast, pork sausage and bacon at concentrations of 240, 110, 80, 60, 60 and 30 ng/kg

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wet weight, respectively (visual determination from graph ; lipid percents were respectively 11.1, 75.1, 6.4, 4.9, 23.7 and 35.3%). In the same study, cheese and a soy formula were also tested and DBDPE was measured respectively at 480 and 15 ng/kg wet weight (lipid percents = 39.2 and 3.2).

Exposure due to inhalation

The maximum exposure concentration predicted in EUSES calculation is 5.9 ng/m3. This concentration is lower than the indoor air concentrations measured at a plant for recycling electronic equipment (12 to 200 ng/m3) but higher than occupational exposure measured in other facilities and offices (< 0.32 ng/m3), Sjödin et al., 2001a. Besides, a recent study demonstrated that abrasion of particles from polyurethane foam or textile backcoatings could be an important source of PBDE in dust samples, Knoth et al., 2003. Therefore, products in use are an emission source for indoor exposure and can explain in some extent the widespread presence of PDBE in the environment.

Levels in humans

In recent studies (see section 3.1.4.2.3), decabromodiphenyl ether was found in blood / blood serum samples at a median concentration of 82.9 µg/kg lipid and a maximum concentration of 241 µg/kg lipid in a monitoring study by WWF (WWF, 2003). However, there are some uncertainties about the volunteers recruited for the study. Any occupational exposure could not be excluded (see point 4.1.2.1.1. Levels in humans).Besides, decabromodiphenyl ether was also found in 30% samples of mother’s milk from Dallas in 2002 (Schecter et al., 2003) (see section 3.1.4.2.3 and 4.1.1.5.1). The estimated concentration in cows’ milk using EUSES model is 240 µg/kg for the local scenarios (worst case) and 0.44 µg/kg at the regional level. These estimated concentrations are much higher than that found in mothers breast. Although routes of exposure are quite different for Humans and cows and could hardly be compared, based on the regional levels in milk that could be estimated by EUSES model it can be concluded that total daily intake by Humans is not underestimated and would therefore represent a worst case situation.

4.1.1.5 Exposure to infants via milk

As DBDPE has been detected in milk, it seems appropriate to determine the levels of DBDPE in infants due to the absorption of milk (breast milk and cows’ milk). Exposure to infants via milk will be estimated based on the local and regional sources of exposure and/or based on measured data.

4.1.1.5.1 Exposure to infants via human breast milk

A summary of breast milk data is given in the Health part of the risk assessment report for DBDPE (see part on breast milk excretion).

Estimation of the average daily uptake for infants via breast milk

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In order to estimate the average daily uptake of DBDPE for infants via breast milk, a scenario similar to the one described in the risk assessment of pentaBDE is used (E.C., 2001). The different hypothesis developed in this report are shown hereafter (any deviation from the pentaBDE report to take into consideration specific data on DBDPE are indicated with *).

For this evaluation, it is assumed that an infant breast feeds for a year1, and that this year of life is subdivided into two periods (0 to 3 months and 3 to 12 months), reflecting the changing feeding demands of the infant. It is assumed that over the first 3 months the infant has an average weight of 6 kg and that he ingests 0.8 kg of milk per day, that 1002* % of the ingested DBDPE is absorbed and that the breast milk has a fat content of 3.5%. From 3 to 12 months, it is assumed that the infant has an average weight of 10 kg and that he ingests 0.5 kg of milk per day, that 100* % of the ingested DBDPE is absorbed and that the breast milk has a fat content of 3.5%. It is also assumed that the content of DBDPE remains constant during the breast-feeding period.

The average daily uptakes (ADUinfant) are calculated using the following equations:

Where:Cmilk-fat the concentration of DBDPE in mg/kg of fat in the breast milk (as a worst case,

the highest level of DBDPE measured in mothers’ milk (8.24 µg/kg of fat) will be used in the infant exposure estimation.

f3 the fraction of fat in the breast milk (0.035)f4 the fraction of the ingested DBDPE absorbed (1)IRmilk the ingestion rate of milk by the infant (kg/d)BWinfant the average infant body weight over the exposure period (kg)Calculations of average daily uptakes for the different periods defined are given hereafter:

- 0-3 months:

- 3-12 months:

Weighted average for first 12 months:

4.1.1.5.2 Exposure to infants via cows’ milk

The estimates for the concentrations of DBDPE in cows’ milk obtained using EUSES model are presented in Table 4.1.1.4B. They are between 0.44 µg/kg and 240 µg/kg for the regional and the worst hypothetical local scenarios (generic production site) respectively. The latter is far above the concentrations measured in human breast milk whereas the concentration estimated for the regional scenario is quite similar.1 World Health Organisation recommends breastfeeding a baby until it is at least two years old. WHO supports breastfeeding exclusively for six months and then supplementing breast milk with other forms of food for two years or longer (WHO/UNICEF, 1990). Mean breastfeeding duration for study samples can be found in literature. For example, 6.02-6.85 months in Hungary (Nagy et al., 2001), 7.9 months in Denmark (Vestermark et al., 1991cited in Nagy et al., 2001), 11.8 months in Latin America (Perez-Escamilla, 1994 cited in Nagy et al., 2001).2 For the human exposure an absorption figure of 26% is taken into account by default. However, this value should not be used for exposure scenarios where decaBDE is already on a bioavailable form as it is the case in breast milk. In this scenario a default assumption of 100% absorption will be used.

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4.1.1.6 Combined exposure

The estimated maximum human intake from environmental sources is estimated to be in the range 0.05 - 12 µg/kg bw/day from local and regional sources.The maximum occupational exposure (inhalation and dermal routes) is predicted to be 0.94 mg/kg/day.

The consumer exposure to DBDPE is planned to be reviewed in a further update

At the moment, the maximum combined exposure from these sources is consequently0.94 mg/kg/day for both local and regional scenarios. Contribution of the exposure via the environment could be considered as negligible in comparison to an occupational exposure.

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4.1.2 Effects assessment: Hazard identification and dose (concentration)-response (effect) assessment:

4.1.2.1 Toxicokinetics, metabolism and distribution:

Updated information:

Recent work by Mörck et al. (2003) and Sandholm et al. (2003) have shown that the potential for uptake of decabromodiphenyl ether by mammalian systems may be higher than indicated by many of the previous laboratory studies. The study investigated the use of several different solvents in order to maximise the solubility of decabromodiphenyl ether in the test vehicle used to dose the rats. In vitro dermal absorption data are available on decabromodiphenyl ether (Hughes et al., 2001) showing a low in-vitro dermal absorption (around 2-20%).

4.1.2.1.1 Summary and discussion

Oral absorption, distribution, excretion and metabolism

Klasson Wehler et al., 2001 and Mörck and Klasson Wehler, 2001 studies were initially included and discussed in the previous human health risk assessment report. Recent publications by Mörck et al. (2003a and b) give additional information.

This study was designed to identify the metabolites of decabromodiphenyl ether and the absorption of decabromodiphenyl ether in the study was maximised by careful choice of test vehicle (the study investigated the use of several different solvents in order to maximise the solubility of decabromodiphenyl ether in the test vehicle used to dose the rats). The substance used in the study was synthesised by a multi-step process involving the bromination of 14C-labelled phenol to give 14C-labelled 2,4-dibromophenol, reaction of the 14C-2,4-dibromophenol with 2,2’4,4’-tetrabromodiphenyliodonium salt to give 14C-2,2’4,4’-tetrabromodiphenyl ether (this was diluted with unlabelled tetrabromodiphenyl ether), followed by further bromination to give 14C-decabromodiphenyl ether. The product was isolated by thin layer chromatography and had a purity of >98%. Before use, the 14C-decabromodiphenyl ether was diluted with unlabelled decabromodiphenyl ether (the unlabelled product was synthesised using a similar method to the radiolabelled product) to a specific activity of 15 Ci/mol.

Three potential dosing vehicles were investigated. These were dimethyl sulphoxide:peanut oil (50:50 mixture), anisole/peanut oil (30:70 mixture) and a solution of soya phospholipone:Lutrol (16:34 w/w) in water (concentration 0.11 g/l). The soya phospholipone/Lutrol/water mixture was found to be the most suitable (the solubility of decabromodiphenyl ether in this mixture was determined to be 7 g/l, compared to 3.8 g/l in the anisole/peanut oil mixture and 2.5 g/l in the dimethyl sulphoxide/peanut oil mixture).

In the experiment, eight male Harlan Sprague-Dawley rats were given a single oral dose of the 14C-labelled decabromodiphenyl ether solution by gavage (total dose 3 mol/kg (2.9

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mg/kg), 15 Curie/mol) and urine and faeces were collected at 24-hour intervals for three days (urine) or 7 days (faeces). Four rats were sacrificed after 3 days and the remaining four rats after 7 days (conventional rats). In addition various tissues and organs (liver, adipose tissue, lung, kidney, adrenals, skin, muscle, spleen, testis, thymus, heart, plasma, colon wall and contents, small intestine contents and small intestine wall) were analysed for the presence of 14C. Experiments were also carried out with two bile duct cannulated rats and bile was collected from these rats after 4, 12, 24, 48 and 72 hours.

