Appendices of the State of the Science Report

Phthalates Substance Grouping
Long-chain Phthalate Esters

1,2-Benzenedicarboxylic acid, diisodecyl ester
(diisodecyl phthalate; DIDP)
and
1,2-Benzenedicarboxylic acid, diundecyl ester
(diundecyl phthalate; DUP)

Chemical Abstracts Service Registry Numbers
26761-40-0, 68515-49-1;
3648-20-2

Environment Canada
Health Canada
August 2015

Appendix A: Information on analogues used for substances in the Long-Chain Phthalates Grouping
Appendix B: Physical and chemical properties for substances in the Long-Chain Phthalates Grouping
Appendix C: Estimates of daily intake of DIDP and DUP
Appendix D: Methodology for biomonitoring intake calculations
Appendix E: Description and Application of the Downs and Black Scoring and Guidance for Level of Evidence of An Association
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Appendix A: Information on Analogues used for Substances in the Long-Chain Phthalates Grouping

Table A-1. Structures and property data for DIDP, DUP and analogues used to inform the assessment of DIDP and DUP
CAS RN Common name	Representative molecular formula / molecularweight (g/mol) / chemical properties^a	Similarity index (%)^{Footnote Table A-1[b]}
Target substance: 26761-40-0 Diisodecyl phthalate (DIDP)	C₂₈H₄₆O₄ MW: 446.68 Low water solubility (1.7 × 10^-4 mg/L) Log K_ow: greater than 8 Log K_oc: 5.5 - 6.5 D_max, D_eff: 30, 20 nm	n/a
Target substance: 68515-49-1 Diisodecyl phthalate (DIDP)	C₂₈H₄₆O₄ MW: 446.68 Low water solubility (1.7 × 10^-4 mg/L) Log K_ow: greater than 8 Log K_oc: 5.5 - 6.5 D_max, D_eff: 27, 19 nm	n/a
Target substance: 3648-20-2 Diundecyl phthalate (DUP)	C₃₀H₅₀O₄ MW: 474.73 Low water solubility (1.73 × 10^-6 mg/L) Log K_ow: greater than 8 Log K_oc: 6.7 - 7.1 D_max, D_eff: 35, 22 nm	n/a
Analogue substance: 28553-12-0 68515-48-0 Diisononyl phthalate (DINP)	C₂₆H₄₂O₄ MW: 418.62 Low water solubility (6.1 × 10^-4 mg/L) Log K_ow: 8.8 Log K_oc: 5.5 - 5.7 D_max, D_eff: 28 - 30, 19 - 20 nm	with DIDP: 85 - 94 with DUP: 89 - 91
Analogue substance: 85507-79-5 Diisoundecyl phthalate (DIUP)	C₃₀H₅₀O₄ MW: 474.73 Low water solubility (4.4 × 10^-6 mg/L) Log K_ow: 10.3 Log K_oc: 7.1 D_max, D_eff: 31, 20 nm	with DIDP: 84 - 92 with DUP: 81

Footnote

Abbreviations: D_eff, effective molecular cross-sectional diameter; D_max, maximum molecular diameter; MW, molecular weight.
Sources: Chemical structure and property data for DIDP and DUP are from Table 2-1 and Appendix B of this report; data for DINP are from Environment Canada and Health Canada 2015b; data for DIUP are from ECHA 2014 and EPI Suite 2000-2008. All D_max, D_eff values are from CPOPs 2012.

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Footnote a

DIDP and DINP are isomeric mixtures and DIUP is a UVCB (i.e. substance of Unknown or Variable composition, Complex reaction products, or Biological materials). As such, the chemical structures, formulae and molecular weights provided in Table A-3 are considered to be representative for the substances.

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Footnote b

Source: OECD QSAR Toolbox 2012.

