1.Collection of relevant data – toxicity and exposure 2.Selection of critical studies and/or HCVs 3.Health risk assessment – systemic 4.Health risk assessment.

Slides:



Advertisements
Similar presentations
HYGIENE STANDARDS AND OCCUPATIONAL EXPOSURE LIMITS
Advertisements

Overview Nanomaterials and Risk Assessment (Example: RA for Inhaled Nanoparticles and Inhaled Benzene) Michael A. Jayjock, PhD CIH The LifeLine Group and.
Evaluation of a potential mutagenic MOA based on analysis of the weight of evidence and using the modified Hill criteria Martha M. Moore, Ph.D. Director,
© FSANZ © FSANZ 2002 FUNCTIONS OF FSANZ  FSANZ is a partnership between the Australian Commonwealth,
Regulatory Toxicology James Swenberg, D.V.M., Ph.D.
Classification of substances and mixtures on the basis of health hazard Semira Hajrlahović Mehić, LL.M. Tatjana Humar – Jurič, M.Sc.
Is depleted uranium a carcinogen? Keith Baverstock PhD Department of Environmental Science University of Kuopio Finland.
Chemical Carcinogens – workplace risk assessment and health surveillance Tiina Santonen Paide.
Risk Assessment.
Health Hazards The overall objective for this module is that given a Material Safety Data Sheet (MSDS), the participant will interpret health hazard information.
Fundamentals of Industrial Hygiene 6th Edition
W507 – Dose response and toxicity testing
CE 510 Hazardous Waste Engineering
Principles of Occupational Toxicology 2 – Types of toxicity
6/14/2012FDA/CVM 1 Tong Zhou, Ph.D., DABT Division of Human Food Safety Office of New Animal Drug Evaluation Center for Veterinary Medicine US Food and.
NSF/ANSI STANDARD 61 FRAMEWORK FOR RISK ASSESSMENTS For use by Toxicology Sub-committee only Please do not copy or distribute.
Copyright 2002 Marc Rigas Issues in Exposure Assessment Marc L. Rigas, Ph.D. National Exposure Research Laboratory, U.S. Environmental Protection Agency.
Information requirements for reproductive toxicity under REACH EU-OSHA Workshop Ulrike REUTER Senior Scientific Officer European Chemicals Agency 15. January.
Food and Drug Administration Preclinical safety data for “first in human” (FIH) clinical trials in healthy volunteer subjects Oncology Drug Advisory Committee.
ILSI Risk Science Institute Acrylamide Toxicity: Research to Address Key Data Gaps Presented by Dr. Stephen S. Olin ILSI Risk Science Institute.
Phthalates in Toys A number of different phthalates are used to manufacture toys and child care products Di-n-butyl phthalates makes up less than 0.01%
Toxicology Component of FDA’s Action Plan for Acrylamide Richard Canady, PhD DABT US Food and Drug Administration Center for Food Safety and Applied Nutrition.
Committee on Carcinogenicity (COC) Approach to Risk Assessment of Genotoxic Carcinogens David H. Phillips* COC Chairman Descriptive vs. Quantitative.
Determinants of Repeated exposure Toxicity
28/05/12 Questions (Rispondete alle domande che seguono usando il colore rosso per il testo) Tossicologia - Rubbiani Maristella.
TRAINING FOR THE HEALTH SECTOR
Approaches for Evaluating the Relevance of Multiroute Exposures in Establishing Guideline Values for Drinking Water Contaminants Kannan Krishnan, Université.
U.S. Food and Drug Administration Notice: Archived Document The content in this document is provided on the FDA’s website for reference purposes only.
Production of Nitric Acid Environmental Impact Assessment Erik TolonenNick Poulin Environmental Engineering Environmental Planning and Decision Making.
TOXICOLOGY Trina Redford, Industrial Hygienist National Naval Medical Center Naval Business Bldg 615, 2 nd Fl. Philadelphia, PA.
Health Hazards Instructional Goal
CA-1 Preclinical Studies Philip Bentley, PhD Vice President Toxicology/Pathology Novartis Pharmaceuticals Corporation Philip Bentley, PhD Vice President.
