Indoor Air Reference Levels for Chronic Exposure to Volatile Organic Compounds

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Organization: Health Canada

Date published: 2018-02-05

Water and Air Quality Bureau
Healthy Environments and Consumer Safety Branch

Health Canada is the federal department responsible for helping the people of Canada maintain and improve their health. We assess the safety of drugs and many consumer products, help improve the safety of food, and provide information to Canadians to help them make healthy decisions. We provide health services to First Nations people and to Inuit communities. We work with the provinces to ensure our health care system serves the needs of Canadians.

Également disponible en français sous le titre : Niveaux de référence dans l’air intérieur liés à l’exposition chronique aux composés organiques volatils : document de synthèse

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Publication date: October 2017

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Cat.: H144-48/2017E-PDF
ISBN: 978-0-660-23532-5

Table of contents

List of tables

List of acronyms

AEL
Adverse Effect Level
ATSDR
Agency for Toxic Substances and Disease Registry
BMC
benchmark concentration
BMCL
benchmark concentration (lower limit of a one-sided 95% confidence interval on the BMC)
BMD
benchmark dose
BMDL
benchmark dose (lower limit of a one-sided 95% confidence interval on the BMD)
CalEPA
California Environmental Protection Agency
COHb
carboxyhemoglobin
DAF
dosimetric adjustment factor
HEC
human equivalent concentration
IARL
indoor air reference level
LEC
lowest effective concentration
LOAEL
lowest observed adverse effect level
NOAEL
no observed adverse effect level
PBPK
physiologically based pharmacokinetic
PoD
point of departure
RfC
reference concentration
RGDR
regional gas dose ratio
RIAQG
Residential Indoor Air Quality Guideline
RIVM
National Institute for Public Health and the Environment
TC
tolerable concentration
TC01, TC05
tumorigenic concentration (concentration of a contaminant in air generally associated with a 1% or 5% increase in incidence or mortality due to tumours, respectively)
TRV
toxicological reference value
UF
uncertainty factor
UFA
uncertainty factor for interspecies variability
UFDB
uncertainty factor for database deficiency
UFH
uncertainty factor for intraspecies variability
UFL
uncertainty factor for use of a LOAEL or effect level extrapolation factor
UFs
uncertainty factor for study duration
US EPA
United States Environmental Protection Agency
VCCEP
Voluntary Children’s Chemical Evaluation Program
VOC
volatile organic compound
WHO
World Health Organization

1.0 Introduction

Volatile organic compounds (VOCs) are a diverse group of chemicals characterized by a high vapour pressure, as they are emitted in the form of a gas from solids or liquids at ordinary room temperatures.Footnote 1 They are ubiquitous since they are found in both ambient and indoor air.

Known or suspected human health effects of VOCs vary considerably from one compound to another and with respect to the level of exposure. Levels of different VOCs present in the home depend on indoor sources (e.g., smoking, cooking, combustion appliances, building materials, furniture, and a wide range of consumer products) as well as infiltration of VOCs from outdoors (Health Canada 2017) or from an attached garage (Mallach et al. 2017). Strength of emissions, changes in emissions over time, adsorption and desorption processes, secondary reactions with other chemicals, and amount of ventilation in different rooms and in the house as a whole, all influence the levels of VOCs that may be measured at any given time.

For a given VOC, the indoor air reference level (IARL) for chronic exposure is an estimate of a concentration limit for continuous long-term inhalation exposures (up to a lifetime) below which adverse health effects are not expected to occur. In the case of carcinogenic substances, the IARL is an estimate of the continuous lifetime exposure associated with a negligible cancer risk.Footnote 2 The IARL applies to the general population including vulnerable subgroups.

Indoor air reference levels are intended to supplement Health Canada’s Residential Indoor Air Quality Guidelines (RIAQGs), which are based on comprehensive reviews of the literature, are externally peer-reviewed, and are submitted for public comment. In developing IARLs, the Health Canada review is limited to hazard assessments from internationally recognized health and environmental organizationsFootnote 3 and the key studies identified in these assessments.

This overview document provides a summary of IARLs for chronic exposure to VOCs that are current as of December 2016. This document, along with the derived IARLs, will be updated periodically to reflect changes in the hazard assessments that form the basis of these values. Details on the methodology for selecting VOCs for evaluation and deriving IARLs can be found in the companion document Derivation of Health Canada Indoor Air Reference Levels: Methodology for Volatile Organic Compounds (Health Canada 2013). The methodology describes criteria for evaluating hazard assessments on the basis of the strength of the underlying science as well as consistency with Health Canada policies and practice.

2.0 Considerations in the determination of indoor air reference levels

Authoritative agencies and organizations follow similar procedures for conducting hazard assessments for cancer and non-cancer endpoints. Generally, hazard assessments lead to the derivation of toxicological reference values (TRVs). The TRV nomenclature varies among the different organizations and includes chronic reference exposure level, reference concentration (RfC), tolerable concentration (TC), and minimal risk level. These all provide a quantitative value below which adverse non-cancer health effects are not expected to be observed for durations of up to a lifetime exposure, including consideration of vulnerable and susceptible subpopulations. For non-threshold carcinogenic effects, the TRVs are often referred to as cancer potency factors, slope factors or inhalation unit risks. For these TRVs, it is necessary to define the level of potential excess lifetime cancer risk that would be considered negligible or acceptable. For the purpose of IARLs, a risk level of 1 in 100 000 is retained.

For some VOCs, both cancer and non-cancer TRVs have been derived. Assessments for cancer and non-cancer health endpoints are considered independently, and the most appropriate TRV for each effect is identified. The IARL is typically based on the most conservative value of the selected cancer and non-cancer TRVs, but might vary depending on the mode of action of carcinogenesis.

No IARL was determined in cases where the available assessments were considered inadequate. The specific reasons for such a conclusion are included in the rationale of the individual substance report.

3.0 Application of indoor air reference levels

The primary use of IARLs is to evaluate the health impacts of indoor VOC emissions from building materials and consumer products. On the basis of the measured emission factors and assumptions about typical product use and building characteristics, indoor air concentrations of different VOCs can be estimated. The associated potential health risks may then be evaluated by comparing estimated concentrations with IARLs.

In addition to working to promote the development of Canadian standards, Health Canada may collaborate with other international organizations in developing new health-based emission standards or in promoting the use of an existing standard. The IARLs provide benchmarks for Health Canada to evaluate VOC product emission standards produced internationally and endorse such standards when appropriate.

In some cases, a VOC may be produced primarily by sources other than building materials or consumer products (e.g., certain VOCs produced by fuel combustion). In these cases, IARLs may also be used to identify VOCs in the indoor environment of greatest potential concern to health and in support of the development of appropriate risk management actions.

Derivation of an IARL is also the first step in determining if a full assessment leading to an RIAQG is required and if so, the level of priority for such an assessment. The framework for this prioritization process is included as well in the aforementioned Health Canada document published in 2013. If an RIAQG is subsequently developed, this guideline value would supersede the IARL in risk management and communication actions.

4.0 Uncertainties and assumptions in hazard and exposure assessments

All hazard assessments must consider the uncertainties in the underlying toxicological and epidemiological data. Assumptions with respect to intraspecies variability, interspecies extrapolation, and/or extrapolation from high to low levels of exposure as well as adjustments related to exposure patterns and duration of toxicological studies are inherent in the hazard assessment process. The completeness of the scientific literature with respect to the range of potential health effects on different subpopulations also varies considerably from one compound to another. In deriving a TRV, these uncertainties are addressed through the use of uncertainty factors applied in a precautionary manner. Variability and uncertainty can also be addressed using chemical-specific data (e.g., with the application of physiologically-based pharmacokinetic models or chemical-specific adjustment factors). This approach allows health organizations to determine a level of exposure that would not be expected to result in adverse effects, based on the information available at the time of the assessment.