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Appendix B: Physical and Chemical Properties for Substances in the Long-Chain Phthalates Grouping

Table B-1. Physical and chemical properties for DIDP and DUP
CAS RN Acronym	Physical form	Melting point (°C)	Boiling point (°C)	Density (kg/m³)	Vapour pressure (Pa)
26761-40-0 DIDP	Liquid^{Footnote Table B-1[a]}	-46 - -50* (Exp)^{Footnote Table B-1[b]},^{Footnote Table B-1[c]} 105.95 (Mod)^{Footnote Table B-1[d]}	450* (Exp)^c 463.36 (Mod)^d	966 (Exp)^b	7.0 × 10^-5 (Exp, 25°C)^{Footnote Table B-1[g]} 6.7 × 10^-5* (Exp, 25°C)^c,^{Footnote Table B-1[f]} 1.8 × 10^-6 (Cal, 25°C)^{Footnote Table B-1[h]} 6.55 × 10^-5 (Mod, 25°C)^d
68515-49-1 DIDP	Liquid^a	-45 - -50* (Exp)^a,^{Footnote Table B-1[e]} 141.06 (Mod)^d	450* - 463 (Exp)^c,^e 454.16 (Mod)^d	968 – 970 (Exp)^a,^e	6.7 × 10^-5* (Exp, 25°C)^c,^f 5.1 × 10^-5 (Cal, 25°C)^e 1.8 × 10^-6 (Cal, 25°C)^h 6.55 × 10^-5 (Mod, 25°C)^d
3648-20-2 DUP	Liquid^a	-9* (Exp)^f -40 (Exp)^e 35.5 (Exp)^b 155.88 (Mod)^d	336* (Exp)^e 500.56 (Mod)^d	954 (Exp)^a 960 (Exp)^c	6.67 × 10^-5* (Exp)^c 4.97 × 10^-7 (Cal)^h 0.0377 (Mod, 25°C)^d

Footnote

Abbreviations: Cal, calculated value; Exp, experimental value; Mod, modelled value.
* Indicates selected value for modelling.

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Footnote a.1

European Commission 2000.

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Footnote b.1

Haynes and Lide 2010.

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Footnote c

Mackay et al. 2006.

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Footnote d

MPBPVPWIN 2010.

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Footnote e

ECHA 2014.

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Footnote f

Staples et al. 1997.

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Footnote g

Yaws 1994.

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Footnote h

Cousins and Mackay 2000.

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Table B-2. Physical and chemical properties for DIDP and DUP (continued)
CAS RN	Water solubility (mg/L)	Henry's law constant (Pa·m³/mol)	Log K_ow (unitless)	Log K_oc (unitless)	Log K_oa (unitless)
26761-40-0 DIDP	1.7 × 10^-4* (Exp, 20°C)^{Footnote Table B-2[a]} 1.19 (Exp, 25°C)^{Footnote Table B-2[b]} less than 0.001 (Exp, 25°C)^{Footnote Table B-2[c]},^{Footnote Table B-2[d]} 3.8 × 10^-5 (Cal, 25°C)^{Footnote Table B-2[e]} 9.97 × 10^-6 (Mod, 25°C)^{Footnote Table B-2[f]} 5.40 × 10^-5 (Mod, 25°C)^{Footnote Table B-2[g]} 0.010 (Mod, 25°C)^{Footnote Table B-2[h]} 0.041 (Mod, 25°C)^{Footnote Table B-2[i]}	21.6 (Cal, 25°C)^e 3.72 (Mod, Bond estimate, 25°C)^{Footnote Table B-2[j]} 4.11 (Mod, Group estimate, 25°C)^j 1.75 × 102 (Mod, VP/WS estimate, 25°C)^j,^{Footnote Table B-2[k]}	greater than 8.0 (Exp)^c 9.46 (Cal)^e 9.78 (Mod)^{Footnote Table B-2[l]} 9.48 (Mod, 25°C)^h 9.24 (Mod, 25°C)ⁱ	5.46 (Exp)^{Footnote Table B-2[m]} 6.04 (Mod, MCI estimate)^{Footnote Table B-2[n]} 6.52 (Mod, Log K_ow estimate)ⁿ	11.52 (Cal)^e 14.70 (Mod)^{Footnote Table B-2[o]}
68515-49-1 DIDP	1.7 × 10^-4* (Exp, 21°C)^{Footnote Table B-2[p]} 3.8 × 10^-5 (Cal, 25°C)^e less than 0.001 (Exp, 25°C)^c,^d 1.18 × 10^-5 (Mod, 25°C)^f 1.16 × 10^-4 (Mod, 25°C)^g 4.4 × 10^-3 (Mod, 25°C)^h 0.078 (Mod, 25°C)ⁱ	21.6 (Cal, 25°C)^e 3.72 (Mod, Bond estimate, 25°C)^j 4.11 (Mod, Group estimate, 25°C)^j 1.75 × 102 (Mod, VP/WS estimate, 25°C)^j,^k	greater than 8.0 (Exp)^c 9.46 (Cal)^e 9.71 (Mod)^l 9.47 (Mod, 25°C)^h 9.12 (Mod, 25°C)ⁱ	5.46 (Exp)^m 5.82 (Mod, MCI estimate)ⁿ 6.48 (Mod, Log K_ow estimate)ⁿ	11.52 (Cal)^e 13.10 (Mod)°
3648-20-2 DUP	1.11 (Exp, 25°C)^b less than 0.001 (Exp, 25°C)^c 4.41 × 10-6 (Cal, 25°C)^e 7.125 × 10^-7, (Mod, 25°C)^f 1.73 × 10^-6* (Mod, 25°C)^g 4.6 × 10^-6 (Mod, 25°C)^h 0.019 (Mod, 25°C)ⁱ	50.5 (Cal, 25°C)^e 6.55 (Mod, Bond estimate, 25°C)^j 5.68 (Mod, Group estimate, 25°C)^j 4.44 × 104 (Mod, VP/WS estimate, 25°C)^j,^k	greater than 8 (Exp)^c 10.33 (Cal)^e 10.91 (Mod)^l 12.13 (Mod, 25°C)^h 10.50 (Mod, 25°C)ⁱ	6.71 (Mod, MCI estimate)ⁿ 7.15 (Mod, Log K_ow estimate)ⁿ	12.02 (Cal)^e 14.07 (Mod)°