The major route of excretion was found to be via faeces. Around 90% of the initial dose of 14C was found to be excreted within three days of dosing, with only a small additional amount being excreted by day seven (around 91% was excreted by day seven). The experiments with bile duct cannulated rats showed a similar excretion via the faeces (88% within three days), with 9.5% of the dose recovered in bile within 3 days. The report indicates that the results for the two bile duct cannulated rats showed a large variation and it was thought that this may have been due to the fact that no bile salts were added to compensate for the collected bile, and that this may have affected the absorption of the test substance. Excretion via the urine was very small (<0.1% of the dose) in all groups.

This is in agreement with excretion data on PBDEs and their metabolites which are rapidly excreted, primarily in faeces. The route of excretion is secretion from the liver into the bile and subsequent excretion via faeces. Moreover given the high molecular weight of decabromodiphenyl ether > 350 g/mol primarily excretion in bile was expected as well as a limited urinary elimination (Rowland and Tozer, 1980).

The amount of radioactivity remaining in the body at three and seven days after dosing was estimated to be around 9% (this was estimated by totalling the amount of 14C collected in urine and faeces and substracting from 100% and was not measured directly). The highest levels of radioactivity on a wet weight basis were found to be present in adrenals, kidney, heart and liver after both 3 and 7 days. When the results were considered on a lipid weight basis, plasma and liver were found to contain the highest concentrations. The concentration of radioactivity in other tissues, including adipose tissue, was found to be low.

Detailed analytical work was carried out in order to try to identify any metabolites present in faeces, bile and tissues. In the faeces, the fraction of the radioactivity present as parent compound was found to decrease over the three day sampling period, whereas the radioactivity in the lipid-bound fraction was found to increase. Amongst other metabolites, phenolic compounds were found to be present with between five to seven bromine atoms/molecule, and a small amount (corresponding to <0.5% of the initial dose) of three nonabrominated diphenyl ethers was also found to be present in the faeces (these substances were not present in the decabromodiphenyl ether administered to the rats). 65% of the dose excreted in faeces represented metabolised decabromodiphenyl ether (Mörck et al., 2003b).

The radioactivity present in the bile was found to be dominated by lipid-bound metabolites over the first 24 hours but, by day two and three, water-soluble metabolites were also found to be present. Parent compound and traces of three nonabrominated diphenyl ethers were also present. Eight phenolic compounds were found and appeared to be the same as those found in faeces.

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Evidence for the presence of parent compound, lipid-bound metabolites, phenolic metabolites and nonabrominated diphenyl ethers was also found in tissues (liver, lung, kidney, adipose tissue and small intestine wall).

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Fig 4.1.2.1.1A: Fecal and biliary metabolites formed and identified by mass spectrometryfollowing dose of decabromodiphenyl ether in the rat (quoted in Hakk and Letcher, 2003).

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Overall it was concluded that at least 10% (9.5 %) of the initial oral dose in the experiment had been adsorbed (based on the excretion seen via bile). The authors assumed that the actual absorption could be higher than this. Since 65% of the dose excreted in faeces was as metabolites and 10% of the dose excreted in faeces (almost all of which represented by metabolites), came from the bile, approximately 55% of the dose was excreted as faecal metabolites arising from non-biliary sources (Mörck et al. 2003a). The authors suggest that active transport proteins may have been involved such as P-Glycoprotein. An alternative explanation could be first pass metabolism by CYP 450 enzymes in the intestine wall (Mörck et al. 2003b). However, this latter hypothesis is not supported by the following observations: one of the used formulating agent, PEG 400 has been shown to inhibit the drug efflux transporter, p-glycoprotein as well as cytochrome P-450 activity in intestinal cells in vitro. Thus a likely hypothesis is that “faecal” metabolites were initially formed in the liver and then either be excreted into the gut lumen or absorbed into the circulation and then be observed as metabolites in faeces.

It was also concluded that distribution of decabromodiphenyl ether to adipose tissue did not occur to any great extent. The highest concentrations of decabromodiphenyl ether were generally found in the plasma- and blood-rich tissues.

Sandholm (2003a) and Sandholm et al. (2003b) investigated further the bioavailability and half-life of decabromodiphenyl ether in blood of rats. The study used recrystallised unlabelled decabromodiphenyl ether (>98% purity). The dose used in the study was prepared by dissolving 4.5 g/l of the test substance in dimethylamide and mixing the solution with an equal volume polyethylene glycol (PEG 400). Water was then added dropwise to give a final solvent composition of 4:4:1 v/v/v of dimethylamide:polyethylene glycol:water and a final decabromodiphenyl ether concentration of 2 mol/ml (1.92 g/l).

In the pharmacokinetic study, 18 male Sprague-Dawley rats (200-220 g) were given a single oral dose (2 mol/kg, 1.92 mg/kg) of the decabromodiphenyl ether solution by gavage. In addition 18 male rats were dosed at a similar level by intravenous injection in the tail vein. Blood samples were collected at 1, 3, 6, 24, 48, 72, 96, 120 and 144 hours after administering the doses.

In the metabolism study, the metabolites present in the plasma were determined. For quantitative analysis, unchanged compound (decabromodiphenyl ether) and neutral metabolites were separated and analysed. For qualitative analysis in the phenolic fraction, all samples 1-144 h were pooled for each administration method (oral and I.V.) In addition, plasma samples (collected on days three and seven after administration of 14C-labelled decabromodiphenyl ether at 3 mol/kg (2.9 mg/kg)) from the animals used in the Mörck et al. (2003a and b) metabolism study were used for qualitative analysis (parent compound, phenolic and neutral fractions).

The oral bio-availability (defined as the fraction of the administered parent compound reaching systemic circulation) was determined to be 26% and the maximum plasma concentration after oral dosing was found to be 264 pmol/ml (~253 ng/ml) and occurred 6 hours after dosing (the actual bioavailability could be higher than this as a 5-fold higher concentration of metabolites was present in the plasma relative to decabromodiphenyl ether itself (KEMI, pers. com). The terminal (elimination) half-life from the plasma was determined

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to be around 2.5 days (51 hours) for both administration. The total plasma clearance (CL) was 0.6 ml/min*kg and the apparent volume of distribution at steady-state (Vss) was 1.3 L/kg.

Similar metabolic profiles were obtained from both the animals dosed by gavage and those dosed intravenously. The pooled neutral fraction was dominated by unchanged decabromodiphenyl ether, but traces of three nonabromodiphenyl ethers (<0.5% of the total peak area) were also found. The pooled phenolic fraction was found to contain at least thirteen metabolites containing bromine, but only three were present in high enough concentration to allow tentative identification. Monohydroxylated nonabromodiphenyl ether and monohydroxylated octabromodiphenyl ether were found to be present. The third metabolite was not unambiguously identified.

Analysis of the plasma samples from the Mörck et al. (2003) metabolism study showed that the level of radioactivity present in the phenolic fraction was around 4 times higher than in the neutral fraction at both days 3 and days 7. The neutral fraction was again found to contain mainly unchanged decabromodiphenyl ether, along with traces (<0.5% of the total peak area) of three nonabromodiphenyl ethers. However, it was not possible to determine the nature of the metabolites in the phenolic fraction.

Overall, the metabolic pathway indicated several types of metabolites, e.g. phenolic, neutral, non-extractable, water-soluble and lipid-bound metabolites. No glutathione metabolites are observed. Decabromodiphenyl ether is not distributed to adipose tissue. The terminal (elimination) half-life from the plasma was determined to be around 2.5 days. The authors speculated that a possible explanation for the high concentrations of metabolites relative to the parent compound found in plasma at day three could be as a result of reversible binding of the metabolites to the thyroxine hormone transporting protein transthyretin. The results also showed that around 26% of the administered dose was bioavailable and, since the total concentrations of radioactivity in plasma were generally higher than the concentration of the parent compound, the actual overall absorption was likely to be higher than indicated by this figure. Twenty-six percent of oral absorption may be considered in the risk assessment part.

Following a single oral dose of decabromodiphenyl ether (purity not given), urinary and biliary excretion were quantified in Hakk et al., 2000 study as well as the nature and extent of binding to any proteins in the excreta.

In the experiment, four male Sprague-Dawley rats were given a single oral dose of the 14C-labelled decabromodiphenyl ether solution by gavage (0.3 mg/kg) in peanut oil (conventional rats) and urine and bile were collected at 24-hour intervals for three days. In addition, tissues and organs (liver, lung, kidney, intestinal mucosal cells) were analysed for the presence of 14C. Experiments were also carried out with four bile duct cannulated rats and bile was collected from these rats after 24, 48 and 72 hours.

Daily urinary excretion of decabromodiphenyl ether was extremely low (< 0.02% of the administered dose). The major route of excretion was found to be via the bile. Six percent of the dose was eliminated in bile in 24 hours and cumulative excretion (0-74 h) was around 9%.

The nature and extent of binding to any proteins were characterised in bile and urine. In the bile, essentially all of the detectable 14C was protein bound (> 97%) with predominant binding to a 79 kDa bile protein. In urine, the majority of detectable 14C remained unbound in

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the conventional rats whereas in cannulated rats, a majority was bound to an urinary protein (albumin).

