December 4, 2013
Toxics Use Reduction Institute Science Advisory Board Meeting Minutes
December 4, 2013
DEP Boston, Conference Room A/B
12:00 PM
Members present: Dave Williams (Chair), Martha Mittelstaedt, Amy Cannon, Ken Weinberg, Robin Dodson, Christine Rioux, Larry Boise (Vice-Chair), Hilary Hackbart
Others present: Mary Butow (TURI), Liz Harriman (TURI), Heather Tenney (TURI), Carol Rowan-West (DEP), John Raschko (OTA), Sean Moynihan (MCTA), Robert Barter (ExxonMobil Biomedical Science), Tsedash Zewdie (DEP), Margaret Gorman (ACC), Tricia McCarthy (ACC), Dave Wawer (MCTA), Tim Wilkerson (Administrative Council), Ellen Kornmehl (Silent Spring Institute), Mike Ellenbecker (TURI)
Members not present: Igor Linkov
Welcome and Introductions
Program Updates
TURI held the TUR Planner conference in November. It was well attended.
A demonstration event of solvent recovery was held at Chemgenes in November.
The Methylene chloride regulatory package is at the Governor’s Office.
CERCLA Categories: Phthalate esters
Program staff reviewed the status of the discussion on phthalate esters and that the DEP was asking the SAB to provide guidance with regard to which phthalates from the category are a concern from an EHS standpoint. Teams of SAB Members and Program staff were assigned to review additional information on each of ten chemicals selected by the Board in the September 25, 2013 meeting. The following is a list of comments each of the teams made on their respective chemicals including key points/concerns/outstanding questions:
• DMEP - Bis(2-methoxyethyl) phthalate - #117-82-8
- Metabolite information [Campbell, et al, 1984]
o MMEP
o 2ME -> MMA
- DMEP and metabolites rapidly transferred to fetus through placenta [Campbell, et al, 1984]
- DMEP and metabolites are embryotoxic and fetotoxic [Campbell, et al, 1984]
- Cause severe reproductive toxicity in adult animals; testicular atrophy; sperm damage; decreased testicular weight [CPSC 2011a: Kodak 1984, Cassidy et al. 1983]
- Cause severe teratogenicity in utero [CPSC 2011a: Parkhie et al. 1982, Singh at al. 1972]
- Genotoxic [CPSC 2011a: NTP 1993]
- No cancer studies have been performed [CPSC 2011a]
- All animal studies-there are many (DEP provided table) [Campbell, et al, 1984; CPSC 2011a]
- Liver and kidney effects [Campbell, et al, 1984]
- Severe skeletal malformations [CPSC 2011a: Parkhie et al. 1982]
• DnOP - Di-n-octyl phthalate - #117-84-0
- C8 [CPSC 2010a]
- Already TURA listed (CERCLA list origin) [MassDEP 2013]
- Probable hepatotoxicant (per FHSA) [CPSC 2010a: Several studies listed]
- NTP stated no estrogenic effects
- NTP stated no reproductive/developmental effects 2003 [NTP-CERHR 2003a]
- *Change in guidelines for repro studies ~ 2000
- Limited studies in animals show developmental effects at high doses [NTP-CERHR 2003a]
- NTP insufficient info for humans [NTP-CERHR 2003a (developmental; repro notes not likely to affect human reproductive systems)]
- Anogenital distance not affected by DnOP [Saillenfait et al. 2011]
• DINP - Diisononyl phthalate - #28553-12-0; 68515-48-0
- Mixture if C9-rich, diC8 to C10 branched chain [CPSC2010g}]
- NTP said no concern in 2003 [NTP-CERHR 2003c]
- Probable developmental toxicant, probable liver/kidney histopathology [CPSC 2010g: Several studies listed]
- Key studies, testosterone production, anogenital distance [Borch et al. 2004; Boberg et al. 2011]
- Find effects at high dose; less potent
- DINP quantitatively different [than other phthalates such as DEHP] but not qualitatively [Hannas et al. 2011]
- Cumulative effects [CPSC 2010g]
- CA-OEHHA evaluating 12/5/13 for carcinogenicity, Prop 65 list
- 2000 2-Generation gross effects [Waterman et al. 2000]
- Liver and kidney tumors, not genotoxic [McKee et al. 2000]
- Peroxisomal proliferation [Kaufmann et al. 2002]
- Reduction in testosterone in utero (study) [Clewell et al. 2013a]
• DIDP - Diisodecyl phthalate - #26761‐40‐0; 68515‐49‐1
- Complex mixture of branched C9-C11 isomers containing mainly C10 isomers[CPSC 2010f]
- Unlikely to be carcinogenic to humans
- Liver and kidney effects (not carcinogenic)
o Do these translate to humans? (note mammalian beagle study, Hazelton 1968 w/ dose related increase in liver wt, but small sample size)[NTP-CERHR 2003b]
o Increased liver/kidney weights
o Peroxisomal Proliferation
- Metabolites ~ breaks down to carboxylic acid by oxidation, don’t get shorter side chain monoesters [ Saravanabhavan 2012]
- Minimal reproductive effects – Less potent than DEHP
- Kwack – No significant change in sperm count, but effect on sperm motility; less potent than DEHP [Kwack et al. 2009]
- Evidence for developmental effects – anti-androgenic effects [Lee and Koo 2007]; decreased pup survival, increase in skeletal malformations [CPSC 2010f, NTP-CERHR 2003b]
- No concern about skin sensitization
- Outstanding question: low dose thyroid study – Are there other studies?