Footnote

Abbreviations: Cal, calculated value; Exp, experimental value; log K_oc, organic carbon-water partition coefficient; log K_ow, octanol-water partition coefficient; log K_oa, organic carbon-air partition coefficient; Mod, modelled value.
*Indicates selected value for modelling.

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Footnote a.2

Letinski et al. 2002.

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Footnote b.2

Howard et al. 1985.

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Footnote c.1

Staples et al. 1997.

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Footnote d.1

Mackay et al. 2006.

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Footnote e.1

Cousins and Mackay 2000.

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Footnote f.1

WSKOWWIN 2010.

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Footnote g.1

Value adjusted using EVA method in WATERNT 2010 and empirical water solubility value of 6.0 × 10^-4 mg/L for DINP (CAS RNs 28553-12-0 and 68515-48-0).

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Footnote h.1

ACD/Percepta c1997–2012.

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Footnote i

VCCLab 2005.

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Footnote j

HENRYWIN 2011.

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Footnote k

VP/WS estimate derived using empirical values for vapour pressure and/or water solubility.

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Footnote l

Value adjusted using EVA method in KOWWIN 2010 and empirical log Kow value of 8.8 for DINP (CAS RNs 28553-12-0 and 68515-48-0).

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Footnote m

Williams et al. 1995.

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Footnote n

KOCWIN 2010.

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Footnote o

KOAWIN 2010.

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Footnote p

ECHA 2014.

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Appendix C: Estimates of Daily Intake of DIDP and DUP

Appendix C-1. Estimates of daily intake of DIDP

Table C-1a. Estimates of daily intake of DIDP in µg/kg-bw per day. Presented as: central tendency (upper bound)
Route of exposure	0–0.5 year^{Footnote Table C-1a[a]}; Breast milk fed^{Footnote Table C-1a[b]}	0–0.5 year^a; Formula fed^{Footnote Table C-1a[c]}	0–0.5 year^a; Not formula fed	0.5–4 years^{Footnote Table C-1a[d]}	5–11 years^{Footnote Table C-1a[e]}	12–19 years^{Footnote Table C-1a[f]}	20–59 years^{Footnote Table C-1a[g]}	60+ years^{Footnote Table C-1a[h]}
Food and beverages^{Footnote Table C-1a[i]}	-	F	F	0.12 (1.33)	0.12 (1.07)	0.068 (0.70)	0.062 (0.69)	0.044 (0.49)
Dust^{Footnote Table C-1a[j]}	0.562 (2.199)	0.562 (2.199)	0.562 (2.199)	0.394 (1.540)	0.186 (0.728)	0.007 (0.026)	0.006 (0.025)	0.006 (0.024)
Total oral intake	0.562 (2.199)	0.562 (2.231)	0.562 (2.199)	0.514 (2.87)	0.306 (1.798)	0.075 (0.726)	0.068 (0.715)	0.05 (0.514)