RISK ASSESSMENT. Major Issues to be considered in designing the Study 1.- Emission Inventory What is the relative significance of the various sources.
MAIN TOXICITY TESTING. TESTING STRATEGIES A number of different types of data are used in order to establish the safety of chemical substances for use.
Prof. Dr. Wolfgang Dekant Department of Toxicology University of Würzburg Germany Risk, Hazard, and Innovation.
1.Collection of relevant data – toxicity and exposure 2.Selection of critical studies and/or HCVs 3.Health risk assessment – systemic 4.Health risk assessment.
1.Collection of relevant data – toxicity and exposure 2.Selection of critical studies and/or HCVs 3.Health risk assessment – systemic 4.Health risk assessment.
Health risk assessment – systemic effects (1) REMINDER OF INHALED DOSE PG intake of 3.2 mg/day or mg/kg bw/day for a 60-kg bw consumer Systemic.
Unit 3 – Environmental Chemistry.  A pollutant is any material or energy that can cause harm to a living thing.  Pollution is a change to the environment.
EHS 507 Potential dose: the amount of chemical that is ingested or inhaled, or the amount of chemical contained in material applied to skin. Applied dose:
TOXICOLOGY OCCUPATIONAL HAZARDS CHEMICAL PHYSICAL ERGONOMIC PSYCHOLOGIC BIOLOGIC.
1.Collection of relevant data – toxicity and exposure 2.Selection of critical studies and/or HCVs 3.Health risk assessment – systemic 4.Health risk assessment.
NUATRC/TCEQ Air Toxics Workshop October Air Toxics Air Toxics: What We Know, What we Don’t Know, and What We Need to Know Human Health Effects –
1.Collection of relevant data – toxicity and exposure 2.Selection of critical studies and/or HCVs 3.Health risk assessment – systemic 4.Health risk assessment.
RISK DUE TO AIR POLLUTANTS
Health risk assessment – systemic effects (1) REMINDER OF INHALED DOSE PO intake is 7.2 mg/day 0.12 mg/kg bw/day for a 60-kg adult 2.
The Future of Chemical Toxicity Testing in the U.S.
Dose-Response ENVR430 Nov 09, 2009 Casarett and Doull, Chapter 2, pp (6 th Edn) Chapter 2, pp (7 th Edn) Timbrell Chapter 2, pp (3 rd.
TOXICOLOGY The study of chemical or physical agents and their interaction with biologic systems to produce a response in a organism. The dose makes the.
Toxic effects Acute / chronic Reversible / irreversible Immediate / delayed Idiosyncratic - hypersensitivity Local / systemic Target organs.
 DDT is a synthetic chemical compound once used widely in US and throughout the world as pesticide- a chemical substance used to kill weeds, insects,
Basic information OEL & PBOEL-HHC for API & IPI
The new chemicals risk matrices. Workshop focus use of new online categorisation tools criteria used to categorise new chemicals under the proposed framework.
Transforming Our World: Delivering affordable medicines to anyone, anywhere, any day 1 Health hazards of substances Annex 1 – Part 3 of CLP Date: Name:
Volker J. Soballa Evonik Degussa GmbH Essen, Germany
Acute Toxicity Studies Single dose - rat, mouse (5/sex/dose), dog, monkey (1/sex/dose) 14 day observation In-life observations (body wt., food consumption,
ICCA GPS Hazard Characterization
 Hazardous substances are those that, following worker exposure, can have an adverse effect on health. Examples of hazardous substances include poisons,
DOSE-RESPONSE ASSESSMENT
Prof.Dr. Bilal Cem LİMAN University of Erciyes Turkey
Use of sodium bromide in swimming pools resulting in exposure to bromate Kevin Cox Senior Research Toxicologist NSF International.
Use of Borates in Swimming Pools: Consideration of Health Effects
Chapter 6 Dose and Response. Chapter 6 Dose and Response.
Introduction to Environmental Engineering and Science (3rd ed.)
HYGIENE STANDARDS AND OCCUPATIONAL EXPOSURE LIMITS
Fundamentals of Industrial Hygiene 6th Edition
Safety Tests in Cosmetics
Bart Ostro, Chief Air Pollution Epidemiology Unit
TOXICOLOGY.
Risk, Toxicology, and Human Health
Presentation transcript:

1.Collection of relevant data – toxicity and exposure 2.Selection of critical studies and/or HCVs 3.Health risk assessment – systemic 4.Health risk assessment – respiratory tract irritation Presentation overview

Collect background exposure data Can be helpful Precursor to various polymers (especially polyesters) Use in cosmetics, pharmaceuticals, tobacco, food and drink Used in anti-freezing and cleaning agents, paints, resins and paper 3

Collect background exposure data Use in aerosol mists/smoke 1 ppm PG is equivalent to 3.11 mg/m 3 (based on MWt) No measured environmental or occupational air concentration data Estimated food flavouring intake is mg/kg bw/day in the US 4

Exposure example Propylene glycol (PG) intake = 3.2 mg/day [for systemic effects assessment] 600 puffs/day Puff volume 55 mL Total puff volume = m 3 Puff PG concentration = 97 mg/m 3 [for local effects assessment] 5

ADME data Oral – rapidly and extensively absorbed from the GI tract Inhaled – rapid pulmonary absorption; blood levels similar to those from oral administration Likely to be 100% for both routes Extensively metabolised to endogenous compounds (lactate, pyruvate, acetate, propionaldehyde) 6

Toxicity If available, start with likely key studies – inhalation acute, inhalation repeated Other route studies give additional insights into toxicity potential – oral, dermal Mutagenicity, carcinogenicity, reproductive/developmental, sensitisation, etc May use read-across data to fill gaps and/or enrich data set 7

Acute inhalation toxicity Humans (Wieslander et al.) 1 ‑ min exposure of 27 non-asthmatic volunteers to PG mist (concentration range 176 to 851 mg/m 3 ; geometric mean 309 mg/m 3 ), no symptoms indicative of systemic toxicity 8

Acute inhalation toxicity Laboratory animals (Werley et al.) 4-hr Rat LC 50 >44.9 g/m 3 No indication of multiple concentrations tested Nose-only exposure No mortality (7-day observation) 9

Acute inhalation toxicity Slight body weight decrease on day 1-3 though growth was normal by day 7 Mild irritation (localised bleeding around the eyes/nose) seen at day 7. Acute inhalation toxicity is very low 10

Humans – No data Laboratory animals - Study 1 (key study) by Suber et al. Effects on blood parameters Rats (group size unspecified) exposed to PG vapour 0, 160, 1000 and 2200 mg/m 3 for 90 days (no further duration data given but assumed to be 6 hr/day, 5 days/wk) Repeated dose inhalation toxicity 11

SYSTEMIC EFFECTS – Females: decreased white blood cell (WBC) counts at 1000 mg/m 3 and above; decreased mean corpuscular haemoglobin concentrations at top concentration; no dose-related changes in RBCs were observed in males. NOAEC for systemic = 160 mg/m 3 Repeated dose inhalation toxicity 12

LOCAL EFFECTS – Nasal haemorrhaging at LOAEC of 160 mg/m 3 ; thickened respiratory epithelium with enlarged goblet cells at higher concs; no local NOAEC determined No details given regarding examination. Study was reported by ATSDR (i.e. check to confirm details). Repeated dose inhalation toxicity 13

Laboratory animals – Study 2 (supporting study) Limited reporting of study details in profile Rhesus monkeys and rats, continuous exposure to PG concs up to 350 mg/m 3 for months caused no adverse effects on the respiratory system Increased haemoglobin counts seen in monkeys 14

Laboratory animals – Study 3 (supporting study) Limited reporting of study details in profile 28-day inhalation studies in rats and dogs Systemic NOELs of 20 and 6.05 mg/kg bw/day, respectively 15

Other toxicity data – Acute oral/dermal Human Unreliable TDLo values of 10 and 79 g/kg bw for children (oral) Behavioural/brain/metabolic changes at very high doses Non-human Oral LD 50 >>2 g/kg bw in rats, mice, rabbits, guinea pigs and dogs Dermal toxicity is also very low in rabbits 16

Repeated oral dose studies Human - no data Non-human - various studies are available. Rats (30/sex/dose) given PG in diet at 0, 0.625, 1.25, 2.5 and 5% (nominal doses of 310, 630, 1300 or 2500 mg/kg bw/day) for 2 yr. No treatment-related adverse effects on growth, haematology, urine, clinical chemistry, or organ weights. No details on the effects (evidently not considered adverse) seen at the high dose. The NOEL was 1300 mg/kg bw per day (though expert groups have said the top-dose was the NOAEL, and cited this as providing 1700 or 2500 mg/kg bw/day) 17

Repeated oral dose studies Rats exposed in drinking water for 140 days at calculated doses of 1.6, 3.7, 7.7 or 13.2 g/kg bw/day i.e. well above limit dose of 1000 mg/kg/day established (by EPA) for an oral subchronic toxicity study in rats (CNS effects at top dose, see later). No histopathological abnormalities [no details of gross examination] Dogs dosed at 2 or 5 g/kg in the diet for 2 years; minor blood effects at higher dose Conclusion: PG is well-tolerated by the oral route 18

Repeated dermal dose studies Female mice (group size unknown) 2.1, 10 or 21 mg/day over a lifetime Extent of examination was not specified in the profile (study listed as “chronic exposure/carcinogenicity”) No adverse effects reported (but poor reporting in abstract) 19

Genotoxicity Expect to assess all studies for quality and reliability Overview: Inactive in Ames bacterial reverse mutation tests Inactive in mammalian cell assays for chromosome aberration Inactive in mammalian cell assays for sister chromatid exchange 20