There are also major uncertainties in estimating indoor air concentrations over long periods of time in Canadian homes. In particular, if the indoor air concentration is modelled on the basis of VOC emissions from products, as measured in chamber tests, the estimated long-term indoor air concentration may be quite different from the actual measured concentration over time. Factors influencing this estimate include the number and type of source materials, patterns of use, age of the material, and rate of decay of the emissions over time as well as home environmental conditions (e.g., temperature, humidity, ventilation rate, presence of reactive compounds). If the indoor air concentration is based on measured concentrations in Canadian homes, the type, location, and number of homes as well as the demographics of the study participants may limit the representativeness of the measured concentrations.

Given these uncertainties, any comparison of an estimated indoor air concentration with an IARL should be interpreted as providing an indication of potential risk and not a measure of actual risk. The level of uncertainty in risk estimates may be reduced through additional health or exposure data. For example, population-based epidemiological studies may provide more information for evaluating health effects at low concentrations typically encountered in the home. Furthermore, emission testing under more realistic conditions, or modelling with inputs that are more specific to the material or environment under consideration, may also reduce the overall uncertainty in risk estimates.

5.0 Indoor air reference levels

The methodology for selecting IARLs has been previously presented (Health Canada 2013). Table 1 summarizes the IARLs identified for selected VOCs as well as the critical effect on which the IARL is based and the source of the underlying TRV. Summary tables of the TRVs are presented in Section 6.

The derivation of each IARL is documented in a separate report. These individual substance reports are available upon request (air@hc-sc.gc.ca).

Indoor air reference levels were not reported for acetaldehyde as Health Canada is currently undertaking a full risk assessment. Should new data become available for the remaining VOCs, a reevaluation of the IARLs will be completed on a cyclical basis.

Table 1. Indoor Air Reference Levels
VOCTable 1 - Footnote 1 IARL
(µg/m3)
Critical Effect Reference
Cancer Non-Cancer

1,3-Butadiene

1.7

leukemia

-

EC/HC (2000a)

1,4-Dichlorobenzene

60

-

nasal lesions

ATSDR (2006)

2-Butoxyethanol

11 000

-

hematological effects

EC/HC (2002)

2-Ethoxyethanol

70

-

testicular degeneration and hematological changes

CalEPA (2000)

3-Chloropropene

1

-

peripheral nerve damage

US EPA (1991)

AcetaldehydeTable 1 - Footnote 2

 

- - -

Acetone

70 000

-

developmental effects

VCCEP (2003)

Acrolein

0.35

-

respiratory epithelial lesions

CalEPA (2008)

Aniline

1

-

effects on spleen

US EPA (1990a)

Carbon tetrachloride

1.7

adrenal gland tumours

-

US EPA (2010)

Chloroform

300

-

kidney and liver toxicity

CalEPA (2000)

Cyclohexane

6000

-

reduced pup weight

US EPA (2003a)

Dichloromethane

600

-

effects on liver

US EPA (2011)

Epichlorohydrin

1

-

histological changes in the nose

US EPA (1994)

Ethylbenzene

2000

-

effects on, pituitary gland and liver

CalEPA (2000)

Ethylene oxide

0.002

lymphoid and breast cancer

-

US EPA (2016)

Isopropyl alcohol

7000

-

kidney lesions

CalEPA (2000)

IsopropylbenzeneTable 1 - Footnote 3

400

-

effects on kidney

US EPA (1997)

Methyl ethyl ketone

5000

-

developmental effects

US EPA (2003b)

Methyl isobutyl ketoneTable 1 - Footnote 3

3000

-

developmental effects

US EPA (2003c)

Propionaldehyde

8

-

olfactory epithelium atrophy

US EPA (2008)

Propylene oxide

2.7

nasal cavity tumours

-

US EPA (1990b)

Styrene

850

-

neurotoxicity

ATSDR (2010)

Tetrachloroethylene

40

-

neurotoxicity, visual impairment, and neurobehavioural effects

US EPA (2012), ATSDR (2014)

Toluene diisocyanate

0.008

-

decreased lung function

CalEPA (2016)

Xylenes, mixture

100

-

increased sensitivity to pain

US EPA (2003d)

6.0 Table of TRVS for individual VOCS

TOXICOLOGICAL REFERENCE VALUES FOR 1,3-BUTADIENE (CAS No. 106-99-0)
OrganizationTable 2 - Footnote 1 NEOPLASTIC NON-NEOPLASTIC
CalEPA Health CanadaTable 2 - Footnote 2 US EPA CalEPA US EPA

Year of publication

1992Table 2 - Footnote 3

2000

2002

2013Table 2 - Footnote 3

2002

Species

Mice

Humans

Humans

Mice

Mice

Endpoint

Lung tumours

Leukemia

Leukemia

Ovarian atrophy

Ovarian atrophy

Unit risk (µg/m3)-1

1.7 x 10-4

5.9 x 10-6

3 x 10-5

- -

Concentration at 1 x 10-5 risk level (µg/m3)

17

1.7

0.3

- -

Point of departure

- - -

BMCL05 HEC = 0.664 mg/m3

BMCL10 HEC = 2 mg/m3

Uncertainty factorsTable 2 - Footnote 4

- - -

300
(UFH = 10, UFA = 30)

1000
(UFH = 10, UFA = 3, UFL = 10, UFDB = 3)

Concentration (µg/m3)

- - -

2.2

2

Critical studyTable 2 - Footnote 5

1

2

2

3

3

Comments

-

TC01 = 1.7 mg/m3

Unit risk = (0.01)/TC01

LEC01 = 300 µg/m3 with adjustments from Health Canada and further adjustment for cancer incidence not mortality.
Factor of 2 applied to adjust for potential for females to be more susceptible.

BMCL05 HEC: Benchmark concentration adjusted for continuous exposure and dosimetric differences between rats and humans (using PBPK model data):
BMCL05 x 5/7 days x 6/24 hours x 1.68 DAF

US EPA expressed medium confidence in the study selected, but low confidence in the dataset and resulting reference concentration. [Suggested by application of UFL to a BMCL.]
BMCL10 HEC based on 2 lower doses, adjusted for continuous exposure and time to response (5/7 days x 6/24 hours).
ppm equivalence across species assumed (equal to use RGDR = 1)
UFDB mainly for lack of 2-generational reproductive and neurodevelopmental studies.