Footnote a.3

Assumed to weigh 7.5 kg, to breathe 2.1 m³ of air per day, to drink 0.2 L/day (not formula fed) and to ingest 30 mg of soil per day. Consumption of food groups reported in Health Canada (1998). Median and 90^thdietary intake estimates (food) for the less than 6 months age group, as presented in Table C-1a, were used to represent dietary intake for this age group (applicable to formula and non-formula fed group).

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Footnote b.3

No data were identified on the levels of DIDP in breast milk in Canada or elsewhere.

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Footnote c.2

Formula-fed infants are assumed to have an intake rate of 0.75 kg of formula per day.

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Footnote d.2

Assumed to weigh 15.5 kg, to breathe 9.3 m³ of air per day, to drink 0.7 L of water per day and to ingest 100 mg of soil per day. Consumption of food groups reported in Health Canada (1998). Median and 90^thdietary intake estimates (food) for the 1 to 3 years age group, as presented in Table C-1a, were used to represent dietary intake for this age group.

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Footnote e.2

Assumed to weigh 31.0 kg, to breathe 14.5 m³ of air per day, to drink 1.1 L of water per day and to ingest 65 mg of soil per day. Consumption of food groups reported in Health Canada (1998). Median and 90^thdietary intake estimates (food) for the 4 to 8 years age group, as presented in Table C-1a, were used to represent dietary intake for this age group.

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Footnote f.2

Assumed to weigh 59.4 kg, to breathe 15.8 m³ of air per day, to drink 1.2 L of water per day and to ingest 30 mg of soil per day. Consumption of food groups reported in Health Canada (1998). Highest median and 90^th dietary intake estimates (food) for the 9 to 13 years age group, as presented in Table C-1a, were used to represent dietary intake for this age group.

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Footnote g.2

Assumed to weigh 70.9 kg, to breathe 16.2 m³ of air per day, to drink 1.5 L of water per day and to ingest 30 mg of soil per day. Consumption of food groups reported in Health Canada (1998). Highest median and 90^th dietary intake estimates (food) for the 19 to 30 years age group, as presented in Table C-1a, were used to represent dietary intake for this age group.

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Footnote h.2

Assumed to weigh 72.0 kg, to breathe 14.3 m³ of air per day, to drink 1.6 L of water per day and to ingest 30 mg of soil per day. Consumption of food groups reported in Health Canada (1998). Highest median and 90^th dietary intake estimates (food) for the 51 to 70 years age group, as presented in Table C-1a, were used to represent dietary intake for this age group.

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Footnote i.1

Probabilistic intakes (50^th and 90^th). Intakes and methodology are outlined in Appendix C-4. DIDP concentrations in food were reported in the Canadian Food Inspection Agency's 2013-2014 Food Safety Action Plan (FSAP). Note that gender and age groups do not match fully; therefore the highest intake from within an age group was inputted into the table: i.e., female intakes (greater than 71 years) were inputted into the 60 + (unisex) column because this age group had the highest intake of all the groups in the 51 – 71 year range. F: denotes significant variation, therefore estimates not presented.

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Footnote j.1

The amount of indoor dust ingested each day is based on Wilson et al. (2013). The 50^th (111 µg/g) and 95th percentile concentrations (433.9 µg/g) of DIDP in indoor dust, based on 126 samples collected from homes in 10 cities across Canada, between 2007 and 2010 (Kubwabo et al. 2013).