- Are there other non-rat studies?
• DAP - Diallyl phthalate - #131-17-9
- C3 [CPSC 2011b]
- Liver – hepatotoxic – maternal effects – NOAEL 50 mg/kg [CPSC 2011b; Saillenfait et al. 2008]
- Nakai 1999 – most potent in ortho form to bind to estrogen receptor [Nakai et al. 1999]
- Reduced fetal weight 250 mg/kg and bone growth delay [Saillenfait et al. 2008]
- Not found to be teratogenic until >250 mg/kg [Saillenfait et al. 2008]
- Lowest effect dystocia (difficult labor) 50 mg/kg [CPSC 2011b]
- No mutagenic effects
- Uterine tumor effects (negative correlation – control highest) [NTP 1983]
- Saillenfait 2008 – carbon backbone length alone does not predict developmental effects [Saillenfait et al. 2008]
• DPHP - Di‐2‐propyl heptyl phthalate - #53306-54-0
- Only one study was reviewed; focused only on metabolites of several phthalates [Wittassek and Angerer 2007]
- Secondary oxidized metabolites are main metabolites; have longer half-lives than simple monoesters and therefore may reside longer in body (also true for DIDP, DINP)
- Dr. Barter:Readily found longer chain length oxidative metabolites in greater abundance in urine, but no difference in half life because they are readily oxidized
- Saravanabhavan (DINP, DIDP) [Saravanabhavan and Murray 2012]
o Secondary metabolites are better biomarkers of exposure as monoesters are oxidized quickly; secondary have longer half lives
o Dr. Barter disagrees: Oxidative metabolites in greater abundance in urine but no difference in half life; because they are readily oxidized.
- Dr Barter: A number of studies on DPHP are available in REACH, CPSC (not found in PubMed)
• DUP - Diundecyl phthalate - #3648‐20‐2
- C11 [CPSC 2010c]
- CPSC: sufficient animal evidence of hepatotoxicity (Kwack et al. 2009, Saillenfait et al. 2013) [CPSC 2010c; Saillenfait et al. 2013; Kwack et al. 2009]
- Kwack – significant effects sperm on sperm counts and motility [Kwack et al. 2009]
- Saillenfait et al. 2013
o Small decreases in anogenital distances in male fetuses
o Supernumerary lumbar ribs significantly higher than controls (this reverses)
• Din911P - 1,2‐Benzenedicarboxylic acid, 1‐nonyl 2‐undecyl ester, branched and linear - #111381-91-0
- C9-11 [CPSC 2010b]
- CPSC Cited EPA 2001 EM-BMS 1995 study [CPSC 2010b]
- General statement re: predictive/read across
- Peroxisomal proliferation- relevance to humans?
- Willoughby Repro/Developmental Toxicity
- Need more time on this chemical-warrants a better look.
- Question about maternal toxicity; EMBMS study only back to 1995 for literature
- 1970 CPSC repro; oral LD50 mice/rat > 20,000 mg/kg [CPSC 2010b; Brown et al. 1970]
- Systemic studies, some liver effects not of toxicological significance [CPSC 2010b; Brown et al. 1970]
- Some skin findings [CPSC 2010b: Brown et al. 1970]
• DIUP - Diundecyl phthalate, branched and linear - #85507‐79‐5
- C11 branched and linear [CPSC 2010d]
- Group noted it needs more time on this chemical.