TOXICOLOGICAL REFERENCE VALUES FOR 1,4-DICHLOROBENZENE (CAS No. 106-46-7)
OrganizationTable 3 - Footnote 1 NEOPLASTIC NON-NEOPLASTIC
CalEPA ATSDRTable 3 - Footnote 2 CalEPA Health Canada RIVM US EPA

Year of publication

1999Table 3 - Footnote 3

2006

2001Table 3 - Footnote 3

1993c; 1996

2001

1994

Species

Mice

Rats

Rats

Rats

Rats

Rats

Endpoint

Liver tumours

Nasal lesions

Reduced body weight and food consumption; tremors; nasal and ocular discharge; increased liver and kidney weights

Increased liver and kidney weights; increased urinary protein/coproporphyrin

Increased liver and kidney weights; increased urinary protein/coproporphyrin

Increased liver weight

Unit risk (µg/m3)-1

1.1 x 10-5

- - - - -

Concentration at 1 x 10-5 risk level (µg/m3)

0.9

- - - - -

Point of departure

-

LOAEL = 450 mg/m3
NOAEL = 120 mg/m3
BMCL10 = 57 mg/m3
BMCL10 ADJ = 10 mg/m3
BMCL10 HE = 1.6 mg/m3

LOAEL = 900 mg/m3
NOAEL = 300 mg/m3
NOAELADJ = 78mg/m3
NOAELHE = 78 mg/m3

LOAEL = 3000 mg/m3
NOAEL = 450 mg/m3
NOAELADJ = 67 mg/m3
NOAELHEC = 48 mg/m3

LOAEL = 3000 mg/m3
NOAEL = 450 mg/m3
NOAELADJ = 67 mg/m3

LOAEL = 900 mg/m3
NOAEL = 300 mg/m3
NOAELADJ = 75 mg/m3
NOAELHEC = 75 mg/m3

Uncertainty factorsTable 3 - Footnote 4

-

30
(UFH = 10, UFA = 3)

100
(UFH = 10, UFA = 3, UFS = 3)

500
(UFH = 10, UFA = 10, UFS = 5)

100
(UFH = 10, UFA = 10)

100
(UFH = 10, UFA = 3, UFS = 3)

Concentration (µg/m3)

-

60

800

95

670

800

Critical studyTable 3 - Footnote 5

1

2, 3

4

5

6

4

Comments

-

BMCL10 HE = NOAEL x 5/7 days x 6/24 hours x 0.16 (RGDR)

NOAELHEC = NOAEL x 7/7 days x 6/24 hours x 1.0 (RGDR)

NOAELHEC = NOAEL x 5/7 days x 6/24 hours x 0.71 (breathing rate adjustment)

NOAELADJ = NOAEL x 5/7 days x 5/24 hours x 0.71 (breathing rate adjustment).
Appears to be same critical study as Loeser and Litchfield (1983).

NOAELHEC = NOAEL x 7/7 days x 6/24 hours

TOXICOLOGICAL REFERENCE VALUES FOR 2-BUTOXYETHANOL (CAS No. 111-76-2)
OrganizationTable 4 - Footnote 1 NON-NEOPLASTIC
ATSDR Health CanadaTable 4 - Footnote 2 US EPA

Year of publication

1998

2002

2010

Species

Humans

Rats

Rats

Endpoint

Hematological effects

Hematological effects

Hemosiderin deposition

Point of departure

NOAEL = 2.9 mg/m3

BMC05 = 5.3 mg/m3

BMCL10,HEC = 16 mg/m3

Uncertainty factorsTable 4 - Footnote 3

3
(UFH = 3)

0.5
(UFH = 10, UFA = 0.05)

10
(UFH = 10, UFA = 1, UFDB = 1)

Concentration (µg/m3)

970

11 000

1600

Critical studyTable 4 - Footnote 4

1

2

2

Comments

The small significant effects on hematological parameters reported in humans were within the range of normal clinical values (hence the concentration was designated a NOAEL).

UFA includes adjustment factors of 0.5 (toxicokinetics) and 0.1 (toxicodynamics) to account for lower sensitivity of humans compared to rats.

The BMCL10,HEC was back-calculated from the BMCL10 for 2-butoxyacetic acid (area under the curve in blood = 133 µmol-hour/L) using a PBPK model.

US EPA has high confidence in the study, and a medium-to-high confidence in the RfC and database.

TOXICOLOGICAL REFERENCE VALUES FOR 2-ETHOXYETHANOL (CAS No. 110-80-5)
Organization NON-NEOPLASTIC
CalEPATable 5 - Footnote 1 US  EPA WHO

Year of publication

2000Table 5 - Footnote 2

1991

2010

Species

Rabbits

Rabbits

Rats

Endpoint

Testicular degeneration and hematological changes

Testicular degeneration and hematological changes

Developmental toxicity

Unit risk (µg/m3)-1

- - -

Concentration at 1 x 10-5 risk level (µg/m3)

- - -

Point of departure

NOAEL = 380 mg/m3
NOAELADJ = 68 mg/m3
NOAELHEC = 68 mg/m3

NOAEL = 380 mg/m3
NOAELADJ = 68 mg/m3
NOAELHEC = 68 mg/m3

NOAEL = 40 mg/m3
NOAELADJ = 10 mg/m3

Uncertainty factorsTable 5 - Footnote 3

1000
(UFH = 10, UFA = 10, UFS = 10)

300
(UFH = 10, UFA = 3, UFS = 10)

100
(UFH = 10, UFA = 10)

Concentration (µg/m3)

70

200

100

Critical studyTable 5 - Footnote 4

1

1

2, 3

Comments

LOAEL = 1485 mg/m3

NOAELADJ = NOAEL x 6 hours/24 hours x 5 days/7 days

NOAELHEC = NOAELADJ x 1 (RGDR)

LOAEL = 1485 mg/m3

NOAELADJ = NOAEL x 6 hours/24 hours x 5 days/7 days

NOAELHEC = NOAELADJ x 1 (RGDR)

US EPA has medium confidence in the study, database and RfC.

NOAELADJ = NOAEL x 6 hours/24 hours

TOXICOLOGICAL REFERENCE VALUES FOR 3-CHLOROPROPENE (CAS No. 107-05-1)
Organization NEOPLASTIC NON-NEOPLASTIC
CalEPA US EPATable 6 - Footnote 1

Year of publication

1999Table 6 - Footnote 2

1991

Species

Mice

Rabbits and rats

Endpoint

Squamous cell papillomas and carcinomas of the forestomach

Peripheral nerve damage

Unit risk (µg/m3)-1

6.0 x 10‑6

-

Concentration at 1 x 10-5 risk level (µg/m3)

1.67

-

Point of departure

-

NOAEL = 17 mg/m3
NOAELADJ = 3.6 mg/m3
NOAELHEC  = 3.6 mg/m3

Uncertainty factorsTable 6 - Footnote 3

-

3000
(UFH = 10, UFA = 3, UFS = 10, UFDB = 10)

Concentration (µg/m3)

-

1

Critical studyTable 6 - Footnote 4

1

2

Comments

Inhalation unit risk derived from an oral cancer potency factor in female mice exposed by gavage

NOAELADJ = NOAEL x 6 hours/24 hours x 6 days/7 days

NOAELHEC  = NOAELADJ x 1 (RGDR)

US EPA has low confidence in the study, database and RfC.

TOXICOLOGICAL REFERENCE VALUES FOR ACETONE (CAS No. 67-64-1)
OrganizationTable 7 - Footnote 1 NON-NEOPLASTIC
ATSDR VCCEPTable 7 - Footnote 2

Year of publication

1994

2003

Species

Humans

Rats

Endpoint

Neurological effects

Developmental effects

Point of departure

LOAEL = 3000 mg/m3

NOAEL = 5300 mg/m3
NOAELHEC = 2100 mg/m3

Uncertainty factorsTable 7 - Footnote 3

100
(UFH = 10, UFL = 10)

30
(UFH = 10, UFA = 3)

Concentration (µg/m3)

31 000

70 000

Critical studyTable 7 - Footnote 4

1

2

Comments

-

NOAELHEC calculated using PBPK modelling

TOXICOLOGICAL REFERENCE VALUES FOR ACROLEIN (CAS No. 107-02-8)
OrganizationTable 8 - Footnote 1 NON-NEOPLASTIC
CalEPATable 8 - Footnote 2 Health Canada US EPA

Year of publication

2008Table 8 - Footnote 3

2000

2003

Species

Rats

Rats

Rats

Endpoint

Respiratory epithelial lesions

Respiratory epithelial lesions

Respiratory epithelial lesions

Point of departure

LOAEL = 1400 µg/m3
NOAEL = 460 µg/m3
NOAELADJ = 82 µg/m3
NOAELHEC = 70 µg/m3

BMC05 = 141 µg/m3
BMC05 ADJ = 35 µg/m3

LOAEL = 900 µg/m3
LOAELADJ = 160 µg/m3
LOAELHEC = 20 µg/m3

Uncertainty factorsTable 8 - Footnote 4

200
(UFH = 10, UFA = 2 (toxicokinetics) x 3 (toxicodynamics), UFS = 3)

100
(UFH = 10, UFA = 10)

1000
(UFH = 10, UFA = 3, UFL = 3, UFS = 10)

Concentration (µg/m3)

0.35

0.4

0.02

Critical studyTable 8 - Footnote 5

1

2

3

Comments

NOAELHEC = NOAEL x 5/7 days x 6/24 hours x 0.85 (DAF)
UFA of 2 (toxicokinetics) was due to uncertainty in use of a DAF from a chemical analogue.