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Table C-1b. Probabilistic estimates of daily intake of DIDP from food and beverages (µg/kg/day)
Gender - Age group	Median	90^th percentile
under 6 months	0	F^{Footnote Table C-1b[a]}
6 months to 1 year	F^a	F^a
1 to 3 years	0.128	1.327
4 to 8 years	0.120	1.074
M - 9 to 13 years	0.0865	0.758
F - 9 to 13 years	0.0687	0.695
M - 14 to 18 years	0.0666	0.659
F - 14 to 18 years	0.0523	0.550
M - 19 to 30 years	0.0619	0.687
F - 19 to 30 years	0.0450	0.483
M - 31 to 50 years	0.0529	0.551
F - 31 to 50 years	0.0470	0.553
M - 51 to 70 years	0.0540	0.435
F - 51 to 70 years	0.0444	0.492
M - 71 or more	0.0555	0.428
F - 71 or more	0.0486	0.392

Appendix C-2. Estimates of daily intake of DUP

Table C-2a. Estimates of daily intake of DUP in µg/kg-bw/day. Presented as: central tendency (upper bound)
Route of exposure	0–0.5 year^{Footnote Table C-2a[a]}	0.5–4 years^{Footnote Table C-2a[b]}	5–11 years^{Footnote Table C-2a[c]}	12–19 years^{Footnote Table C-2a[d]}	20–59 years^{Footnote Table C-2a[e]}	60+ years^{Footnote Table C-2a[f]}
Dust^{Footnote Table C-2a[g]}	0.0198 (0.349)	0.0138 (0.244)	0.00654 (0.115)	less than 0.001 (0.00417)	less than 0.001 (0.00397)	less than 0.001 (0.00382)

Footnote a.5

Assumed to weigh 7.5 kg, to breathe 2.1 m³ of air per day, to drink 0.2 L/day (not formula fed) and to ingest 30 mg of soil per day. Consumption of food groups reported in Health Canada (1998).

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Footnote b.4

Assumed to weigh 15.5 kg, to breathe 9.3 m³ of air per day, to drink 0.7 L of water per day and to ingest 100 mg of soil per day. Consumption of food groups reported in Health Canada (1998).

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Footnote c.3

Assumed to weigh 31.0 kg, to breathe 14.5 m³ of air per day, to drink 1.1 L of water per day and to ingest 65 mg of soil per day. Consumption of food groups reported in Health Canada (1998).

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Footnote d.3

Assumed to weigh 59.4 kg, to breathe 15.8 m³ of air per day, to drink 1.2 L of water per day and to ingest 30 mg of soil per day. Consumption of food groups reported in Health Canada (1998).

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Footnote e.3

Assumed to weigh 70.9 kg, to breathe 16.2 m³ of air per day, to drink 1.5 L of water per day and to ingest 30 mg of soil per day. Consumption of food groups reported in Health Canada (1998).

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Footnote f.3

Assumed to weigh 72.0 kg, to breathe 14.3 m³ of air per day, to drink 1.6 L of water per day and to ingest 30 mg of soil per day. Consumption of food groups reported in Health Canada (1998).

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Footnote g.3

The ingestion of indoor dust is considered a significant source of indoor exposure to Phthalates, including DUP, and the amount of indoor dust ingested each day is based on Wilson et al. (2013). The 50^th (3.9 µg/g) and 95^thpercentile concentrations (68.8 µg/g) of DUP in indoor dust, based on 126 samples collected from homes in 10 cities across Canada, between 2007 and 2010 (Kubwabo et al. 2013).

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Appendix C-3. Derivation of dietary intakes

Occurrence data – DIDP

Phthalate occurrence data for DIDP were available from foods sampled as part of the 2013-2014 Food Safety Action Plan (FSAP) survey conducted by the CFIA; this dataset was determined to be the most recent and comprehensive Canadian survey of the occurrence of these phthalates in foods. Duplicate foods were included in earlier CFIA FSAP surveys (i.e., 2011 to 2012 and 2012 to 2013); therefore, only data from the most recent (i.e., 2013 to 2014) FSAP survey were employed in the exposure assessment. Occurrence data for DIDP in foods not analyzed as part of the CFIA surveys were obtained from an American total diet study (Schecter et al. 2013) and any remaining data gaps were filled using data from a British total diet study (Bradley et al. 2013). Note that these data were only used to fill data gaps. Duplicate occurrence data from these studies for a given food or phthalate were not included if such data were already available from the CFIA's 2013-2014 FSAP survey.

Occurrence data for DIDP in food that was reported as less than the analytical LOD were assigned values of ½ LOD. However, a value of 0 (zero) was assigned to all samples within a broad food category when no phthalates were detected above the LOD in any sample in that category.