The tissue disposition of decabromodiphenyl ether showed the highest levels of radioactivity in the liver of conventional rats (8.5%, data not shown) and in a lesser extent in lung (> 2%). Intestinal cells and kidney were minor deposition sites for decabromodiphenyl ether.

A further study from Hakk et al., 2002, designed to quantify urinary and biliary excretion as well as the nature and extent of binding to any proteins in the excreta, was conducted at a higher dose of 14C-labelled decabromodiphenyl ether (3 mol/kg (2.9 mg/kg) - purity > 98%) compared to Hakk et al., 2000 with administration of decabromodiphenyl ether in solution with Lutrol F127, soya phospholipid and water.

The substance used in the study was synthesised from [UL-14C and 12C] 2,2’4,4’-tetrabromodiphenyl ether via direct bromination with a large excess of bromine in tetrachloromethane. The product was purified by thin layer chromatography and had a purity of >98%. The specific activity was 15 mCi/mmol.

In the experiment, a single oral dose of the 14C-labelled decabromodiphenyl ether solution (2.9 mg/kg) was administered to four male conventional rats and four bile duct-cannulated rats. Urine and bile were collected at 24-hour intervals for three days. In addition, liver, lung, kidney, intestinal mucosal cells were analysed for the presence of 14C.

Biliary and urinary excretion rates were in the same order as Hakk et al., 2000 with ≤ 0.02% daily urinary excretion and 6% (at 24 hours) and 9% (0-74 h) biliary excretion values.

As in Hakk et al., 2000, the majority of detectable 14C (73.4% of 0-72 h urine) remained unbound in the conventional rats urine whereas in cannulated rats, a majority (68.3% of 0-72 h urine) was bound to an urinary protein. The urinary protein associated with decabromodiphenyl ether-derived 14C was a 66.2 kDa protein. In the bound fraction of conventional urine, two polar metabolites (not characterised) were detected but no parent compound was detected. In the unbound fraction of urine, highly polar metabolites were detected.

In the bile, essentially all of the detectable 14C was protein bound (> 97%) with predominant binding to a 79 kDa bile protein. Approximately 17% of the extractable 14C, protein bound fraction, from 0-24 h bile was parent compound and the remainder was metabolites (not characterised). No parent compound was detected in this fraction at 48 and 72 h.

14C-labelled decabromodiphenyl ether from each sampled tissue was associated in majority with the membrane fraction compared to the microsomal fraction (0-29%) and the soluble fraction (4-24%). It was shown that in the soluble fraction of livers, detectable 14C was bound to a 14 kDa protein which was characterised as a liver fatty acid-binding protein by the FABP assay.

In summary

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The majority of a single, oral dose of 14C-labelled decabromodiphenyl ether administered to male rats either in soya phospholipid-Lutrol F127 (Mörck et al. (2003a and b) or in peanut oil vehicle (Hakk et al., 2000) was excreted in the faeces (> 90%) and less than 0.05% in the urine at 3 days. 65% of the decabromodiphenyl ether dose excreted in faeces was excreted as metabolites (Mörck et al. (2003a and b)). In bile duct-cannulated rats, around 9% of the dose was excreted in the bile within 3 days (Mörck et al. (2003a and b) and Hakk et al., (2000 and 2002)).

Decabromodiphenyl ether-derived 14C excreted in bile was essentially bound to a bile protein, with a predominant binding to a 79 kDa bile protein. Decabromodiphenyl ether-derived 14C was characterised essentially as metabolites in urine (Hakk et al., 2002) and bile (Hakk et al., 2000). The protein associated with decabromodiphenyl ether-derived 14C in urine was identified as albumin (Hakk et al., 2000). In sampled tissue, 14C-labelled decabromodiphenyl ether was associated in majority with the membrane fraction compared to the microsomal fraction andsuggested to be bound to fatty acid binding protein in the liver soluble fraction (Hakk et al., 2002).

Parent compound, non-extractable metabolites, protein or lipid-bound metabolites, mono-hydroxylated metabolites (including nona and octabromodiphenyl ethers), phenolic metabolites with 5 to 7 bromine atoms possessing a guaiacol-structure (a hydroxy- and methoxy-group in one of the rings) and traces of nonabrominated diphenyl ethers were found in plasma, bile/faeces or tissues. In addition, water-solubility was suggested. Decabromodiphenyl ether is not so rapidly excreted. The terminal (elimination) half-life from the plasma was determined to be around 2.5 days. The total plasma clearance (CL) was 0.6 ml/min*kg and the apparent volume of distribution at steady-state (Vss) was 1.3 L/kg. In Sandholm (2003a) and Sandholm et al. (2003b), the oral bioavailability was determined to be 26%. According to the authors, the actual bioavailability might be higher than this. The highest concentrations on a lipid weight basis were found in plasma and blood rich tissues whereas decabromodiphenyl ether is not distributed to adipose tissue in any great extent. Twenty-six percent of oral absorption may be considered in the risk assessment part.

Percutaneous absorption

Skin from the adult hairless female mouse (SKH1) was mounted in flow-through diffusion cells. 14C decabromodiphenyl ether (radiochemical purity > 99%) was applied at three dose levels (6, 30 and 60 nmol) in tetrahydrofuran (THF) vehicle. Twenty-four hour after application, the skin was washed with THF to remove unabsorbed chemical. The skin wash, the skin and the receptor fluid were analysed for chemical-derived radioactivity. The skin from the high dose group was analysed for parent compound and metabolites by HPLC.

The 24-h cumulative percent of the dose of decabromodiphenyl ether in the receptor fluid was very low (0.07-0.34%). The applied dose of decabromodiphenyl ether detected in the skin ranged from 2 to 20% and was inversely proportional to the dose. The major portion of the applied dose was removed by washing the skin after 24 h after application of decabromodiphenyl ether, and ranged from 77% to 92%. While the 24-h cumulative percent of the dose absorbed decreased as applied dose increased, the mass of chemical absorbed increased. The metabolism of decabromodiphenyl ether in the skin appeared to be minimal. The major peak detected by HPLC analysis co-eluted with 14C -decabromodiphenyl ether. A minor peak was also detected. If the dose in the receptor fluid and skin is considered to be

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absorbed, then the absorbed dose of decabromodiphenyl ether was 20.5, 3.3 and 1.9 % of the dose for 6, 30 and 60 nmol decabromodiphenyl ether respectively.

Because of the trend of higher dermal absorption of chemicals in mouse skin at least in vitro, than either rat, pig or human skin, the authors considered that the amount of decabromodiphenyl ether that would be absorbed by human skin may have been overestimated. Moreover, dermal absorption was initially estimated to be around 1% based on its physico-chemical properties (high molecular weight (959) and log Kow ≥ 4) and analogy with PCBs.

Overall, given the physico-chemical properties of decabromodiphenyl ether (high molecular weight (959) and high log Kow ≥ 4), the probably overestimated in-vitro dermal absorption (2-20%), dermal absorption still can be considered around 1-2%.

Levels in humans:

In general population:

The levels of decabromodiphenyl ether present in twelve blood serum samples collected in 1988 from blood donors in the United States have been determined (Sjödin et al., 2001b). The analytical conditions were the same as (Sjödin et al., 2001a). Due to the relatively complex cleanup and analysis procedures, recovery experiments (n = 5) were made with serum samples (0.5 ng in 5 g serum) and showed an average recovery of 70% (SD = 5.4). The median and range of BDE-209 serum concentrations were evaluated as <1 and <1-35 pmol/g lipid weight (l.w.), respectively (<0.96 g/kg lipid to 33.6 g/kg lipid), with decabromodiphenyl ether being present above the detection limit in five out of the twelve samples.

A survey of the levels of decabromodiphenyl ether in blood samples from the general public has been carried out in the United Kingdom (WWF, 2003). In all 155 samples were collected from individuals in thirteen towns between March and July 2003. Both males (50) and females (105) were included in the sampling (approximate ratio 1:2 males:females) and the age range covered was between 22 and 80 (median 40.5 years). Although some of the volunteers sampled had some occupational exposure to chemicals, the vast majority had no specific chemical exposure. It should be noted that no question about potential occupational exposure were asked in the personal and lifestyle questionnaire, so detailed occupational exposure information are not available.

Decabromodiphenyl ether was found to be present in eleven (7%) of the samples at a concentration between 35.1 µg/kg lipid and 241 µg/kg lipid (the detection limit of the method was not stated). The values considered as positive are as follows : 35, 36, 37, 57, 71, 82, 86, 114, 151, 155 and 241 µg/kg. lipid. The median level found in the eleven positive samples was 82.9 µg/kg lipid. The eleven positive samples came from five different towns, with four coming from one town. It should be noted that values below the detection limit were

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excluded when calculating the minimum, median, and quartile values; this is of importance because the results of this study come from a very limited population (11 volunteers), from which too much should not be read (especially in term of extrapolation to the general population). The detection limit of the method was not stated clearly : “eleven samples are considered as positive of which 3 samples are considered close to the detection limits”; that means 35 µg/kg. lipids was close to the detection limit of the method.