BMC05 ADJ = BMC05 x 6/24 hours
Based on a 3-day rat inhalation study with only 5 to 6 males for each of 2 treated doses; LOAEL approach also considered.

NOAELHEC = NOAEL x 5/7 days x 6/24 hours x 0.14 (RGDR)
The UFL was for use of a minimal LOAEL. Dose-related effects were observed, although only in 1 out of 12 animals at this dose. Similar effects were observed at a lower dose in another study.

TOXICOLOGICAL REFERENCE VALUES FOR ANILINE (CAS No. 62-53-3)
Organization NEOPLASTIC NON-NEOPLASTIC
CalEPA US EPATable 9 - Footnote 1

Year of publication

1999Table 9 - Footnote 2

1990

Species

Rats

Rats

Endpoint

Spleen tumours

Effects on spleen

Unit risk (µg/m3)-1

1.6 x 10‑6

-

Concentration at 1 x 10-5 risk level (µg/m3)

6.25

-

Point of departure

-

NOAEL = 19 mg/m3
NOAELADJ = 3.4 mg/m3
NOAELHEC = 3.4 mg/m3

Uncertainty factorsTable 9 - Footnote 3

-

3000
(UFH = 10, UFA = 10, UFS = 10, UFDB = 3)

Concentration (µg/m3)

-

1

Critical studyTable 9 - Footnote 4

1

2, 3

Comments

Based on a US EPA oral slope factor. US EPA (1994) did not derive an inhalation unit risk.

NOAELADJ = NOAEL x 6 hours/24 hours x 5 days/7 days

NOAELHEC = NOAELADJ x 1 (RGDR)

US EPA has low confidence in the study, database and RfC.

TOXICOLOGICAL REFERENCE VALUES FOR CARBON TETRACHLORIDE (CAS No. 56-23-5)
NEOPLASTIC NON-NEOPLASTIC
OrganizationTable 10 - Footnote 1 CalEPA US EPATable 10 - Footnote 2 ATSDR CalEPA RIVM US EPA WHO

Year of publication

1987Table 10 - Footnote 3

2010

2005

2001Table 10 - Footnote 3

2001

2010

1999

Species

Mice

Mice

Rats

Guinea pigs

Rats

Rats

Rats

Endpoint

Hepatomas

Adrenal gland tumours

Liver toxicity

Liver toxicity

Liver toxicity

Liver toxicity

Liver and kidney toxicity

Unit risk (µg/m3)-1

4.2 x 10-5

6 x 10-6

- - - - -

Concentration at 1 x 10-5 risk level (µg/m3)

0.24

1.7

- - - - -

Point of departure

- -

NOAEL = 32 mg/m3
NOAELHEC = 5.7 mg/m3

LOAEL = 32 mg/m3
LOAELHEC = 11 mg/m3

NOAEL = 32 mg/m3
NOAELHEC = 6.3 mg/m3

BMCL10 HEC = 14.3 mg/m3

(1) NOAEL = 6.1 mg/m3
(2) NOAEL = 32 mg/m3; NOAELHEC = 6.7 mg/m3
(3) NOAEL = 32 mg/m3; NOAELHEC = 5.7 mg/m3

Uncertainty factorsTable 10 - Footnote 4

- -

30
(UFH = 10, UFA = 3)

300
(UFH = 10, UFA = 3, UFL = 3, UFS = 3)

100
(UFH = 10, UFA = 10)

100
(UFH = 10; UFA = 3; UFDB = 3)

(1) 1000
(UFH = 10, UFA = 10, UFS = 10)
(2) 1000
(UFH = 10, UFA = 10, UFS = 10)
(3) 500
(UFH = 10, UFA = 10, UFL = 5)

Concentration (µg/m3)

- -

190

40

60

100

(1) 6.1
(2) 6.7
(3) 11.4

Critical studyTable 10 - Footnote 5

1

2, 3

3

4

5

2, 3

(1) 6
(2) 4
(3) 3

Comments

Linear multistage procedure

Single treated dose

BMD modelling with PBPK to get LEC10 from which unit risk was calculated.

NOAELHEC = NOAEL 5/7 days x 6/24 hr x 1 (RGDR)

LOAELHEC = LOAEL 5/7 days x 7/24 hr x 1.7 (RGDR)

NOAELHEC =  NOAEL 5/7 days x 7/24 hr

BMD with PBPK to estimate BMDL10, converted to human equivalent.
UFDB for lack of a reproductive study

Three TCs were derived based on three different studies.
(3) UFL of 5 used for marginal effect instead of NOAEL.

TOXICOLOGICAL REFERENCE VALUES FOR CHLOROFORM (CAS No. 67-66-3)
OrganizationTable 11 - Footnote 1 NEOPLASTIC NON-NEOPLASTIC
CalEPA Health Canada US EPA ATSDR CalEPATable 11 - Footnote 2 RIVM

Year of publication

1990Table 11 - Footnote 3

2001

2001

1997

2000Table 11 - Footnote 3

2001

Species

Rats

Rats

Mice

Humans

Rats

Rats

Endpoint

Kidney tumours

Kidney tumours

Hepatocellular carcinoma

Liver toxicity

Kidney and liver toxicity

None

Unit risk (µg/m3)-1

5.3 x 10-6

-

2.3 x 10-5

- - -

Concentration at 1 x 10-5 risk level (µg/m3)

1.9

-

0.4

- - -

Point of departure

- - -

LOAEL = 10 mg/m3

LOAEL = 120 mg/m3
LOAELHEC = 75 mg/m3

NOAEL = 110 mg/m3

Uncertainty factorsTable 11 - Footnote 4

- - -

100
(UFH = 10, UFL = 10)

300
(UFH = 10, UFA = 3, UFL = 10)

1000
(UFH = 10, UFA = 10, UFS = 10)

Concentration (µg/m3)

-

147 000

-

100

300

100

Critical studyTable 11 - Footnote 5

1, 2, 3, 4

1

2

5

6

6

Comments

Linear multistage procedure with PBPK
Based on a 1990 California Department of Health Services analysis.

PBPK used to determine 3.9 mg/L per hour, the rate of metabolism associated with a 5% increase in tumour risk (TC05).
Adjusted for lifetime to TC05 = 147 mg/m3

Linearized multistage procedure, extra risk

-

LOAELHEC = LOAEL x 5/7 days x 7/24 hours x 3 (RGDR)
CalEPA used a different part of the same study as RIVM.

UFS for 4 hour/day, 5 days/week, 6-month exposure.
RIVM used a different part of the same study as CalEPA.