Food Consumption Data and Matching to Occurrence Data

The phthalate concentrations in individual foods were matched to consumption figures for these foods from the Canadian Community Health Survey (CCHS) Cycle 2.2 on Nutrition, (Statistics Canada 2004), to generate distributions of phthalates exposure for various age-sex groups. The CCHS included 24-hour dietary recall information for over 35,000 respondents of all ages across Canada.

If a food line item belonged to a recipe that was matched to a set of the assayed foods, then the associated phthalate levels matched to the recipe were assigned to the ingredient. Otherwise, if the food line item itself matched to a set of the assayed foods, then the phthalate levels matched to the food line item were assigned for DIDP; 1003 foods and 153 recipes were matched with the list of assayed foods.

Body Weight Information

For the purpose of determining per kilogram body weight exposure estimates, infant body weights were set to the mean body weights as derived from the body weight data from the United States Department of Agriculture Continuing Survey of Food Intakes by Individuals (CSFII; 1994-96, 1998). For all age groups, body weights reported in the CCHS, whether measured or self-reported, were used and where missing were imputed using the median for the corresponding age-sex group and quintile of energy intake.

Probabilistic Exposure Assessment

For each food consumed by a respondent in the CCHS survey, phthalate concentrations were randomly selected from the matching list of assayed values. For each individual respondent, exposure estimates from each food were summed, generating a distribution of exposure for all respondents. This was repeated 500 times (500 iterations) to model the variability of the distribution of exposures due to the variability of the phthalates levels. For each age-sex group, the median and 90^th percentile exposures were derived from the empirical distribution generated by the 500 iterations.

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Appendix D: Derivation of daily intakes for DIDP based on biomonitoring

P4 Pregnant Women

Equation 1:

Daily intake (µg/kg bw•day) = [C_Sum (mole/g Cr) × CER (g/day) × MW_parent (g/mole)] / [FUE_Sum× BW (Kg)]

Where,

C _Sum (mole/gCr) =: sum of molar concentrations of the metabolites
CER (g/day) =: Creatinine excretion rate using Mage equation
MW _parent (g/mole) =: Molecular weight, DINP: 418 g/mol
FUE _Sum =: Sum of fractional urinary excretion values of the metabolites MHINP and MOINP = 0.18
BW (Kg) =: Body weight of the participant

Step 1: Converting the urinary metabolite concentration from µg/g Cr to moles/g Cr

Equation 2:

C_metabolite (mole/g Cr) = [C_metabolite(µg/g Cr)] / [MW_metabolite]

DIDP metabolites: MHIDP and MOIDP

For MHIDP,

C_MHINP (mole/g Cr) = [C_MHINP (µg/g Cr)] / 322 g/mol

For MOIDP,

C_MOIDP (mole/g Cr) = [C_MOIDP (µg/g Cr)] / 320 g/mol

Step 2: Sum the metabolite concentration (moles/g Cr) from Step 1

C_Sum (mole/g Cr) = Σ C_MHINP + C_MOINP

Step 3: Compute CER for individual participants using Mage equation

Step 4: Calculate intake using Equation 1

NHANES

Statistical analysis: The data were analyzed with SAS 9.2 (SAS Institute Inc., USA) and SUDAAN 10.0.1 software (RTI International, USA). Variance estimates were produced using the Taylor Series Linearization approach as recommended by the NHANES analytical guidelines. All analyses were weighted using the NHANES survey weights (environmental subsample) in order to be representative of the U.S. population. Phthalates concentrations that were below LOD were assigned a value of LOD/2.

Estimation of creatinine excretion rate (CER): For each study participant, creatinine excretion rate was calculated using the Mage equations (Huber et al. 2010). The adiposity adjustment (discussed in the supplemental information; Huber et al 2010) was applied for all participants and the body surface area adjustment was applied for children under the age of 18. Median BMIs by age for the adiposity adjustment were computed using the entire NHANES sample. The 2009-2010 and 2011-2012 NHANES phthalates datasets had 58 and 49 children who exceeded the height limits in the Mage equations (186 cm for males and 172 cm for females). The Mage equations were applied directly to the observed heights in order to extrapolate creatinine excretion rates for these participants. The predicted excretion rates for these individuals appeared to be reasonable despite the extrapolation.