- Peroxisomal proliferation in CPSC summary [CPSC 2010d: ECB 2000]
- Reproductive/Developmental no studies (2010) review [CPSC 2010d]
- European Chemicals Bureau, repeated dose toxicity evidence of peroxisomal proliferation [CPSC 2010d: ECB 2000]
- REACH dossier, read across to DIDP?
- EMBMS Holland 1985 – 21 day rat study
• DTDP - Ditridecyl phthalate & 1,2‐Benzenedicarboxylic acid, di‐C11‐14‐branched alkyl esters, C13‐rich - #119-06-2; 68515-47-9
- C13 rich [CPSC 2010e]; C11-C14
- Low acute toxicity [CPSC 2010e: NICNAS 2008]
- Japanese study showed small thymus effects in all dose groups – not statistically significant or dose related [CPSC 2010e: CIPC 2010b,c]
- Positive endocrine disruption effect likely due to BPA contamination) [CPSC 2010e: Harris et al. 1997]
- Is BPA contamination a common issue?
- Japanese study showed reproductive effects at higher doses [CPSC 2010e: CIPC 2010b,c]
- Developmental evidence not sufficient [CPSC 2010e: CIPC 2010b,c]
- Saillenfait no anogenital distance or other developmental effects at 250 mg/kg to 1 g/kg [Saillenfait et al. 2013]
- CPSC didn’t calculate ADI, limited studies [CPSC 2010e]
Overall Thoughts:
- Contamination of bedding and feed with phthalates - do low dose effects confound studies?
- General environmental exposure
- Effects in controls (study should control for these)
- Reproductive effect not many at low dose
- EPA report, non-monotonic dose response
o Mixtures are dose additive (effects additive)
- More studies on low doses (check with Dr. Gray)
- Richard Sharpe – BBP low doses 1990’s; low dose not reproducible
- Cumulative effects studies – see ECHA (distribute)
- Peroxisomal proliferation-see 1968 Beagle study
- Non-rodent PP studies. Rhesus monkeys/marmoset studies for liver effects [Dr. Barter]
- IARC – Peroxisomal proliferation
- Male reproductive/liver/skeletal present in most
- Kwack structure/effect [Kwack et al. 2009]
- Campbell metabolites cause teratogenicity [Campbell, et al, 1984]
- Look at REACH dossiers for all reproductive/developmental studies
- Program is adjusting the Reproductive Effects Table and will post a revised version on LibGuide.
- Change in guidelines for repro studies ~ 2000 [Dr. Foster]
Approve September Meeting Minutes
Amend to read “PBT Profiler information comparable.”
Vote: Approved: 6 in favor, 2 abstentions.
Review n-propyl bromide (nPB)
Heather confirmed that the Board received comments from Dr. Stelljes following the last meeting.
Consider Ethyl acetate as potential lower hazard substance
Program staff reviewed the status of Lower Hazard substances (LHS) and the benefits to companies for switching to them, including the removal of the per-chemical fee. LHS often serve as guidance for companies looking to switch away from the use of higher hazard substances. Board reviewed EHS comparison sheet, including environmental, health and safety information on Ethyl Acetate , Amyl Acetate (Delisted 2010), Iso-butyl Acetate (LHS), and Butyl Acetate (LHS).
Some notes from the discussion:
- Higher LC50
- Higher Exposure limit
- TLV higher
- Higher vapor pressure
- Lower flash point 24F (occupational safety issue)
- 10 million lbs used by 25 companies TURA
- Aquatic toxicity higher
- What is RfD based on?
o Rat study, NOEL 900 mg/kg
* Key effect, mortality/body weight loss
Motion: Recommend to Administrative Council the designation of Ethyl Acetate as a Lower Hazard Substance.
Vote: 8 in favor.
Next Meeting
Early February 2014 (Heather will send an email with dates)
Handouts (limited copies available):
• TURI – Response to comments from Exxon-Mobil Biomedical Sciences on the Ortho Phthalate Esters Scientific Data Sorted by Carbon Chain Length (Excel Sheet)
• TURI – Ethyl Acetate EHS Comparison with Amyl/Iso-butyl/Butyl Acetate Sheet (Updated 12/13)