Genotoxicity Inactive mammalian cell assay for mutation Induced DNA damage in mouse oocytes but only at very high concs Inactive for in vivo micronucleus induction Inactive in dominant lethal assay in vivo Conclusion: PG is not mutagenic 21

Carcinogenicity No human data Non-human Overview: Limited details only on study and extent of examination Rhesus monkeys and rats (unspecified group sizes) continuous exposure to PG concs up to 350 mg/m 3 for months, no increase in tumour incidence No evidence of carcinogenicity in a 2-yr dietary rat study at up to a nominal dose of 2500 mg/kg bw/day Unchanged tumour incidences in dogs at up to 5 g/kg bw/day in diet for 2 yr [short study for dogs] 22

Reproductive and developmental toxicity Human - no data Non-human No repro/developmental toxicity in various NTP studies (rats, mice, hamsters and rabbits) at oral doses of >1000 mg/kg bw/day (during pregnancy) Conclusion: Repro/developmental toxicity is not a critical endpoint for PG 23

Other relevant data – skin irritation Human Many studies so focus on Expert Groups CIR refs: 138 irritant reactions upon patch testing (48-hr closed /covered) of 866 patients with neat PG; 190 irritant reactions when 1556 patients patch tested with neat PG )duration not specified) OECD report of patch testing studies (n>300) demonstrates PG is “not irritating to skin” 24

Other relevant data – skin irritation Non-human Undiluted PG was at most a mild dermal irritant in a Draize test using rabbits with intact and abraded skin Conclusion: skin irritation – mild 25

Other relevant data – eye irritation Human Again note Expert Groups 1 min exposure of volunteers to a PG mist (concentration range 176 to 851 mg/m 3 ; geometric mean 309 mg/m 3 ) induced reduced tear film stability and sensations of eye irritation 26

Other relevant data – eye irritation OECD report of patch testing studies (n>300) demonstrates PG is “not irritating to eye” Non-human mL PG [presumably 100%] was non-irritating in rabbits Conclusion: vapour may cause mild eye irritation 27

Other relevant effects – neurotoxicity Some evidence of neurotoxicity (e.g. CNS depression) has been seen in humans and laboratory animals exposed to high levels of PG. In rats, such effects are seen following subchronic oral (drinking water) treatment with doses exceeding 13,200 mg/kg bw/day 28

Other relevant effects – sensitisation and intolerance No data on respiratory sensitisation Human OECD report of patch testing studies (n>300) - PG is “does not cause sensitisation upon skin contact” CIR reports note a very small number of allergic reactions in large-scale patch tests 29

Other relevant effects – sensitisation and intolerance Non-human Series of skin sensitisation tests, 70% solutions do not sensitise guinea pigs Conclusion: PG lacks significant sensitising potential NB. PG is actually a vehicle control for the LLNA 30

Additional useful information regarding classification C&L inventory – no harmonised classification Most notifiers (4551/4862) did not classify PG as hazardous Classified as a respiratory tract, skin and eye irritant by 0, 9 and 52 suppliers, respectively Classified for sensitisation by 0 suppliers (skin or respiratory tract) 31

Expert Group Health Criteria Values No inhalation HCVs (applicable to the general population) for PG were identified in the profile. However, the REACH dossier includes a DNEL for systemic effects in the general population exposed long-term by inhalation. While this is not an HCV as such, it does nevertheless provide the submitter’s view of a tolerable level: 32

Expert Group Health Criteria Values HCV (mg/m 3 ) Basis 50 The EU REACH registration dossier on PG includes long-term inhalation DNELs (derived no-effect levels) of 50 mg/m 3 for systemic effects and 10 mg/m 3 for local effects in the general population. Detail on the ECHA website is insufficient for easy or independent verification. An assessment factor (AF) of 5 (for intraspecies differences alone) was applied to an NOAEC of 250 mg/m 3. As an interspecies AF of 1 was applied the data used for the derivation is likely to have been human rather than experimental animal, though there was no further information provided in the dossier

Occupational Exposure Levels Inhalation HCVs HCV (mg/m 3 ) Basis UK HSE WEL (8-hr TWA) 10 (particulate s) No details available. 474 (total vapour and particulates ) Long-term DNEL (worker) 168 The derivation of the REACH DNELs is unclear. Apparently an AF of 3 was applied to an NOAEC (which would be about 500 mg/m 3 ) to generate the chronic systemic value for workers, and a factor of 9 was applied to an LOAEC (which would be about 90 mg/m 3 ) for local effects

Key HCVs for other routes of exposure Other HCVs HCV (mg/kg bw/day) BasisReference Oral acceptabl e daily intake (ADI) 0-25 Presumably from application of a total UF of 100 to the NOAEL of 2500 mg/kg bw/day observed in the 2- year rat study JECFA,