The authors stated that the highest levels found in “non occupationally exposed” volunteers in UK were very similar to those of people occupationally exposed to decabromodiphenyl ether (workers in flame retarded rubber industry) in Swedish study (Jakobsson 2003). But it seems difficult to compare these two studies because the detection limit in the Swedish study is far lower (< 1.5 µg/kg. lipid) than that of the WWF study. If such a method with this low detection limit was applied to the WWF survey, the results of the median would have been quite different.

Even if the submitted study is one of the few available in Europe, some questions still exist, that could have biased the results of the study:

- the representativeness of the population studied compared with the general population is not assured because twice as many women as men are examined which could have biased the results (for example because of differences in blood lipid content or composition, which is important since decaBDE will most likely be associated with the blood lipids)

- the potential occupational exposure of the population is difficult to appreciate because no clear information about occupational exposure are available

- the method and quality control of analysis : - the use of water as analytical blank (non-contaminated medium) appears

inappropriate: even if it is a non-contaminated medium, water is an unrepresentative solvent in this case and not comparable to clean blood or serum) ; the use of “field blank” with the exact matrix utilised (blood in this case) would have been preferable (a pilot study was performed to determine the best sampling, analytical methods and media for this project; report of this study was asked but not available at the moment ;

- differences in the detection limits of the method make it difficult to compare results of the studies (i.e. inoccupational exposed subjects).

Other remarks on the study can be make and perhaps the results could be reviewed in this way: only 11/155 results have been considered to calculate the median value of the samples collected that means that the median value of 82.9 µg/kg lipid is only the median of the positive samples ; a new evaluation of the median level should be done considering all the 155 samples and in that case the median value would be under the detection limit value of the method.

A survey of the levels of decabromodiphenyl ether in blood serum samples from the general public has been carried out in 47 volunteers (citizens of European countries, living and working in Europe); this study is a continuation of the WWF 2003 survey. Both males and females were included in the sampling with 51% males (24) and 49% females (23) and the age range covered was 35 and 66 years with a median age of 52 years (WWF, 2004). The same questionnaire as the WWF 2003 study was used, without any question about occupational exposure (the fact that the volunteers were essentially Members of Parliament is not an assurance of an absence of previous or present occupational exposure).

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The same laboratory was in charge of the sample analysis, using the same methods of sampling, analysis and quality control than the WWF 2003 survey; the levels were expressed in terms of pg/g serum in this study (1 pg/g serum is equivalent to 0.13 µg/kg. lipid, unity used in the WWF 2003 survey).

Decabromodiphenyl ether was found to be present in sixteen (34%) of the samples with a highest value in one sample at 18,430 pg/g serum (equivalent to 2,400 ng/g. lipid)2. The median level found in the sixteen positive samples was 407 pg/g serum (equivalent to 53 µg/kg. lipid). The values considered as positive are as follows : 8 around the detection limit and 8 as follows :410, 420, 560, 750, 860, 2,100, 8,700, 18,000 pg/g. serum (53, 55, 73, 97, 111, 273, 1,300, 2,400 µg/kg. lipid).The 16 positive samples came from 11 countries, including UK (precise number of positive samples for each country is unknown). It should be noted that values below the detection limit were excluded when calculating the minimum, median, and quartile values ; this is of importance because the results of this study come from a limited population (16 volunteers) from which too much should not be read.The detection limit of the method was not stated clearly : 8 of the sixteen positive samples are considered “close to the detection limits”, that means that the detection limit of the method has to be considered around 230 pg/g. serum (equivalent to 30 µg/kg. lipids).The highest value (18,430 pg/g serum (equivalent to 2,400 ng/g. lipid) was approximately ten times higher than found in workers occupationally exposed to decabromodiphenyl ether and ten times higher than found in WWF 2003 survey ; three values in this study were higher or around that found in workers occupationally exposed to DecaBDPE (18,000 ; 8,700 and 2,100 pg/g serum, respectively equivalent to 2,400 ; 1,300 and 273 µg/kg. lipid).

The lifestyle questionnaires revealed that there is potential link between recent purchases of flame-retarded goods and elevated blood concentrations of Decabromodiphenyl ether .

As this survey is quite similar to the WWF 2003 survey, some of the limits or bias are the same. They concern :

- the potential occupational exposure of the population of the survey- the method, quality control of analysis, and the detection limit- the few samples used (16) to calculate the median of the survey and not the whole

data set- but also the median age of the population studied (which is quite high compared to

other studies).

The following table 4.1.2.1.1.A summarised the levels of decabromodiphenyl ether in human blood serum collected in a general population (WWF, 2003 and 2004 studies and in Sjödin et al., 2001b) in Swedish workers (Jakobsson et al., 2003).

Table 4.1.2.1.1.A: Summary of levels of decabromodiphenyl ether in human blood serum collected in a general population (WWF 2003 and 2004 and Sjödin et al., 2001b) and in Swedish workers (Jakobsson et al., 2003).

Survey Concentration in µg/kg.lipid

2 The equivalence of pg decaBDE/g serum to g decaBDE/kg lipid is given in the WWF 2004 survey ; it is said that ten times the highest level (that is 240 n/g lipid) of the WWF 2003 survey is equivalent to the highest wwF 2004 level (18430 pg/g serum) ; that means 2400 ng/g lipid is equivalent to 18430 pg/g serum (1 ng/g lipid X 7,68 (conversion factor) = 9g/g serum)

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Total serum samples

Serum samples considered as positive

Median Maximum Minimum

WWF 2003

(general public in UK)

155105 females / 50 males)

(median age : 40.5 years)

11 (7%) 83 (of the positive samples)

241 35(limit of detection around 35)

WWF 2004

(general public in Europe, 17 countries included UK)

47(23 females /24 males)

(median age : 52 years)

16 (34%) 53 (of the positive samples)

2,400(3 values > 270)

30(limit of detection around 30)

Sjödin et al., 2001b(US blood donors)

12 (gender unknown)

5 (42%) < 0.96 33.6 <0.96(limit of detection around 1)

Jakobsson 2003

(occupational exposure in rubber industry)

7 males (rubber mixers)

28 144 1.2(limit of detection around 1)

12 males (rubber wire producers)

35 278 6.7(limit of detection around 1)

In worker population:

The concentration of decabromodiphenyl ether in blood serum from 19 computer technicians in Sweden has been determined to be in the range <1-7.1 pmol/g lipid (<0.96-6.8 µg/kg lipid). The median level in the nine samples in which decabromodiphenyl ether was above the detection limit of the method used was 1.6 pmol/g lipid (1.5 g/kg lipid). The sampling was carried out during 1999 (Hagmar et al., 2000; Jakobsson et al., 2002). The analytical conditions were the same as that reported by Sjödin et al., 2001a. In this study (Jakobsson et al., 2002), the levels of several polybrominated diphenyl ethers (one of the HexaBDE, HeptaBDE and octa-BDE) were positively correlated with the duration of computer work among technicians. On a group level, an exposure gradient was observed from the least exposed cleaners to the clerks, and to the highest exposed group of computer technicians. A dose (duration of computer work)-response relationship among computer technicians was demonstrated for some higher brominated PBDE congeners. The computer technicians had serum concentrations of BDE-153, BDE-183 and BDE-209 (n = 9; median 1.6 pmol/g l.w., range not detected to 7.1 pmol/g l.w.) that were around five times higher than those previously reported (Sjödin et al., 1999) among hospital cleaners (n = 20; max. 3.9 pmol/g l.w.) and computer clerks (n = 20; max. 8 pmol/g l.w.). The authors concluded that PBDEs

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used in computers and electronics, including the fully brominated BDE-209, contaminate the work environment and accumulate in the workers tissues.

Jakobsson et al. (2003) have recently published a summary and analysis of their work on the levels of decabromodiphenyl ether in blood serum of Swedish workers. Analytical conditions were the same as previously described (cf. Sjödin et al., 2001a). The results are summarised in table 4.1.2.1.1B. The rubber (male only) workers, who were assumed to be exposed only to decabromodiphenyl ether, had markedly elevated levels of this compound. Eleven out of 19 workers had levels that exceeded the median in the reference group by a factor of 10 or more but a gender difference cannot be ruled out. The half-life of decabromodiphenyl ether in blood serum was estimated to be around 14 days based on samples from four employees at an electronics recycling plant and four employees at a rubber mixing plant taken both before and at various times during 4-5 week vacation.

Table 4.1.2.1.1B Summary of levels of decabromodiphenyl ether in blood serum Swedish workers (Jakobsson et al., 2003)

Study group Concentration of decabromodiphenyl ether

pmol/g lipid µg/kg lipid

Exposed Electronics dismantlers, 1997 (15 males and 4 females)

Median 5.0Range <0.3-9.9


Circuit board recyclers, 1998 (6 males and 3 females)

Median 2.4Range <1-5.8


Rubber mixers, 2000 (7 males) Median 29Range 1.3-150

Median 28.1Range 1.2-144

Rubber wire producers, 2000 (12 males) Median 36Range 7.0-290

Median 35Range 6.7-278

Computer technicians, 1999 (15 males and 4 females)

Median 1.6Range <1-7.1


Office clerks, 1997 (20 females) Median <0.7Range <0.7-8.0

Median <0.7Range <0.7-7.7

Unexposed Hospital cleaners, 1997 (20 females) Median <0.7Range <0.7-3.9

Median <0.7Range <0.7-3.7

Abattoir workers, 2000 (17 females) Median 2.5Range 0.96-9.7

Median 2.4Range 0.92-9.3

Overall, these two recent studies shown a concentration of decabromodiphenyl ether in blood serum of Swedish workers in the range of < 0.7g/kg lipid up to 278g/kg lipid in rubber wire producers.