TOXICOLOGICAL REFERENCE VALUES FOR CYCLOHEXANE (CAS No. 110-82-7)
Organization NON-NEOPLASTIC
US EPATable 12 - Footnote 1

Year of publication

2003

Species

Rats

Endpoint

Reduced pup weight (F1 and F2 generations)

Point of departure

NOAEL = 6886 mg/m3
NOAELADJ = 1700 mg/m3
BMCL1sdTable 12 - Footnote 2 = 1822 mg/m3

Uncertainty factorsTable 12 - Footnote 3

300
(UFH = 10, UFA = 3, UFDB = 10)

Concentration (µg/m3)

6000

Critical studyTable 12 - Footnote 4

1, 2

Comments

NOAELADJ = NOAEL x 6/24 hours x 1 (RGDR)
UFDB for lack of data for chronic and developmental neurotoxicity studies

TOXICOLOGICAL REFERENCE VALUES FOR DICHLOROMETHANE (CAS No. 75-09-2)
OrganizationTable 13 - Footnote 1 NEOPLASTIC NON-NEOPLASTIC
CalEPA Health Canada US EPA ATSDR CalEPA RIVM US EPATable 13 - Footnote 2

Year of publication

1989Table 13 - Footnote 3

1993

2011

2000

2000Table 13 - Footnote 3

2001

2011

Species

Mice

Mice

Mice

Rats

Humans

Humans

Rats

Endpoint

Lung tumours

Lung tumours

Lung and liver tumours

Effects on liver

Increased carboxyhemoglobin

Increased carboxyhemoglobin

Effects on liver

Unit risk (µg/m3)-1

1.0 x 10-6

2.3 x 10-8

1.0 x 10-8

- - -

Concentration at 1 x 10-5 risk level (µg/m3)

10

435

1000

- - -

Point of departure

- - -

NOAEL = 170 mg/m3
NOAELADJ = 31 mg/m3

LOAEL = 139 000 mg/m3
LOAELADJ = 48 700 mg/m3

LOAEL = 90 mg/m3
LOAELADJ = 3 mg/m3

BMDL10 = 532 mg dichloromethane metabolized via CYP pathway/L liver tissue/day
HEC1% = 17.2 mg/m3

Uncertainty factorsTable 13 - Footnote 4

- - -

30
(UFH = 10, UFA = 3)

100
(UFH = 10, UFL = 10)

0

30
(UFH = 3, UFA = 3, UFDB = 3)

Concentration (µg/m3)

- - -

1000

400

3000

600

Critical studyTable 13 - Footnote 5

1, 2

1, 2

1, 2

3

4

4

3

Comments

-

Based on the lowest PBPK modified TD0.05 value.

Application of age-dependent adjustment factors results in a 70-year risk of 1.7 x 10-8.

NOAELADJ = NOAEL 5/7 days x 6/24 hours
UFA = 3 because of consideration of RGDR (value of 1 used).
COHb levels also increased >10% at 700 mg/m3.

LOAELADJ = LOAEL x 5/7 days x [(10 m3/d)/(20 m3/d)]
Limited subjects and exposure information.

LOAELADJ = LOAEL x 5/7 days x 7.5/24 hours x (0.1/1). The last factor was to adjust for an unacceptable 0.1% increase in COHb, relative to the observed 1% COHb increase.
Limited subjects and exposure information.

HEC1% determined by PBPK modelling of calculated BMDL10 value.
Value of 600 µg/m3 was rounded from 573 µg/m3.

TOXICOLOGICAL REFERENCE VALUES FOR EPICHLOROHYDRIN (CAS No. 106-89-8)
Organization NEOPLASTIC NON-NEOPLASTIC
CalEPA US EPA CalEPA US EPATable 14 - Footnote 1

Year of publication

1999Table 14 - Footnote 2

1988

2001

1994

Species

Rats

Rats

Rats and mice

Rats and mice

Endpoint

Papillomas and carcinomas of the forestomach

Nasal cavity tumours

Histological changes in the nose

Histological changes in the nose

Unit risk (µg/m3)-1

2.3 x 10-5

1.2 x 10-6

- -

Concentration at 1 x 10-5 risk level (µg/m3)

0.43

8

- -

Point of departure

- -

NOAEL = 19 mg/m3
NOAELADJ = 3.4 mg/m3
NOAELHEC = 0.31 mg/m3

NOAEL = 19 mg/m3
NOAELADJ = 3.4 mg/m3
NOAELHEC = 0.36 mg/m3

Uncertainty factorsTable 14 - Footnote 3

- -

100
(UFH =10, UFA = 3, UFS = 3)

300
(UFH = 10, UFA = 3, UFS, DB = 10)

Concentration (µg/m3)

- -

3

1

Critical studyTable 14 - Footnote 4

1

2

3

3

Comments

Inhalation unit risk derived from oral cancer potency factor in male rats exposed via drinking water.
Data from the Laskin et al. (1980) inhalation study were not retained due to the poor survival of the study animals (data considered to be less suitable for generating a cancer potency factor than the data from the study of Konishi et al. (1980)).
Relevance of forestomach tumours in rodents to humans is unclear and not well addressed in this assessment.

-

NOAELADJ = NOAEL x 6 hours/24 hours x 5 days/7 days

NOAELHEC = NOAELADJ x 0.14 m3/day / 20 m3/day x 200 cm2/15 cm2 (based on rat data)

NOAELADJ = NOAEL x 6 hours/24 hours x 5 days/7 days

NOAELHEC= NOAELADJ x 0.14 m3/day / 20 m3/day x 177 cm2/11.6 cm2 (based on rat data)

US EPA has medium confidence in the RfC, in the study and in the database.

TOXICOLOGICAL REFERENCE VALUES FOR ETHYLBENZENE (CAS No. 100-41-4)
OrganizationTable 15 - Footnote 1 NEOPLASTIC NON-NEOPLASTIC
CalEPA VCCEP ATSDR CalEPATable 15 - Footnote 2 RIVM US EPA VCCEP WHO

Year of publication

2007Table 15 - Footnote 3

2007

2010

2000Table 15 - Footnote 3

2001

1991

2007

1996

Species

Rats

Mice

Rats

Rats and mice

Rats and mice

Rabbits

Rats

Rats and mice

Endpoint

Kidney tumours

Lung tumours

Effects on kidney

Effects on pituitary gland and liver (mice)

Effects on liver and kidney

Developmental effects

Auditory effects

Effects on liver and kidney

Unit risk (µg/m3)-1

2.5 x 10-6

- - - - - - -

Concentration at 1 x 10-5 risk level (µg/m3)

4

- - - - - - -

Point of departure

-

40 500 mg metabolised in lung/kg lung/wk

LOAEL = 330 mg/m3

LOAEL = 1100 mg/m3
NOAEL = 330 mg/m3
NOAELADJ = 57 mg/m3

NOAEL = 430 mg/m3
NOAELADJ = 77 mg/m3

LOAEL = 4340 mg/m3

LOEL = 860 mg/m3
LED0105Table 15 - Footnote 4 = 272.8 mg-h ethylbenzene/L RPTTable 15 - Footnote 5/wk

NOEL = 2150 mg/m3

Uncertainty factorsTable 15 - Footnote 6

-

300
(UFH = 10, UFA = 3, UFseverity of lesion = 10)

300
(UFH = 10, UFA = 3, UFL = 10)

30
(UFH = 10, UFA = 3)

100
(UFH = 10, UFA = 3)

300
(UFH = 10, UFA = 3, UFS = 10)

100
(UFH = 10, UFA = 3, UFS = 3)

100
(UFH = 5, UFA = 10; UFDB = 2)

Concentration (µg/m3)

-

2100

260

2000

770

1000

1300

22 000

Critical studyTable 15 - Footnote 7

1

1

1

1, 2

3

4, 5

6

3

Comments

More recent evidence suggests ethylbenzene may be a threshold carcinogen.