Daily intake estimation: The daily intake of each phthalate was estimated for each participant using the following equations and procedure (David et al. 2000; Koch et al. 2007):

Equation 1:

Daily intake (µg/kg bw•day) = [C_SUM (mole/g Cr) × CER (g/day) × MW_parent (g/mole)] / [FUE_SUM× BW (Kg)]

Where,

C _SUM(mole/gCr) =: sum of molar concentrations of the metabolites. In this case, only one metabolite was measured, MCINP = 336.
CER (g/day) =: Creatinine excretion rate using Mage equation
MW _parent (g/mole) =: Molecular weight, DIDP: 447 g/mol
FUE _SUM =: Sum of fractional urinary excretion values of the metabolites. In this case only one metabolite was measured, MCINP = 0.69
BW (Kg) =: Body weight of the participant

Step 1: Converting the urinary metabolite concentration from µg/g Cr to moles/g Cr

Equation 2:

C_metabolite (mole/g Cr) = [C_metabolite(µg/g Cr)] / [MW_metabolite]

DIDP metabolite: MCINP

For MCINP,

C_MCINP (mole/g Cr) = [C_MCINP (µg/g Cr)] / 320 g/mol

Step 2: Sum the metabolite concentration (moles/g Cr) from Step 1(if more than one metabolite was measured).

C_Sum (mole/g Cr) = Σ C_MHINP + C_MOINP

Step 3: Compute CER for individual participants using Mage equation

Step 4: Calculate intake using Equation 1

For each selected phthalate diester, the daily intake for each study participant was computed using equation 1. Arithmetic and geometric means and selected percentiles along with their 95% confidence intervals of daily intake were produced for the U.S. population by age group and sex. Descriptive statistics were computed using SUDAAN proc DESCRIPT.

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Appendix E: Description and Application of the Downs and Black Scoring System and Guidance for Level of Evidence of An Association

Evaluation of study quality

A number of systematic approaches for assessing the quality of epidemiologic studies were identified and evaluated. The Downs and Black method was selected based on: (1) its applicability to the phthalate database; (2) applicability to multiple study designs; (3) established evidence of its validity and reliability; (4) simplicity; (5) small number of components; and (6) epidemiologic focus. Downs and Black consists of a checklist of 27 questions broken down into the following five dimensions: 1) reporting; 2) external validity; 3) internal validity study bias; 4) internal validity confounding and selection bias; and 5) study power. Overall study quality is based on a numeric scale, summed over the five categories. The range of the scale allows for more variability in rating study quality. The 27 questions are applicable to observational study designs including case-control, cohort, cross-sectional, and randomized controlled trials.

Studies retained for assessment were scored for quality using the Downs and Black tool. As previously mentioned, the Downs and Black allows for a range of scores from 27 questions and each epidemiological study design has a maximum score (the maximum score for cohort studies is 21, case-control studies 18, and cross-sectional studies 17). Studies were divided into quartiles based on the scoring distribution for each study design; the distribution of scores for cohort, case-control and cross-sectional studies appears in Figure E-1. The average scores for cross-sectional and case-control studies were 13.1, whereas cohort studies had higher scores than both other study designs with an average score of 14. 4.

Figure E-1. Distribution of Downs and Black scores by study design

Long description for figure 1

The figure is bar graph describing the range and frequency of Downs and Black scores given to studies of different designs.

The bar graph has the x-axis as the Downs and Black score ranging from 7 to 19 and the y-axis as the frequency of score up to 15. The figure displays the frequency of the following types of studies: cohort, case-control, and cross-sectional.

1) For the cohort studies, 2 studies received a score of 12, 6 studies received a score of 13, 8 studies received a score of 14, 6 studies received a score of 15, 3 studies received a score of 16, 3 studies received a score of 17, and 1 study received a score of 19.

2) For the case-control studies, 1 study received a score of 8, 3 studies received a score of 9, 4 studies received a score of 10, 4 studies received a score of 11, 1 study received a score of 12, 2 studies received a score of 13, 6 studies received a score of 14, 3 studies received a score of 15, and 2 studies received a score of 16.

3) For cross-sectional studies, 1 study received a score of 7, 4 studies received a score of 11, 12 studies received a score of 12, 15 studies received a score of 13, 14 studies received a score of 14, 2 studies received a score of 15, 2 studies received a score of 16, and 1 study received a score of 17.

Guidance for level of evidence of an association

The potential for an association between phthalate exposure and each health outcome was assessed based on strength and consistency as well as the quality of the epidemiology studies as determined by the Downs and Black scores. Descriptions of the levels of evidence of association are as follows:

Sufficient evidence of an association:Evidence is sufficient to conclude that there is an association. That is, an association between exposure to a phthalate or its metabolite and a health outcome has been observed in which chance, bias and known confounders could be ruled out with reasonable confidence. Determination of a causal association requires a full consideration of the underlying biology/toxicology and is beyond the scope of this document.
Limited evidence of an association: Evidence is suggestive of an association between exposure to a phthalate or its metabolite and a health outcome; however, chance, bias or confounding could not be ruled out with reasonable confidence.
Inadequate evidence of an association: The available studies are of insufficient quality, consistency or statistical power to permit a conclusion regarding the presence or absence of an association.
Evidence suggesting no association: The available studies are mutually consistent in not showing an association between the phthalate of interest and the health outcome measured.

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Appendices of the State of the Science Report

Phthalates Substance Grouping
Long-chain Phthalate Esters

1,2-Benzenedicarboxylic acid, diisodecyl ester
(diisodecyl phthalate; DIDP)
and
1,2-Benzenedicarboxylic acid, diundecyl ester
(diundecyl phthalate; DUP)

Chemical Abstracts Service Registry Numbers
26761-40-0, 68515-49-1;
3648-20-2

Environment Canada
Health Canada
August 2015

Table of Contents

Appendix A: Information on Analogues used for Substances in the Long-Chain Phthalates Grouping

Appendix B: Physical and Chemical Properties for Substances in the Long-Chain Phthalates Grouping

Appendix C: Estimates of Daily Intake of DIDP and DUP

Appendix C-1. Estimates of daily intake of DIDP

Appendix C-2. Estimates of daily intake of DUP

Appendix C-3. Derivation of dietary intakes

Occurrence data – DIDP

Food Consumption Data and Matching to Occurrence Data

Body Weight Information

Probabilistic Exposure Assessment

Appendix D: Derivation of daily intakes for DIDP based on biomonitoring

P4 Pregnant Women

Equation 1:

Equation 2:

NHANES

Equation 1:

Equation 2:

Appendix E: Description and Application of the Downs and Black Scoring System and Guidance for Level of Evidence of An Association

Evaluation of study quality

Guidance for level of evidence of an association

Page details

Appendices of the State of the Science Report

Phthalates Substance GroupingLong-chain Phthalate Esters1,2-Benzenedicarboxylic acid, diisodecyl ester(diisodecyl phthalate; DIDP)and1,2-Benzenedicarboxylic acid, diundecyl ester(diundecyl phthalate; DUP)Chemical Abstracts Service Registry Numbers26761-40-0, 68515-49-1;3648-20-2

Environment CanadaHealth CanadaAugust 2015

Table of Contents

Appendix A: Information on Analogues used for Substances in the Long-Chain Phthalates Grouping

Appendix B: Physical and Chemical Properties for Substances in the Long-Chain Phthalates Grouping

Appendix C: Estimates of Daily Intake of DIDP and DUP

Appendix C-1. Estimates of daily intake of DIDP

Appendix C-2. Estimates of daily intake of DUP

Appendix C-3. Derivation of dietary intakes

Occurrence data – DIDP

Food Consumption Data and Matching to Occurrence Data

Body Weight Information

Probabilistic Exposure Assessment

Appendix D: Derivation of daily intakes for DIDP based on biomonitoring

P4 Pregnant Women

Equation 1:

Equation 2:

NHANES

Equation 1:

Equation 2:

Appendix E: Description and Application of the Downs and Black Scoring System and Guidance for Level of Evidence of An Association

Evaluation of study quality

Guidance for level of evidence of an association

Page details

Phthalates Substance Grouping
Long-chain Phthalate Esters

1,2-Benzenedicarboxylic acid, diisodecyl ester
(diisodecyl phthalate; DIDP)
and
1,2-Benzenedicarboxylic acid, diundecyl ester
(diundecyl phthalate; DUP)

Chemical Abstracts Service Registry Numbers
26761-40-0, 68515-49-1;
3648-20-2

Environment Canada
Health Canada
August 2015