Breast milk excretion :

Hori et al. (2002) carried out a study to investigate the levels of polybrominated diphenyl ethers in human mothers’ milk from Japan. As part of this study, some of the samples were screened for the presence of decabromodiphenyl ether using a GC-MS method. The samples were collected in 1999 and a peak corresponding to decabromodiphenyl ether was found in several samples. The actual levels found were not given but they were reported to be in the range from trace amounts to several µg/kg lipid.

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Schecter et al. (2003) determined the levels of polybrominated diphenyl ethers (including decabromodiphenyl ether) in samples of mothers’ milk from Austin (total of 24 individual samples) and Dallas (total of 23 individual samples), Texas. The samples were collected between August and December 2002 and the samples from Austin and Dallas were each sent to a different laboratory for analysis. Only the samples from Dallas were analysed for the presence of decabromodiphenyl ether using high-resolution gas chromatography/high resolution mass spectrometry (HRGC/HRMS). and the substance was found in seven of the 23 samples (the text in the paper indicates that decabromodiphenyl ether was found in only six samples, but seven positive findings are given in the results table in the paper) at a mean concentration of 0.92 µg/kg lipid (the range of concentrations found was 0.48-8.24 µg/kg lipid).

A further study of the levels of decabromodiphenyl ether in mothers’ milk has been carried out by Lunder and Sharp (2003) using high-resolution gas chromatography/high resolution mass spectrometry (HRGC/HRMS). In this study, samples of milk were collected from twenty mothers from various locations from fourteen states within the United States between November 2002 and June 2003. Decabromodiphenyl ether was found to be present in 80% of the samples analysed at a concentration of 0.08-1.23 µg/kg lipid. The median and mean value found was 0.15 and 0.24 µg/kg lipid.

Mazdai et al., 2003 carried out a study to investigate the levels of polybrominated diphenyl ethers (tetra up to octabromodiphenyl ether) in maternal and fetal serum. Their results indicate a high correlation between maternal and fetal blood levels of PBDPEs with approximately a same potential to cross the placenta for all tetra- through hepta-substituted congeners.

Summary: Decabromodiphenyl ether has also been found to be present in blood plasma of humans; both workers possibly occupationally exposed to decabromodiphenyl ether, and the general population (although it cannot currently be excluded that occupational exposure has contributed to the plasma levels in the general population). It has also been reported that decabromodiphenyl ether has been found in breast milk samples from Japan and the United States.

4.1.2.9 Toxicity for reproduction

4.1.2.9.1 Developmental Neurotoxicity:

Updated information:

Full details of the mouse developmental neurotoxicity study with decabromodiphenyl ether have now been published (Viberg et al., 2003). This study was designed to investigate spontaneous behaviour (SB) and habituation capability. Groups of neonatal NMRI mice were administered by gastric intubation a single dose of DecaBDPE (purity greater than 98% quoted in Eriksson and Viberg, 2002) sonicated in a 20 % (w:w) fat emulsion of lecithin/peanut oil and water (in order to give a more physiologically appropriate absorption and distribution). The mice used in the study were NMRI mice and pregnant mice were housed individually at 22oC, with a 12/12 hour light/dark cycle. The pregnant mice were fed a diet of standard pellet food and tap water ad libitum and were checked twice daily for births.

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The day of birth was designated as day 0 for the study. The litters were adjusted to 10-12 mice each and contained both male and female pups.

Three day-old and nineteen day-old mice were given 2.22 or 20.1 mg/kg b.wt. of DBDPO and ten days-old mice were given 1.34, 13.4 or 20.1 mg/kg b.wt. Male and female pups in the litter were dosed to ensure that the dam interacts with the pups in an identical fashion even though only the males were subject to neurobehiavioural testing. Control animals were administered the fat emulsion only (10 ml/kg bw). Each of the different treatment categories, in the different age categories, contained three to five litters. The litters contained pups of both sexes (10-12 mice) during the neonatal period. At the age of 4-5 weeks, the males were kept in their litters with their siblings and were raised in groups of 4-7 animals.

Spontaneous behaviour (SB) was tested in the male mice at the ages of 2, 4 and 6 months. The test measures:

- locomotion: horizontal movements, - rearing: vertical movements,- total activity: all types of vibrations within the test cage.

A total of 10 mice were “randomly” selected from 3-5 different litters in each treatment group.

Animals were tested over a 4 hour period (8 am to 12 noon). Motor activity was measured for a 60 minute period (the time was divided into 3 x 20 minute scoring periods) in an automated Rat-o-Matic device consisting of cages placed within two series of infrared beams. Although in Viberg et al., 2003, it is mentioned that animal selection was randomised, it is not clear if the same animals were tested at 2, 4 and 6 months or if two different test groups of animals were selected. In a personal communication with P. Erikkson (2004), further information was provided. The animals were not individually marked and some of them may have been tested at an earlier occasion; No specific randomisation procedures or random programs were used in this study.

During the studies no clinical signs of toxicity, no mortality or of body weight changes were observed in treated animals compared with concurrent controls. No significant difference in body weight gain or adult weight was observed between the treated and the vehicle control group in the three different age categories.

The group mean values, from the SB study, were presented in graphical form only. The spontaneous motor behaviour data states a disruption of habituation in adult mice exposed to DBDPO on postnatal day 3, but this disruption in habituation can not be seen in mice exposed to DBDPO on postnatal day 10 or 19. Habituation, defined here as a decrease in locomotion, rearing and total activity variables in response to the diminishing novelty of the test chamber over the 60 min test period, was demonstrated in the control groups of the three age categories as well as in the animals exposed to DBDPO on postnatal day 10 or 19. The animals exposed to the highest dose of DBDPO, on postnatal day 3, showed this non-habituating behavioural profile at 2, 4 and 6 months of age. At 6 months of age mice exposed to the lower dose of DBDPO, on post-natal day 3, showed this non-habituating behavioural profile.

During the first 20 minute scoring period the DecaBDPE treated animals at the highest dose were apparently less active compared to controls, and the difference in activity (decrease) between treated and control animals was dose-related while during the third 20 minute scoring period treated animals appeared to be more active than controls. Mice exposed to the lower

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dose of DBDPO, on post-natal day 3, showed at 2 month of age significantly lower activity during the first 20 minute period for the total activity, no significant differences in spontaneous behaviour at 4 month of age and significantly lower activity during the first 20 minute period for the rearing variable only at 6 month of age.

The results of the spontaneous behaviour study are summarised in table 4.1.2.10.5A.

Table 4.1.2.9A: Summary of effects seen on spontaneous behaviour in mice (Viberg et al., 2003)

Study group Endpointa

Administration day Dosage (mg/kg bw)

Observation time Locomotion Rearing Total activity

Day 3 2.22 2 Month No effect No effect Statistically significant effects

4 Months No effect No effect No effect

6 Months No effect Statistically significant effects

No effect

20.1 2 Months Statistically significant effects

Statistically significant effects


4 Months Statistically significant effects



6 Months Statistically significant effects



Day 10 1.34 2 Months No effect No effect No effect



13.4 2 Months No effect No effect No effect






Day 19 2.22 2 Months No effect No effect No effect






Note: a) The statistical significance of the effects were tested against the control group at the p=0.01 level.

The habituation ratio between activity during the last and first (40-60 and 0-20 minute) periods was calculated giving information on the capability to habituate to a novel environment. A significant decrease in habituation capability for locomotion, rearing and total activity variables was shown in mice exposed neonatally to 20.1 mg/kg bw. No significant decrease in habituation capability with age was demonstrated in mice exposed on postnatal day 3 to 2.2 mg/kg bw. The authors concluded that the effects observed at 20.1 mg/kg bw on habituation capability seem to worsen with age.

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Viberg et al. 2003 investigated also the uptake and retention of decabromodiphenyl ether in the brain, heart and liver of neonatal mice. 14C-labelled decabromodiphenyl ether (purity >98%) was administered as a single oral dose in the same fat emulsion as above at a concentration of 2.22 mg/kg body weight to three-, ten- and nineteen-day-old male mice. Each exposure group contained two litters and one male in each litter was used as a background control (Eriksson, 2002). The radioactivity in the brain was determined after 24 hours or 7 days after dosing.