-

More recent data suggest effects on kidney, particularly chronic progressive nephropathy (common in aging rats), are unlikely to be relevant to humans.

NOAELADJ = NOAEL x 5/7 days x 6/24 hours

NOAELADJ = 
NOAEL x 5/7 days x 6/24 hours
Sub-chronic study

US EPA has low confidence in this derivation; published prior to NTP (1999).

Sub-chronic study supportive of chronic effects

Stated NOAEL would be higher than 4300 mg/m3 because organ weight increases were not accompanied by cellular changes.

TOXICOLOGICAL REFERENCE VALUES FOR ETHYLENE OXIDE (CAS No. 75-21-8)
OrganizationTable 16 - Footnote 1 NEOPLASTIC NON-NEOPLASTIC
CalEPA Health Canada US EPATable 16 - Footnote 2 CalEPA

Year of publication

1987Table 16 - Footnote 3

2001

2016

2001Table 16 - Footnote 3

Species

Rats

Rats

Humans

Rats

Endpoint

Mononuclear leukemia

Mononuclear leukemia

Lymphoid and breast cancer

Neurological effects

Unit risk (µg/m3)-1

8.8 x 10-5

2.3 x 10-5

5.0 x 10-3

Concentration at 1 x 10-5 risk level (µg/m3)

0.11

0.43

0.002

Point of departure

- - -

NOAEL = 18 mg/m3
NOAELADJ = 3.2 mg/m3

Uncertainty factorsTable 16 - Footnote 4

- - -

100
(UFH = 10, UFA = 3, UFS = 3)

Concentration (µg/m3)

- - -

30

Critical studyTable 16 - Footnote 5

1

2

3

2

Comments

Based on a 1985 US EPA analysis that considered human equivalent dose

Unit risk of 2.3 x 10-5 (µg/m3)-1 estimated from TC05 value of 2.2 mg/m3

Adult-based value was 3.0 x 10‑3 per µg/m3, to which age-dependent adjustment factors were applied to provide the lifetime exposure value presented above.

NOAELADJ = PoD x 5/7 days x 6/24 hours

TOXICOLOGICAL REFERENCE VALUES FOR ISOPROPYL ALCOHOL (CAS No. 67-63-0)
Organization NON-NEOPLASTIC
CalEPATable 17 - Footnote 1

Year of publication

2000Table 17 - Footnote 2

Species

Rats and mice

Endpoint

Kidney lesions

Point of departure

NOAEL = 1200 mg/m3
NOAELHEC = 220 mg/m3

Uncertainty factorsTable 17 - Footnote 3

30
(UFH = 10, UFA = 3)

Concentration (µg/m3)

7000

Critical studyTable 17 - Footnote 4

1

Comments

NOAELHEC = NOAEL x 5/7 days x 6/24 hours x 1 (RGDR)

TOXICOLOGICAL REFERENCE VALUES FOR ISOPROPYLBENZENE (CAS No. 98-82-8)
Organization NON-NEOPLASTIC
US EPATable 18 - Footnote 1

Year of publication

1997

Species

Rats

Endpoint

Effects on kidney

Point of departure

NOAEL = 2438 mg/m3
NOAELHEC = 435 mg/m3

Uncertainty factorsTable 18 - Footnote 2

1000
(UFH = 10, UFA = 10, UFS = 10)

Concentration (µg/m3)

400

Critical studyTable 18 - Footnote 3

1

Comments

NOAELHEC = PoD x 5/7 days x 6/24 hours x 1 (RGDR)
Since the publication of this assessment, a 2-year study has been published (NTP 2009).

TOXICOLOGICAL REFERENCE VALUES FOR METHYL ETHYL KETONE (CAS No. 78-93-3)
Organization NON-NEOPLASTIC
US EPATable 19 - Footnote 1

Year of publication

2003

Species

Rats

Endpoint

Developmental effects

Point of departure

LEC10 = 5202 mg/m3
LEC10 HEC = 1517 mg/m3

Uncertainty factorsTable 19 - Footnote 2

300
(UFH = 10, UFA = 3, UFDB = 10)

Concentration (µg/m3)

5000

Critical studyTable 19 - Footnote 3

1, 2, 3

Comments

LEC10 HEC = LEC10 x 7/24 hours
UFDB for lack of developmental neurotoxicity data, chronic inhalation toxicity study, and multigeneration reproductive toxicity study.

TOXICOLOGICAL REFERENCE VALUES FOR METHYL ISOBUTYL KETONE (CAS No. 108-10-1)
Organization NON-NEOPLASTIC
US EPATable 20 - Footnote 1

Year of publication

2003

Species

Rats and mice

Endpoint

Developmental effects

Point of departure

NOAEL = 4100 mg/m3
NOAELHEC = 1026 mg/m3

Uncertainty factorsTable 20 - Footnote 2

300
(UFH = 10, UFA = 3, UFDB = 10)

Concentration (µg/m3)

3000

Critical studyTable 20 - Footnote 3

1

Comments

NOAELHEC = PoD x 6/24 hours x 1 (RGDR)
UFDB for lack of developmental neurotoxicity, neurotoxicity, and chronic toxicity studies.
US EPA has low to medium confidence in this RfC. Since the publication of this assessment, a 2-year study has been published by the NTP in 2007, which is under review.

TOXICOLOGICAL REFERENCE VALUES FOR PROPIONALDEHYDE (CAS No. 123-38-6)
Organization NON-NEOPLASTIC
US EPATable 21 - Footnote 1

Year of publication

2008

Species

Rats

Endpoint

Olfactory epithelium atrophy

Point of departure

LOAEL = 357 mg/m3
BMCL10 = 128 mg/m3
BMCL10 HEC = 8.3 mg/m3

Uncertainty factorsTable 21 - Footnote 2

1000
(UFH = 10, UFA = 3, UFS = 10, UFDB = 3)

Concentration (µg/m3)

8

Critical studyTable 21 - Footnote 3

1

Comments

BCMLHEC 10 = BMCL10 x 7/7 days x 6/24 hours x 0.26 (RGDR)
UFDB for lack of a 2-generation reproductive toxicity study.
US EPA has medium confidence in the critical endpoint, low to medium confidence in the study selected, and low confidence in overall database.

TOXICOLOGICAL REFERENCE VALUES FOR PROPYLENE OXIDE (CAS No. 75-56-9)
Organization NEOPLASTIC NON-NEOPLASTIC
CalEPA US EPATable 22 - Footnote 1 CalEPA US EPA

Year of publication

1999Table 22 - Footnote 2

1990

2000Table 22 - Footnote 2

1990

Species

Mice

Mice

Rats

Rats

Endpoint

Nasal cavity tumours

Nasal cavity tumours

Atrophy of olfactory epithelium and degeneration of respiratory epithelium

Atrophy of olfactory epithelium and degeneration of respiratory epithelium

Unit risk (µg/m3)-1

3.7 x 10-6

3.7 x 10-6

- -

Concentration at 1 x 10-5 risk level (µg/m3)

2.7

2.7

- -

Point of departure

- -

LOAEL = 71 mg/m3
LOAELHEC = 3 mg/m3

LOAEL = 71 mg/m3
LOAELHEC = 3 mg/m3

Uncertainty factorsTable 22 - Footnote 3

- -

100
(UFH = 10, UFA = 3, UFL = 3)

100
(UFH = 10, UFA = 3, UFL = 3)

Concentration (µg/m3)

- -

30

30

Critical studyTable 22 - Footnote 4

1, 2

1, 2

3

3

Comments

- -

LOAELHEC = LOAEL x 5/7 days x 6/24 hours x 0.23 (RGDR)
US EPA concluded there was medium confidence in the study selected, dataset, and resulting RfC.

LOAELHEC = LOAEL x 5/7 days x 6/24 hours x 0.23 (RGDR)
No studies in mice at lower concentrations than those in NTP (1985) were identified.

TOXICOLOGICAL REFERENCE VALUES FOR STYRENE (CAS No. 100-42-5)
OrganizationTable 23 - Footnote 1 NON-NEOPLASTIC
ATSDRTable 23 - Footnote 2 CalEPA Health Canada RIVM US EPA WHO

Year of publication

2010

2000Table 23 - Footnote 3

1993

2001

1992

2000

Species

Humans

Humans

Rats

Humans

Humans

Humans

Endpoint

Neurotoxicity

Neurotoxicity

Body weight change; neurotoxicity

Neurotoxicity

Neurotoxicity

Neurotoxicity

Unit risk (µg/m3)-1

- - - - - -

Concentration at 1 x 10-5 risk level (µg/m3)

- - - - - -

Point of departure

LOAEL = 85.2 mg/m3
LOAELADJ = 20.4 mg/m3

BMCL05 = 7.2 mg/m3
BMCL05ADJ = 2.6 mg/m3

LOEL = 260 mg/m3
LOELADJ = 65 mg/m3
LOELHEC = 46 mg/m3

LOAEL = 107 mg/m3
LOAELADJ = 26 mg/m3

NOAEL = 106 mg/m3
Lower 95% confidence limit of the NOAEL = 94 mg/m3
NOAELADJ = 34 mg/m3

LOAEL = 107 mg/m3
LOAELADJ = 26 mg/m3

Uncertainty factorsTable 23 - Footnote 4

30
(UFH = 10, UFL = 3)

3
(UFH = 3)

500
(UFH = 10, UFA = 10,
UFL = 5)

30
(UFH = 10, UFL = 3)

30
(UFH = 3, UFDB = 3,
UFS = 3)

100
(UFH = 10, UFL = 10)

Concentration (µg/m3)

850

900

92

900

1000

260

Critical studyTable 23 - Footnote 5

1

2

3, 4

2*

2

2

Comments

LOAELADJ = LOAEL x 8 hours/24 hours x 5 days/7 days

BMCL05ADJ = BMCL05 x 10 m3/20 m3 x 5 days/7 days

LOELADJ = LOEL x 6 hours/24 hours
LOELHEC = LOELADJ x [(0.11 m3/0.35 kg)/(m3/0.35 kg)]

LOAELADJ = LOAEL x 8 hours/24 hours x 5 days/7 days

*RIVM does not explicitly cite a critical study. It is likely Mutti et al. (1984) .

Lower 95% confidence limit of the NOAEL = NOAEL x 0.88
NOAELADJ = lower 95% confidence limit of NOAEL x 10 m3/20 m3 x 5 days/7 days
US EPA has medium confidence in the RfC and study, and medium to high confidence in the database.

LOAEL adjusted by a factor of 4.2 to convert from occupational to continuous exposure

TOXICOLOGICAL REFERENCE VALUES FOR TETRACHLOROETHYLENE (CAS No. 127-18-4)
OrganizationTable 24 - Footnote 1 NEOPLASTIC NON-NEOPLASTIC
CalEPA US EPA ATSDR Health Canada RIVM US EPATable 24 - Footnote 2 WHO

Year of publication

1991Table 24 - Footnote 3

2012

2014

1993

2001

2012

2010

Species

Mice

Mice

Humans

Mice

Humans

Humans

Humans

Endpoint

Liver tumours

Liver tumours

Neurobehavioral effects

Nephrotoxicity, hepatotoxicity

Nephrotoxicity

Neurotoxicity, visual impairment

Nephrotoxicity

Unit risk (µg/m3)-1

5.9 x 10-6

2.6 x 10-7

- - - - -

Concentration at 1 x 10-5 risk level (µg/m3)

1.7

40

- - - - -

Point of departure

- -

LOAEL = 50.3 mg/m3
LOAELADJ = 12 mg/m3

LOAEL = 678 mg/m3
LOAELADJ = 360 mg/m3

LOAEL = 100 mg/m3
LOAELADJ = 25 mg/m3

From two studies:
Study 6
LOAEL = 156 mg/m3
LOAELADJ = 56 mg/m3
Study 3
LOAEL = 42 mg/m3
LOAELADJ = 15 mg/m3

LOAEL = 100 mg/m3
LOAELADJ = 25 mg/m3

Uncertainty factorsTable 24 - Footnote 4

- -

300
(UFH = 10, UFL = 10, UFDB = 3)

1000
(UFH = 10, UFA = 10, UFL = 10)

100
(UFH = 10, UFL = 10)

1000
(UFH = 10, UFL = 10, UFDB = 10)

100
(UFH = 10, UFL = 10)

Concentration (µg/m3)

- -

40

360

250

40
(rounded average of 15 and 56)

250

Critical studyTable 24 - Footnote 5

1

2

3, 4

1

5

3, 6

5

Comments

-

Unit risk calculated using PBPK modelling

LOAELADJ = LOAEL x 5/7 days x 8/24 hours

LOAELADJ = LOAEL x 5/7 days x 6/24 hours x 3 (volume/body weight adjustment of mice to humans)

LOAELADJ = LOAEL x 40 hr/week/168 hr week

LOAELADJ = LOAEL x 5/7 days x 10/20 m3/d, breathing rate.
UFDB for lack of neurological, developmental, and immunological studies.

LOAELADJ = LOAEL x 40 hr/week / 168 hr week

TOXICOLOGICAL REFERENCE VALUES FOR TOLUENE DIISOCYANATE (MIXED ISOMERS) (CAS No. 26471-62-5)
Organization NEOPLASTIC NON-NEOPLASTIC
CalEPA ATSDR CalEPATable 25 - Footnote 1 US EPA

Year of publication

1999Table 25 - Footnote 2

2015

2016

1995

Species

Rats

Humans

Humans

Humans

Endpoint

Subcutaneous fibroma/fibrosarcoma

Decreased lung function

Decreased lung function

Decreased lung function

Unit risk (µg/m3)-1

1.1 x 10‑5

- - -

Concentration at 1 x 10-5 risk level (µg/m3)

0.91

- - -

Point of departure

-

AEL = 0.0085 mg/m3
AELADJ = 0.00202 mg/m3

NOAEL = 0.006 mg/m3
NOAELADJ = 0.002 mg/m3

NOAEL = 0.006 mg/m3
NOAELADJ = 0.002 mg/m3

Uncertainty factorsTable 25 - Footnote 3

-

100
(UFH = 10, UFA = 10)

300
(UFH = 100, UFS = 3)

30
(UFH = 10, UFS,D = 3)

Concentration (µg/m3)

-

0.02

0.008

0.07

Critical studyTable 25 - Footnote 4

1

2

3

3

Comments

Inhalation unit risk derived from an oral cancer potency factor in male rats exposed by gavage to a commercial mixture of toluene diisocyanate

AELADJ = AEL x 5/7 days x 8/24 hours

NOAELADJ = NOAEL x 10 m3/20 m3 x 5 days/7 days

NOAELADJ = NOAEL x 10 m3/20 m3 x 5 days/7 days

US EPA has medium confidence in the study, database and RfC.

TOXICOLOGICAL REFERENCE VALUES FOR XYLENES, MIXTURE (CAS No. 1330-20-7)
OrganizationTable 26 - Footnote 1 NON-NEOPLASTIC
ATSDR CalEPA Health Canada RIVM US EPATable 26 - Footnote 2 VCCEP

Year of publication

2007

2000Table 26 - Footnote 3

1993

2001

2003

2005

Species

Humans

Humans

Rats

Rats

Rats

Rats

Endpoint

Symptoms of neurotoxicity, sore throat, nose, and eye irritation

Symptoms of neurotoxicity, sore throat, nose, and eye irritation

Unspecified maternal effects and fetal skeletal retardation

Decreased rotarod performance in offspring

Decreased latency in paw-lick response (i.e., sensitivity to pain)

Decreased rotarod performance in males (i.e., decreased motor activity)

Point of departure

LOAEL = 61 mg/m3

LOAEL = 61 mg/m3
LOAELHEC = 22 mg/m3

LOEL = 250 mg/m3
LOELHEC = 180 mg/m3

LOAEL = 870 mg/m3

LOAEL = 434 mg/m3
NOAEL = 217 mg/m3
NOAELHEC = 39 mg/m3

LOAEL = 434 mg/m3
NOAEL = 217 mg/m3
NOAELADJ = 39 mg/m3
NOAELHEC = 66 mg/m3

Uncertainty factorsTable 26 - Footnote 4

300
(UFH = 10, UFL = 10, UFDB = 3)

30
(UFH = 10, UFL = 10)

1000
(UFH = 10, UFA = 10, UFL = 10)

1000
(UFH = 10, UFA = 10,  UFL = 10)

300
(UFH = 10, UFA = 3, UFS = 3, UFDB = 3)

100
(UFH = 10, UFA 3, UFS = 3)

Concentration (µg/m3)

220

700

180

870

100

660

Critical studyTable 26 - Footnote 5

1

1

2

3

4

4

Comments

UFDB for lack of chronic neurotoxicity data

Continuous exposure adjustment: multiplied PoD by [(10 m3/d)/ (20 m3/d) x 5 d/7 d]

0.72 applied to PoD to account for inhalation volume/body weight of young rats relative to humans (i.e., rats [(0.11 m3/day)/0.35 kg] to humans aged 5 to 11 years [(12 m3/day)/27 kg).
UFL also included limitations of critical study.

-

NOAELHEC = NOAEL x 5/7 days x 6/24 hours
UFDB for lack of 2-generation reproduction study.

NOAELADJ = NOAEL x 6/24 hours x 5/7 days

NOAELHEC = NOAELADJ X 1.7 (RGDR)

7.0 Tables of TRVs for individual VOCs (no IARLSs recommended)

TOXICOLOGICAL REFERENCE VALUES FOR 1,1,2,2-TETRACHLOROETHANE (CAS No. 79-34-5)
Organization NEOPLASTIC
CalEPA

Year of publication

1999Table 27 - Footnote 1

Species

Mice

Endpoint

Liver tumours

Unit risk (µg/m3)-1

5.8 x 10-5

Concentration at 1 x 10-5 risk level (µg/m3)

0.17

Critical studyTable 27 - Footnote 2

1

CommentsTable 27 - Footnote 3

Based on a US EPA oral slope factor. US EPA did not derive an inhalation slope factor.

TOXICOLOGICAL REFERENCE VALUES FOR 1,2-DICHLOROETHANE (CAS No. 107-06-2)
OrganizationTable 28 - Footnote 1 NEOPLASTIC NON-NEOPLASTIC
CalEPA RIVM US EPA ATSDR CalEPA

Year of publication

1985Table 28 - Footnote 2

2001

1991

2001

2001

Species

Rats

Rats (assumed)

Rats

Rats

Rats

Endpoint

Hemangiosarcomas

Hemangiosarcomas

Hemangiosarcomas

No effects

Effects on liver

Unit risk (µg/m3)-1

2.1 x 10-5

2.1 x 10-6

2.6 x 10-5

- -

Concentration at 1 x 10-5 risk level (µg/m3)

0.48

4.8

0.38

- -

Point of departure

- - -

NOAEL = 222 mg/m3

NOAEL = 40 mg/m3
NOAELHEC = 12 mg/m3

Uncertainty factorsTable 28 - Footnote 3

- - -

90
(UFH = 3, UFA = 10, UFDB = 3)

30
(UFH = 10, UFA = 3)

Concentration (µg/m3)

- - -

2500

400

Critical studyTable 28 - Footnote 4

1

1, 2

1

3

4

CommentsTable 28 - Footnote 5

Based on gavage study

Based on gavage study

Assessment in Dutch; summary available only in English

Based on gavage study

As of 2000, under review by US EPA IRIS

One dose, no control group

NOAELHEC = PoD x 5/7 days x 7/24 hours x 1.5 (RGDR)

TOXICOLOGICAL REFERENCE VALUES FOR 4,4’-METHYLENEDIANILINE (CAS No. 101-77-9)
Organization NEOPLASTIC NON-NEOPLASTIC
CalEPA CalEPA

Year of publication

1999Table 29 - Footnote 1

2001Table 29 - Footnote 1

Species

Mice

Guinea pigs

Endpoint

Liver tumours

Ocular toxicity

Unit risk (µg/m3)-1

4.6 x 10‑4

-

Concentration at 1 x 10-5 risk level (µg/m3)

0.02

-

Point of departure

-

LOAEL = 440 mg/m3
LOAELADJ = 52 mg/m3
LOAELHEC = 52 mg/m3

Uncertainty factorsTable 29 - Footnote 2

-

3000
(UFH=10, UFA=3, UFS=10, UFL=10)

Concentration (µg/m3)

-

20

Critical studyTable 29 - Footnote 3

1

2

CommentsTable 29 - Footnote 4

Inhalation unit risk derived from an oral cancer potency factor in male mice exposed to 4,4’-methylenedianiline dihydrochloride in drinking water

LOAELADJ = LOAEL x 4 hours/24 hours x 5 days/7 days
LOAELHEC = LOAELADJ x 1 (RGDR)

TOXICOLOGICAL REFERENCE VALUES FOR PHENOL (CAS No. 108-95-2)
OrganizationTable 30 - Footnote 1 NON-NEOPLASTIC
CalEPA RIVM

Year of publication

2000Table 30 - Footnote 2

2001

Species

Rats, mice, and monkeys

Rats, mice, and monkeys

Endpoint

No effect on pulmonary, cardiovascular, hematological, hepatic or renal systems (NOAEL).
Neurological and hepatic effects (LOAEL).

Not reported

Point of departure

NOAEL = 20 mg/m3
NOAELHEC = 20 mg/m3

NOAEC = 20 mg/m3

Uncertainty factorsTable 30 - Footnote 3

100
(UFH = 10, UFA = 3, UFS = 3)

1000
(UFH,A = 100, UFS = 10)

Concentration (µg/m3)

200

20

Critical studyTable 30 - Footnote 4

1, 2

(1)

CommentsTable 30 - Footnote 5

NOAELHEC = NOAEL x 1 (RGDR)
LOAEL = 26 ppm

RIVM cited ATSDR (1998) as the source of the NOAEC. However, the updated ATSDR Toxicological Profile (2008) does not explicitly report a NOAEC and ATSDR considered the reviewed studies as inadequate. The NOAEC was likely derived from the summary of Sandage (1961) reported in ATSDR (1998).

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