The results of the study showed that 14C was taken up into the brain, but there were differences in the amount of radioactivity found in the different age mice. The mice exposed on postnatal day 3 or 10 had around 4‰ of the total administered dose of 14C in the brain at 24-hours after dosing, whereas only 0.6‰ of the total administered dose was found at 24-hours in the brains of mice dosed on postnatal day 19. At day-7 after administration the amount of radioactivity in the brain had increased by around a factor of 2 in the mice exposed on postnatal days 3 or 10, whereas no noticeable increase in the amount of radioactivity present had occurred in brains of the mice dosed on postnatal day 19. In the heart of animals exposed on postnatal day 3 or 10, the amounts of radioactivity were around 3‰ 24 hour and 7 days after administration. In the liver of animals exposed on postnatal day 3 ,10 or 19, the amounts of radioactivity were around 125, 94 or 58‰ respectively at 24 hour after administration, with a significant decrease at 7 days with 48, 46 and 3‰ amounts.

Table 4.1.2.9B: Distribution of 14C-label in mice tissues (Viberg et al. 2003)

Study group 14C-Distribution (as percentage of administered dose)

Dosing day/dose Time after dosing Brain Heart Liver

Day 3, 2.22 mg/kg bw.

24 hours 4.8 ‰ 2.8 ‰ 125.6 ‰

7 days 7.4 ‰ a 3.4 ‰ 47.7‰ b


24 hours 4 ‰ 3.1 ‰ 94.1 ‰

7 days 10.5‰ a 3.2 ‰ 46.3 ‰ b


24 hours 0.6 ‰ 2.2 ‰ 57.8 ‰

7 days 0.6 ‰ 0.8 ‰ b 3.12 ‰ b

Note a) Level after 7 days was statistically significantly higher (p=0.01) than found after 24 hours.b) Level after 7 days was statistically significantly lower (p=0.01) than found after 24 hours.

The toxicological significance of these findings remains unclear. The authors hypothesised that the effects seen on spontaneous behaviour could be due to one or more metabolites of decabromodiphenyl ether present in the brain. This hypothesis was based on the fact that the effects on spontaneous behaviour were only seen in mice exposed on day three. The peak of brain growth spurt (BGS; the rapid growth period of the brain during which it is thought that disturbances in behaviour and cholinergic transmitter systems could be induced) in neonatal mice is around day 10. Thus, it was argued that if the parent decabromodiphenyl ether was responsible for the neurotoxic effects seen, the mice exposed on day 10 would also have shown these effects owing to the amount of radioactivity rapidly distributed to the brain

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within 24 hours of dosing. The authors conclude that further studies are needed to evaluate whether it is the parent compound or debrominated metabolites, or other metabolites, that are present in the brain after neonatal exposure.

From these data it is apparent that statistically significant effects on behaviour were seen at the lowest concentration tested (2.22 mg/kg/day) at two months and six months after dosing for the animals exposed on day three. Overall, the differences at the low dose were marginal and not consistently observed (absence of effect at four months), and do not follow the same pattern as those seen at the high dose. For this reason, it is likely that the differences at the low dose were probably not related to treatment. Thus, a NOAEL of 2.22 mg/kg/day may be derived.

However, the statistical analyses were conducted with regards to the number of animals tested and not the alternative statistical unit the numbers of litters tested (n = 3-5) which it may be appropriate to use. The authors of the study argue that as this is not a “classical” developmental toxicity study and as individual pups were administered the substance directly that the statistical analysis can be based on the number of animals tested rather than on a litter basis. However, it may be questioned whether on a litter basis the findings would be statistically significant and whether a litter effect occurs. The data presented indicate a possible causal link between an observed delay in the onset of activity in male mice and DecaBDPE treatment. The authors report that historical positive and negative control data are available but none were presented in the study report for comparative purposes. As indicated by Crofton et al., 2004, positive control data should be available in developmental neurotoxicity study to help determine the biological significance of results and establish confidence in test results. Moreover, as no standard deviation data are presented, it is difficult to judge the degree of variability that might be expected within this study. The study used a relative small groupe size and t The limited number of dose tested at day 3 (only two dose levels) doest not allow to assess whether the effect is dose-related. No specific randomisation procedures or random programs were used in this study which is an important weakness in this study. Given the limitations of Viberg’s study, the rapporteur is of the opinion that the results of this study could not be used alone, but given the concern raised by these findings, those results could not be dismissed as well. Therefore, the rapporteurrecommended to conduct a confirmatory developmental neurotoxicity study. The results of the Viberg et al. (2003) neurotoxicity study were discussed by human health experts at TC NES I, 2004. Here it was concluded that it was not possible to totally dismiss the results, although the majority of experts indicated some concerns over how certain aspects of the study had been carried out, meaning that it was not possible to use the results directly in the risk characterisation. It was therefore agreed that was a need to conduct a further developmental neurotoxicity study in mice in order to investigate this endpoint further.

Mariussen and Fonnum, 2003 investigated the effects of commercial brominated flame retardants (including decabromodiphenyl ether) on the uptake of the neurotransmitters dopamine, glutamate and g-amino-n-butyric acid (GABA) into rat brain synaptosomes. The assays for determining the effects on the uptake of dopamine, glutamate and GABA into synaptosomes were carried out as follows. Isolated male Wistar rat brain synaptosomes (at a concentration of 50 g protein/ml) were pre-incubated with the flame retardant in a buffer solution (pH 7.4; for the dopamine experiments the solution also contained 1.7 mM ascorbic acid and 80 M pargyline) at 25°C for 15 minutes. The brominated flame retardant was added

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as a solution in dimethyl sulphoxide and the final concentration of solvent in the test was ≤ 0.5%. At least four concentrations of the brominated flame retardants were tested, in the range 2 to 20 M. The uptake experiments were then started by the addition of either 80 nM 3H-glutamate, 40 nM 3H-GABA or 100 nM 3H-dopamine. The mixtures were incubated for either 3 minutes (glutamate and GABA) or 9 minutes (dopamine) and the uptake of the radiolabel into the synaptosomes was then determined. Blanks were treated similarly but incubated at 0°C.

No effect on neurotransmitter uptake into synaptosomes was seen with decabromodiphenyl ether or octabromodiphenyl ether.

.

With regard to the results of decabromodiphenyl ether this study did not investigate the effects of decabromodiphenyl ether on vesicular uptake of dopamine. It is unlikely that metabolism of decabromodiphenyl ether would have occurred in this study. This is potentially important if the effects seen in the Viberg et al. mouse study are a result of metabolites.

4.1.3 Risk characterisation

4.1.3.1 General Aspects:

Given the experimental conditions applied in the available oral repeated toxicity studies (by feeding) and particularly the absence of vehicle and the uncertainties regarding the particles size of the tested material, a poor oral absorption may be anticipated in these studies. Therefore, underestimation of the inherent toxicity of decabromodiphenyl ether in a dissolved form is likely. This may have an impact in the risk characterisation for human exposed via the environment (via the food chain).

For the oral route, a rate of 26% of oral absorption is estimated for exposure via the food chain based on the new toxicokinetic studies available and a rate of 100% for exposure via the breast milk is assumed. A rate of 6% of oral absorption should be applied for the determination of the internal “ NOAELs” derived from feeding studies where prior solubilisation of decabromodiphenyl ether were not carried out. Regarding percutaneous penetration, an absorption rate of 2% is estimated.

4.1.3.2 Workers

For dermal route, maximum skin exposure of 1 mg/cm2/day is predicted by the EASE modelling. Assuming that the skin exposed on the hands represents 840 cm2, a worker’s weight of 70 kg and a skin absorption of 2%, the calculated body burden is revised to 0.24 mg/kg/day.

4.1.3.2.1 and 4.1.3.2.2. Repeated dose toxicity and carcinogenesis

Route-to-route extrapolation and calculation of internal doses:33

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Inhalation and dermal route are the relevant occupational routes whereas all NOAELs are available by oral route only. Therefore route-to-route extrapolation has to be done and corrections should be made for differences in bioavailability as determined by percentages of absorption.

For oral route (starting route), an absorption rate of 6% should be applied for the determination of the internal “ NOAELs” derived from feeding studies such as the oral chronic toxicity study from which a NOAEL of 1,120 mg/kg/day was derived. Therefore, the initial MOS for the inhalation route of 96 remains.

For dermal route, the ratio internal NOAEL/body burden (67.2 mg/kg/day/0.24 mg/kg/day) is now estimated at 280. The conclusions of the report are not affected by this change.

Conclusion ii

4.1.3.2.3 Developmental neurotoxicity

Conclusion (i)A conclusion (i) applies to this part in the human health (section 4.1.2.10.5) because an appropriate NOAEL cannot be derived from the available neurotoxicity study. New data is consequently expected namely a developmental neurotoxicity study before this part of the risk characterisation can be filled.

4.1.3.3 Consumers

Consumers may be exposed to DBDPE released from consumer products (electronic equipment and fabrics). Exposure is not yet quantified in this report but will be considered when further information about the neurotoxic developmental effects become available.

4.1.3.4 Humans exposed via the environment

Although no risk has currently been identified (see details in the sections below), additional information (conclusion i) are needed on current concentrations of decabromodiphenyl ether in humans due to the remaining uncertainties on DecaBDPE exposure. Consequently, a suitable bio-monitoring programme, including breast milk, and a trend analysis over a certain time period, are required.The estimated maximum total human intake from environmental sources is estimated to be in the range 0.05 –12 µg/kg bw/day from local and regional sources.

4.1.3.4.1 Repeated dose toxicity / carcinogenicity

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A NOAEL of 67 mg/kg bw/day (recalculated from a NOAEL of 1,120 mg/kg bw/day and taking an absorption fraction of 0.06 for the test organisms since the substance was not totally bioavailable to the organisms in the conditions of the test)was identified in an oral chronic toxicity study in rats. As the exposure via the environment is mainly through root crops, this value will be used directly. With a maximum intake of 12 µg/kg bw/day, a MOS of 5,583 can be derived. This value does not lead to concern.Although no risk has currently been identified, additional information (conclusion (i)) are needed on current concentrations of decabromodiphenyl ether in humans due to the remaining uncertainties.

4.1.3.4.2 Developmental neurotoxicity

A conclusion (i) applies to this part in the human health section because no study is useable to derive an appropriate NOAEL from. Potential effects on this endpoint should be further investigated in relation to the indications from a not fully valid study of effects. New data is consequently expected before this part of the risk characterisation can be filled.Although no risk has currently been identified, additional information (conclusion (i)) are needed on current concentrations of decabromodiphenyl ether in humans due to the remaining uncertainties.

4.1.3.4.3 Infants exposed via milk

The weighted average daily uptake for infants exposed via breast milk only has been estimated to be 0.021 µg/kg/day which is below the estimated regional exposure for human. Consequently, the MOSs for this scenario will be always above those calculated for other exposure scenarios (e. g. local generic production scenario used as a worst case in this study). As in point 4.1.3.4.2, new data are expected in order to complete the risk assessment for this particular scenario.Conclusion (i)

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5. RESULTS

Workers

Conclusion (i) : There is a need for further information and /or testing.

A conclusion (i) applies to the human health part (section 4.1.2.10.5) because an appropriate NOAEL cannot be derived from the available neurotoxicity study. New data is consequently expected namely a developmental neurotoxicity study before this part of the risk characterisation can be filled.

Consumers

Conclusion (ii): There is at present no need for further information and/or testing and for risk reduction measures beyond those which are being applied already.

This conclusion was reached in the risk assessment report because consumer exposure was considered negligible. However, consumers may be exposed to DBDPE released from consumer products (electronic equipment and fabrics). Exposure is not yet quantified in this report but will be considered when further information about the neurotoxic developmental effects become available.

Humans exposed via the environment

Conclusion (i) applies to the risk characterisation for human exposed via the environment.

- Although no risk has currently been identified, additional information are needed on current concentrations of decabromodiphenyl ether in humans due to the remaining uncertainties on DecaBDPE exposure. Consequently, a suitable bio-monitoring programme, including breast milk, and a trend analysis over a certain time period, are required.

- In order to complete the risk assessment for developmental neurotoxicity an appropriate NOAEL should be derived for this endpoint. A developmental neurotoxicity study is consequently expected.

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Hakk H. and Letcher R.J. (2003). Metabolism in the toxicokinetics and fate of brominated flame retardants – a review. Environment International, 29, 801-828.

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Jakobsson K., Thuresson K., Höglund P., Sjödin A., Hagmar L. and Bergman Å. (2003). A summary of exposures to polybrominated diphenyl ethers (PBDEs) in Swedish workers, and determination of half-lives of PBDEs. Dioxin 2003, Organohalogen Compounds, 60-65, 2003, pages unknown.

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Lepom, P., T. Karasyova and G. Sawal (2002). "Occurrence of polybrominated diphenyl ethers in freshwater fish from Germany." Organohalogen Compounds 58: 209-212.

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Mariussen E. and Fonnum F. (2003). The effect of brominated flame retardants on neurotransmitter uptake into rat brain synaptosomes and vesicles. Neurochemistry International, 43, p 533-542.

Mariussen, E., J. A. Kslss, A. Borgen, N. T. and M. Schlabach (2004). Analysis of brominated flame retardants in liver samples of lynx from the Norwegian biota. SETAC Europe 14th annual meeting, Prague.

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http://www.ewg.org/reports/mothersmilk/es.php

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Mazdai A., Dodder N.G., Abernathy M.P., Hites R.A. and Bigsby R.M. (2003). Polybrominated diphenyl ethers in maternal and fetal blood samples. Environ. Health Perspectives, 111, 1249-1252.

McPherson A., Thorpe B. and. Blake A.(2004). Brominated flame retardants in dust on computers: The case for safer chemicals and better computer design, available online et computertakeback.org.

Mörck A., Hakk H., Örn U. and Klasson Wehler E. (2003a). Decabromodiphenyl ether in the rat – absorption, distribution, metabolism and excretion. Drug. Metabol. Deposit., 31, N° 7, 900-907.

Mörck A., Hakk H., Örn U. and Klasson Wehler E. (2003b). Decabromodiphenyl ether in the rat – absorption, distribution, metabolism and excretion in Sandholm A., 2003 in Sandholm A., 2003 doctoral dissertation. Department of Environmental Chemistry Stockholm University.

Nagy, E., H. Orvos, A. Pal, L. Kovacs and K. Loveland (2001). "Breastfeeding duration and previous breastfeeding experience." Acta Paediatr 90: 51-56.

Perez-Escamilla, R. (1994). "Breastfeeding in Africa and the Latin American and Caribbean region: the potential role of urbanization." J Trop Pediatr 40: 137-143.

Örn U. (1997). Synthesis of polybrominated diphenyl ethers and metabolism of 2,2’,4,4’-tetrabromo[14C]diphenyl ether. Licentiate Thesis, Department of Environmental Chemistry, Stockholm University.

Palm A. (2001). The environmental fate of polybrominated diphenyl ethers in the centre of Stockholm – Assessment using a multimedia fugacity model. IVL Report B 1400. Swedish Environmental Research Institute, January 2001.

Rowland M. and Tozer T.N., (1980). Absorption, Clinical Pharmacokinetics, Concepts and Applications, Rowland M and Tozer T.N., Lea & Febiger, 16-33 quoted in Sandholm A., 2003.

Sandholm A., (2003a). Metabolism of some Polychlorinated Biphenyl and Polybrominated Diphenyl Ether congeners in the rat. Doctoral dissertation. Department of Environmental Chemistry Stockholm University.

Sandholm A., Emanuelsson B-M. and Klasson Wehler E. (2003b). Bioavailability and half-life of decabromodiphenyl ether (BDE-209) in the rat in Sandholm A., 2003 doctoral dissertation. Department of Environmental Chemistry Stockholm University.

Santillo D., Labunska I., Davidson H., Johnston P., Strutt M. and Knowles O. (2003). Consuming chemicals. Hazardous chemicals in house dust as an indicator of chemical exposure in the home. Publication of Greenpeace Environmental Trust, May 2003.

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Schecter A., Pavuk M., Päpke O., Ryan J. J., Birnbaum L., and Rosen R. (2003). Polybrominated diphenyl ethers (PBDEs) in U.S. Mothers’ Milk. Environ. Health Perspectives, 111, 1723-1729.

Schecter A., Päpke O., Tung K-C., Staskal D. and Birnbaum L., 2004. Polybrominated diphenyl ethers contamination of United States food. Environ. Sci. Technol., 38, 5306-5311.

SFT (2004a). Personal communication from Statens forurensningstilsyn (Norwegian Pollution Control Authority).

SFT (2004b). Additional information on decaBDE in polar bears. Document COM013_env_N4. Statens forurensningstilsyn (Norwegian Pollution Control Authority)

Sharp R. and Lunder S. (2004). In the dust toxic fire retardants in American homes. High levels of toxic fire retardants contaminate American homes, publication available on the Environmental Working Group website http://www.ewg.org, 2004 and http://www.ewg.org/reports/inthedust/index.php.

Sjödin A., Carlsson H., Thuresson K., Sjölin S., Bergman Å. and Östman C. (2001a). Flame retardants in indoor air at an electronics recycling plant and at other work environments. Environ. Sci. Technol., 35, 448-454.

Sjödin A., Patterson Jr. D. G. and Bergman Å. (2001b). Brominated flame retardants in serum from U.S. blood donors. Environ. Sci. Technol., 35, 3830-3833.

Skaare J. U. and Jensen B. J. (2004). Norwegian School of Veterinary Science. Summary of results as reported in SFT (2004b)

Smeds A. and Saukko P. (2003). Brominated flame retardants and phenolic endocrine disrupters in Finnish human adipose tissue. Chemosphere, 53, 1123-1130.

TGD (Technical Guidance Document on Risk Assessment) (2003) . Chapter 2. Risk Assessment for Human Health. Toxicokinetics, p97. European Commission Joint research Centre.

Vestermark, V., C. K. Hogdall, G. Plenov, M. Birch and K. Toftager-Larsen (1991). "The duration of breast-feeding. A longitudinal prospective study in Denmark." Scan J Soc Med 19: 105-109.

Viberg H., Fredriksson A., Jakobsson E., Örn U. and Eriksson P. (2003). Neurobehavioral derangements in adult mice receiving decabrominated diphenyl ether (PBDE 209) during a defined period of neonatal brain development. Toxicological Sciences, 76, p 112-120.

WHO/UNICEF (1990). Innocenti declaration on the protection, promotion, and support of breastfeeding. Breastfeeding in the 1990s: global initiative., Florence, Italy, World Health Organisation. http://www.waba.org.my/womenwork/inno.htm

WWF (2003). The detection of BDE 209 (Deca) in WWF-UKs national biomonitoring Survey 2003.WWF, 23 October 2003(available from http://www.wwf.org.uk/filelibrary/pdf/biomonitoringresults.pdf).

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http://www.waba.org.my/womenwork/inno.htm

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WWF (2004). Chemical check up. An analysis of chemicals in the blood of members of the European Parliament. WWF’s report available on the following web site: http://www.panda.org/about_wwf/what_we_do/toxics/news/news.cfm?uNewsID=12622.

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7. OTHER PAPERS REVIEWED THAT DID NOT CONTAIN SIGNIFICANT NEW INFORMATION RELEVANT TO THE RISK ASSESSMENT

Alaee M., Arias P., Sjödin A. and Bergman A, 2003. An overview of commercially used brominated flame retardants, theirs applications, their use patterns in different countries/regions and possible modes of release. Environment International, 29, p 683-689. [Overview on brominated flame retardants]

Guvenius D.M., Aronsson A;, Ekman-Orderberg G;, Bergman Å and Norén K., 2003. Human prenatal and postnatal exposure to polybrominated diphenyl ethers, polychlorinated biphenyls, polychlorobiphenylols, and pentachlorophenol. Environ. Health Perspectives, 111, 1235-1241. [Decabromodiphenyl ether was not analysed in this work.]

Hardy, 2001. Assessment of reported decabromodiphenyloxide blood and air levels in Swedish workers and their workplace. The second International Workshop on brominated flame retardants, Stockholm May 14-16, 2001, 121-124.

Hooper K. and She J., 2003. Lessons from the Polybrominated Diphenyl Ethers (PBDEs) : Precautionary Principle, Primary Prevention, and the value of Community-Based Body-Burden Monitoring Using Breast milk. Environmental Health Perspectives, 111, N° 1, 109-114. [Review on advantages of body burden monitoring using breast milk].

Kalantzi O.I., Martin F.L., Thomas G.O., Alcock R.E., Tang H.R., Drury S.C., Carmichael P.L., Nicholson J.K., and Jones K.C., 2004. Different levels of polybrominated diphenyl ethers (PBDEs) and chlorinated compounds in breast milk from two U.K. regions. Environ. Health Perspectives, 112, 1085-1091. [Decabromodiphenyl ether was not analysed in this work.]

Legler J. and Brouwer A., 2003. Are brominated flame retardants endocrine disruptors ? Environment International , 29, 879-885. [Decabromodiphenyl ether was not reviewed.]

Lichtensteiger W., Ceccatelli R., Faass O., Fleischmann I. and Schlumpf M., 2003. Effects of polybrominated diphenyl ether (PBDPE) on reproductive organ and brain development and gene expression in rats. SOT 2003 Annual meeting, 648, p133. [Decabromodiphenyl ether was not studied in this work but only pentabromodiphenyl ether.]

Lichtensteiger W., Ceccatelli R., Faass O., Ma R. and Schlumpf M., 2003. Effect of polybrominated diphenyl ether and PCB on the development of the brain-gonadal axis and gene expression in rats. Organohalogen Compounds, 61, 84-87. [Decabromodiphenyl ether was not studied in this work but only pentabromodiphenyl ether.]

Meerts I.A.T.M, Letcher R.J., Hoving S., Marsh G., Bergman Å., Lemmen J.G., Van der Burg B., and Brouwer A., 2001. In Vitro Estrogenicity of Polybrominated Diphenyl Ethers, Hydroxylated PBDEs, and Polybrominated Bisphenol A Compounds. Environmental Health Perpectives, 109, N° 4, 399-407. [Decabromodiphenyl ether was not reviewed in this paper.]

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Meerts I.A.T.M., Van Zanden J.J., Luijks E.A.C., Van Leeuwen-Bol I., Marsch G., Jakobsson E., Bergman Å., and Brouwer A., 2000. Potent Competitive Interactions of Some Brominated Flame Retardants and related Compounds with Human Transthyretin in Vitro. Toxicological Sciences, 56, 95-104. [Decabromodiphenyl ether was not tested in this work].

Päpke O., Bathe L., Bergman Å., Fürst P., Guvenius D.M., Herrmann T. and Norén K., 2001. Determination of PBDPEs in human milk from the United States – Comparison of results from three laboratories. Organohalogen Compounds, 52, 197-200. [Decabromodiphenyl ether was not analysed in this work.]

Sjödin A., Patterson Jr. D. G. and Bergman Å. (2003). A review on human exposure to brominated flame retardants – particularly polybrominated diphenyl ethers. Environ. International, 29, 829-839.

Sjödin A, Jones RS, Focant JF, Lapeza C, Wang RY, McGahee EE 3rd, Zhang Y, Turner WE, Slazyk B, Needham LL and Patterson DG Jr, 2004a. Retrospective time-trend study of polybrominated diphenyl ether and polybrominated and polychlorinated biphenyl levels in human serum from the United States. Environ Health Perspect 112(6): 654-8. [Decabromodiphenyl ether was not analysed in this work.]

Thomsen C, Lundanes E, Becher G. Brominated flame retardants in archived serum samples from Norway: a study on temporal trends and the role of age. Environ Sci Technol. 2002 Apr 1;36(7): 1414-8. Comment in: Environ Sci Technol. 2002 May 1;36(9): 188A-192A. [Decabromodiphenyl ether was not analysed in this work.]

Viberg H., Fredriksson A. and Eriksson P. (2003). Neurotoxicity of different polybrominated diphenyl ethers, including PBDE 209. Dioxin 2003, Organohalogen Compounds, 60-65, 2003, pages unknown. [This paper contains a summary of the neurotoxicity data already presented in the main report.]

8. OTHER PAPERS NOT YET REVIEWED:

BFR, 2004. The third international workshop on brominated flame retardants. Toronto, 2004 (Abstracts of the workshop not yet available).

Birnbaum L.S. and Staskal D.F., 2004. Brominated Flame Retardants : Cause for Concern ? Environmental Health Perspectives, 112, N° 1, 9-17

Body of evidence. New science in the debate over toxic flame retardants and our health. Kucher Y. and Purvis M., 2004. US PIRG Education Fund Environment California Research & Policy Center. (http://www.checnet.org/healthehouse/home/index.asp.

Brown D.J., Van Overmeire I., Goeyens L., Denison M.S., De Vito M.J. and Clark G.C. (2004). Analysis of Ah receptor pathway activation by brominated flame retardants. Chemosphere, 55, 1509-1518. [Decabromodiphenyl ether is tested].

Consuming Chemicals. Hazardous chemicals in house dust as an indicator of chemical exposure in the home, 2003. Greenpeace Environmental Trust, May 2003.

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http://www.checnet.org/healthehouse/home/index.asp

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12026967

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Kalantzi O. I., Martin F. L., Thomas G. O., Alcock R. E., Tang H. R., Carmichael P. L., Nicholson J. K., and Jones K. C. (2004). Regional levels of polybrominated diphenyl ethers (PBDEs) and chlorinated compounds in UK breast milk. In press. It has not been possible to incorporate this paper in the updated RAR (In press).

Karmaus W., and Riebow J. F., 2004. Storage of Serum in Plastic and Glass Containers May Alter the Serum Concentration of Polychlorinated Biphenyls. Environmental Health Perpectives, 112, N° 6, 643-647.

LaKind J.S., Wilkins A.A., and Berlin C.M. Jr., 2004. Environmental chemicals in human milk : a review of levels, infant exposures and health, and guidance for future research. Toxicology and Applied Pharmacology, 198, 184-208.

Oskarsson A. and Möller N. , 2004. A method for studies on milk excretion of chemicals in mice with 2,2’,4,4’,5-pentabromodiphenyl ether (BDE-99) as a model. Toxicology Letters, 151, 327-334.

Report of the the Peer Consultation Meeting on decabromodiphenyl ether, 2003. Submission by American Chemistry Council’s Brominated Flame Retardant Industry Panel for the Voluntary Children’s Chemical Evaluation Program (VCCEP). Peer consultation organized by toxicology excellence for risk assessment (http://www.tera.org/peer/vccep).

Sjödin A., McGahee E.E., III, Focant JF., Jones R.S., Lapeza C.R., Zhang Y., and Patterson D.G., Jr (2004). Semiautomated High-Throughput Extraction and Cleanup Method for the Measurement of Polybrominated Diphenyl Ethers and Polybrominated and Polychlorinated Biphenyls in Beast Milk. Analytical Chemistry, 76, N° 15, 4508-4514.

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Documents

UPDATE OF THE HUMAN HEALTH RISK … · Web viewUPDATE OF THE RISK ASSESSMENT ADDENDUM OF BIS(PENTABROMOPHENYL) ETHER (DECABROMODIPHENYL ETHER) CAS Number: 1163-19-5 EINECS Number: