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Workplace

Exposure
Standard
(WES) review

PHTHALIC ANHYDRIDE
(CAS NO: 85-44-9)

May 2019
CONTENTS

1.0 Introduction 2

2.0 Chemical and physical properties 4

3.0 Uses 7

4.0 Health effects 9


4.1 Non-cancer 10

4.2 Cancer 16

4.3 Absorption, distribution, metabolism and excretion 17

5.0 Exposure standards 18


5.1 Other exposure standards 19

5.2 ACGIH® 20

5.3 SCOEL 20

5.4 DECOS 21

5.5 DFG 21

5.6 New Zealand 22

6.0 Analytical methods for the assessment


of airborne phthalic anhydride 24

7.0 Discussion and recommendations 26


appendices
Appendix 1: Glossary 29
Appendix 2: HSNO health-related hazardous substance classifications 32
Appendix 3: References 33

tables
1 Physicochemical properties of phthalic anhydride 5
2 HSNO hazard classifications of phthalic anhydride (EPA, 2018) 6
3 Human respiratory cohort studies 13
4 Exposure standards for phthalic anhydride from around the world 19
1.0
Introduction

2
1.0 Introduction

This WorkSafe New Zealand


(WorkSafe) review considers
whether the WES for
phthalic anhydride should
be changed.

It considers the potential for exposures to phthalic anhydride in New Zealand,


the health effects and risks, exposure standards from other jurisdictions around
the world, and the practicability of measuring exposures.

The review includes a recommendation to change the WorkSafe WES for phthalic
anhydride, which is currently set at a WES-TWA of 1 ppm (16.1 mg/m3) with a
sen notation, as published in the special guide Workplace Exposure Standards
and Biological Exposure Indices, 10th Ed., November 2018 (WorkSafe, 2018). It is
noted that the WES-TWA value expressed in units of mg/m3 has been recorded
incorrectly as 16.1 mg/m3 since the 4th Ed, of September 2010. A concentration
of 1 ppm of phthalic anhydride corresponds to a concentration of 6.1 mg/m3.

Terms that are bold (first occurrence only) are further defined in the Glossary.
Synonyms: 1,3-dihydro-2-benzofuran-1,3-dione; 1,3-isobenzofurandione;
isobenzofuran, 1,3-dihydro-1,3-dioxo-; phthalic acid anhydride; PA.

3
2.0
Chemical
and physical
properties

4
2.0 Chemical and physical properties

Phthalic anhydride exists as white,


crystalline flakes or needles at
room temperature with a strong,
choking odour (ACGIH®, 2017;
OECD SIDS, 2005).

Phthalic anhydride has an odour threshold reported at 0.053 ppm (0.32 mg/m3)
(ACGIH®, 2017).

Chemical and physical properties of phthalic anhydride include:

Molecular weight 148.12 g/mol

Formula C8H4O3

Specific gravity 1.53 g/cm3 at 20°C

Melting point 130.8°C

Boiling point 284°C (sublimes)

Vapour pressure 0.0002 torr at 20°C; 0.0006 hPa at 26.6°C

Saturated vapour 0.3 ppm (1.8 mg/m3)


concentration

Solubility Water: 0.62 g/mL; soluble in alcohol; slightly soluble in ether

Flash point Closed cup: 152°C; open cup: 165°C

Explosive limits Lower: 1.7%; upper: 10.5% by volume in air

Autoignition 570°C
temperature

Dissociation constant As phthalic acid: pKa1 = 2.76 at 25°C; pKa2 = 5.41 at 25°C

Stability Rapidly converted to phthalic acid in the presence of water


with a half-life of 30.5 seconds at pH 7.24 and 61 seconds at
pH 6.8 TABLE 1:
Conversion factors 1 mg/m3 = 0.17 ppm (25°C; 760 torr)
Physicochemical
1 ppm = 6.05 mg/m3 (25°C; 760 torr) properties of
phthalic anhydride
ACGIH®, 2017; OECD SIDS, 2005

5
2.0 Chemical and physical properties

Health-related hazard classifications for phthalic anydride:


TABLE 2:
SUBSTANCE HSNO CLASSIFICATION
HSNO hazard
Phthalic anhydride 6.1D (All); 6.1D (O); 6.3A; 6.5A; 6.5B; 6.8B classifications of
8.3A phthalic anhydride
(EPA, 2018)
For a full listing of all HSNO health-related hazardous substances classification
codes and their descriptions, see Appendix 2.

All
Overall classification for that endpoint.
O
Oral exposure route.
D
Dermal exposure route.
I
Inhalation exposure route.

6
3.0
Uses

7
3.0 Uses

Phthalic anhydride is used


in organic synthesis for the
manufacture of alkyd and epoxy
resins, unsaturated polyester
resins, phthalocyanide dyes,
pharmaceuticals, phthalate
plasticisers and fungicides
(ACGIH®, 2017; SCOEL, 2011).

Phthalic anhydride is also used as a hardener for epoxy resins (SCOEL, 2011).

Occupational exposure to phthalic anhydride can occur during production,


storage, transportation and end-use.

Workers can be exposed to phthalic anhydride as a dust or fume/vapour, when


temperatures are elevated or as thermal degradation products, via inhalation and
dermal or eye contact (SCOEL, 2011).

The number of workers exposed or potentially exposed to phthalic anhydride in


New Zealand workplaces is unknown.

Statistics New Zealand 2017 data indicate that 16,390 New Zealand workers were
working in the areas of:
–– chemical manufacturing
–– basic polymer manufacturing
–– fertiliser and pesticide manufacturing
–– pharmaceutical and medicinal product manufacturing
–– polymer product manufacturing (NZ.Stat, 2018).

8
4.0
Health effects
IN THIS SECTION:

4.1 Non-cancer
4.2 Cancer
4.3 Absorption, distribution,
metabolism and excretion

9
4.0 Health effects

4.1 Non-cancer
The NICNAS review of phthalic anhydride (1,3-isobenzofurandione) noted that
phthalic anhydride rapidly hydrolyses to phthalic acid when in contact with water,
including on moist surfaces such as the skin, lungs or in body fluids and tissues,
and that the data for phthalic acid was considered representative of the systemic
toxicity of phthalic anhydride (NICNAS, 2012).

Humans
The OECD SIDS review of phthalic anhydride summarised the potential acute
toxicity in exposed humans:

“Generalized descriptions of systemic effects with acute exposure are


given in several old, poorly documented reports, which provide no reliable
information on exposure levels. Headache, dizziness, nausea, epigastric
burning and a feeling of suffocation were described after occupational
exposure to phthalic anhydride dust or vapor (Bernard and Marchand, 1945).”

“In one person occasionally exposed to phthalic anhydride by the dermal


route, transient effects on the kidneys (poor function with the suppression of
urinary secretion) were noted (Sagan, 1965).” (References as cited in OECD
SIDS, 2005).

The New Zealand EPA classifies phthalic anhydride as a 6.1D substance – a substance
that is acutely toxic (EPA, 2018).

The OECD SIDS review of phthalic anhydride summarised the potential for
irritation/corrosion:

SKIN
“Contact with either solid phthalic anhydride or its vapor has been reported
to cause skin irritation after occupational exposure. Impurities present in
the technical phthalic anhydride, naphthoquinone and maleic anhydrides,
seem to contribute to these symptoms (Oettel, 1955). Following skin contact
lesions ranging from erythema, blistering, ulceration and necrosis have been
reported. Several authors considered that skin irritation following contact
with solid material was a greater problem in summer when the skin is likely
to be wet due to perspiration.”

EYE
“Reported irritative effects on the eye after occupational exposure included
conjunctivitis, lacrimation, corneal ulceration and necrosis, and photophobia.
In one study workers complained of conjunctivitis when occupationally exposed
to an airborne phthalic anhydride dust concentration of about 6 mg/m3 (1 ppm)
(2-6 hour TWA) (Nielsen et al., 1988, 1991).”

RESPIRATORY TRACT
“In humans, phthalic anhydride in the form of vapor, fumes, or dust is an irritant
to mucous membranes and the upper respiratory tract. Initial exposure produces
coughing, sneezing, burning sensations in the nose and throat, and increased
mucous secretion. Repeated or continued exposures may result in general
inflammation of the respiratory tract, nasal ulceration and bleeding, atrophy
of the mucous membranes (reversible), loss of smell, hoarseness, bronchitis,
urticaria, and symptoms of allergic hypersensitivity (Baader, 1955; Menschick,
1955; Frans and Pahulycz, 1993).” (References as cited in OECD SIDS, 2005).

10
4.0 Health effects

The SCOEL review of phthalic anhydride noted that human nasal irritation
threshold for phthalic anhydride has been reported to be 30 mg/m3 (5 ppm),
although the exposure duration, generation of particles and particle sizes were
not given (Ruth, 1986 cited in SCOEL, 2011).

The OECD SIDS review of phthalic anhydride noted:

“191 workers were patch tested with the resin and hardeners, including
phthalic anhydride at a plastics factory where epoxy resins, including maleic
anhydride and phthalic anhydride, were processed. An allergic response to
a 0.1 % solution of phthalic anhydride in acetone was observed in 14 % of the
workers (Woyton et al., 1976).” (References as cited in OECD SIDS, 2005).

The New Zealand EPA classifies phthalic anhydride as a 6.3A and 8.3A substance
– a substance that is irritating to the skin and corrosive to ocular tissue (EPA, 2018).

The SCOEL review of phthalic anhydride discussed the potential for respiratory
sensitisation in exposed workers:

“Cases of occupational asthma and rhinitis have been reported from various
work environments associated with exposure to PA. Typical environments
include PA production (Moscato et al 1986, Nordman et al. 1986), production
of alkyd or unsaturated polyester resins (Barker et al 1998, Nielsen et al 1988,
Wernfors et al 1986), paint and varnish production (Fawcett et al 1977, Kern
1939, Gervais et al 1972), plastic grinding (Ward and Davies 1983), tyre and
rubber manufacturing (Chester et al 1977).” (References cited in SCOEL, 2011)

“The first case of PA-induced asthma reported by Kern in 1939 was already
demonstrated to have an immunological mechanism; the scratch test with
PA in crystalline form and diluted 1:1000 in alcohol gave positive reactions
whereas tests with control patients were negative. The passive transfer test
was also positive (Kern 1939).

“Specific IgE-antibody in the serum of patients with asthma due to PA has


been reported consistently (eg Maccia et al 1976, Nielsen et al 1988, Topping
et al 1986, Nordman et al 1988, Welinder et al 2001). Inhibition studies and
passive transfer studies have supported the specificity of IgE antibodies
(Welinder & Nielsen 1991).

“Immediate-type skin tests with phthalic anhydride-HSA conjugates have


correlated well with the finding of specific IgE in serum (Baur & Czuppon
1995, Welinder & Nielsen 1991, Welinder et al 2001).” (References as cited
in SCOEL, 2011).

“Studies on dose-response relationships are scarce. The most helpful data


come from a Swedish study carried out in two polyester resins plants, in
which 60 workers exposed to PA for on an average of 12 years were surveyed
(Nielsen et al 1988). The group was divided into a high exposure group of 35
and a low exposure group of 25 workers. The high exposure group had been
exposed as reactor loaders to mean concentration of about 6.6 mg/m3 (1.5 –
17.4 mg/m3) (1.1 ppm (0.2 – 3.0 ppm)) during loading, which lasted for about
30 minutes daily. Otherwise PA concentrations were below the detection
limit of 0.1 mg/m3 (0.02 ppm). An 8-hour TWA was calculated for the high
exposure group at 400 g/m3 (0.07 ppm). They were also exposed to maleic,
trimellitic and isophtalic anhydrides, but to a “much lower amount”. The low
exposure group had been exposed to a TWA<100 g/m3 (0.02 ppm). There
was a reference group of 22 food processors. In the high exposure group
the prevalence of conjunctivitis was 46%, rhinitis 40% and asthma 14%.
The corresponding prevalences for the low exposure group were 20% of
conjunctivitis, 20% rhinitis, and 0% asthma. Similar conditions were not found
among references.

11
4.0 Health effects

“There was no association between specific IgE antibodies and PA exposure.


Specific IgG-levels were at a group level higher in the high exposed group
than in the low exposed group. Five workers with asthma had also higher
IgG-levels than non-asthmatics. IgG-levels were not uniformly increased
among asthmatics and IgG-levels were also increased in some non-asthmatics.

The IgG4 levels were increased in three of the five asthmatics and in one
worker with rhinitis. Nielsen et al (1988) concluded that specific IgG probably
reflects exposure, whereas IgG4 subclass antibody seemed to correlate with
symptoms and thus, may be a pathogenetic factor in asthma. Considering
the rather short daily exposure (about 30 minutes) to high levels of PA during
loading and a fairly low 8-hour TWA in the high exposure group, the authors
suggested that symptoms probably were due to peak exposures. They also
found it reasonable to suggest a ceiling value that should be “well below
6 mg/m3” (1 ppm), the Swedish limit value at that time (Nielsen et al 1988).

“The role of IgG-antibody subclasses in PA-induced respiratory allergy is


not fully evaluated. Results similar to those by Nielsen et al (1988) were
reported in a study carried out in a PA production plant with a work force of
70 exposed workers (Nordman et al 1988). The workers had been exposed
to TWA levels ranging 0.03-10.5 mg/m3 (0.005-1.7 ppm) and some of them
may have been exposed to minute amounts of maleic anhydride (Pfäffli
1986). In nine of the workers rhinitis symptoms had started after about six
months of exposure being followed by breathlessness about one year later.
A clinical evaluation of 26 workers with respiratory work-related symptoms
was performed including bronchial provocation tests with either PA flakes
or PA fumes at 0.35-2.0 ppm (2.1-12.1 mg/m3), simulating the work exposure
conditions. The provocation test resulted in 11 cases of occupational asthma;
8 workers reacted with a positive nasal reaction consistent with their
symptoms at work. The bronchial reactions were immediate (5), late (3) and
dual (3). Six out of 11 asthmatics had at some point of time been exposed
to high concentrations working at the bagging machine. All five asthmatics
with positive skin tests with PA-HSA or RAST displayed immediate bronchial
reactions and were considered IgE-mediated. Of the 8 nasal reactions
only one was skin test positive, none was RAST positive. Out of 15 workers
with increased IgG4 levels only one was symptomless. Thus, the IgG4
concentrations correlated with positive bronchial challenge tests as well as
with work-related symptoms, indicating a possible mechanistic role of IgG4,
similarly to the studies by Nielsen et al (1988, 1991).

“Wernfors et al. studied 118 workers in four plants producing alkyd or


unsaturated polyester resins. Forty-eight were current and 70 former
employees. The PA dust concentrations during loading of reactors and in the
handling of bags were high, up to 13 000 g/m3 (2.1 ppm). The fraction of
respirable dust was about 40%. The authors found 28 (24%) persons with
work-related rhinitis and 21 (18%) with asthma. Symptoms had started after
at least one month of exposure. In 10 of the 21 asthmatics, rhinitis preceded
the asthmatic symptoms. The latency period before the onset of the
respiratory symptoms ranged from 1 month-16 year. A positive skin-scratch
test was found in 3 of the 11 asthmatics but in none of the non-asthmatics.
A Prauznitz -Küstner test was positive with serum of two asthmatics.
The skin positive patients were also challenge tested. The bronchial
provocation tests with PA powder (6 000 g/m3 (1 ppm) for 5 minutes)
caused a dual asthmatic reaction in one patient, whereas the test with was
negative. The other patient experienced a dual reaction when challenged
with the 500 g/m3 (0.08 ppm) of PA (Wernfors et al 1986).

12
4.0 Health effects

“A British historical cohort study has been reported. It consists of 506


workers exposed to PA for more than one month since the beginning of 1960
in four plants. Three factories manufacturing resins used principally PA, but
also MA and TMA. One factory produced cushioned flooring and used only
TMA. The exposure was assessed retrospectively, by job. The current full-
shift and task-specific exposure measurements, the past exposure data and
qualitative information were used and exposure estimates were calculated in
the job-time-exposure matrices (van Tongeren et al 1998). A questionnaire
on employment history, respiratory symptoms and smoking habits was
completed by 401 (79%) workers. Skin prick tests with PA-HSA conjugates
were positive in 12 (3.2%). Thirty-four (8.8%) had respiratory symptoms
related to PA exposure. Positive skin tests correlated with work-related
respiratory symptoms. Exposure to PA or MA was found to be uncommon as
a cause of sensitization at the current low exposure levels measured in 1992
(0,4 – 2500 g/m3 (0.00007 – 0.4 ppm)) (van Tongeren et al 1995; Barker et
al 1998).” (References as cited in SCOEL, 2011).

The New Zealand EPA classifies phthalic anhydride as a 6.5A substance –


a substance that is a respiratory sensitiser (EPA, 2018).

The ACGIH® review of phthalic anhydride also presented the data from Barker
et al. (1998) and van Tongeren et al. (1995, 1998):

Barker et al. (1998) and van Tongeren et al. (1995, 1998) (as cited in ACGIH®,
2017)

EXPOSURE DETAILS DISEASE, CONDITION PREVALENCE OR BIOMARKER


OR BIOMARKER (VERSUS CONTROLS)

Factories #1, 3, 4 (combined) n = 285 PA sensitization uncommon


Exposures at time of study
TWA: 0.009-0.062 mg/m3 (0.001-0.01 ppm)
Task means: 0.017-0.364 mg/m3 (0.003-0.06 ppm)
Task range: 0.006-1.863 mg/m3 (0.001-0.3 ppm)

Factory #1; n = 124 Immediate skin prick 0%


Exposures at time of study reaction to AA-HSA
Task mean: 0.009 mg/m3 (0.001 ppm)
Task range: 0.0005-0.025 mg/m3 (0.00008-0.004 ppm) Work-related respiratory 5.0% ‡
Past exposures symptoms
TWA range: 0.0004-2.5 mg/m3 (0.00007-0.4 ppm)

Factory #3; n = 69 Immediate skin prick 1.6% †


Exposures at time of study reaction to AA-HSA
Task mean: 0.062 mg/m3 (0.01 ppm)
Task range: 0.002-0.138 mg/m3 (0.0003-0.02 ppm) Work-related respiratory 7.8% ‡
Past exposures symptoms
TWA range: 0.002-0.14 mg/m3 (0.0003-0.02 ppm)

Factory #4; n = 92 Immediate skin prick 3.5% †


Exposures at time of study reaction to AA-HSA
Task mean: 0.012 mg/m3 (0.002 ppm)
Task range: 0.002-0.020 mg/m3 (0.0003-0.003 ppm) Work-related respiratory 11.6% ‡
Past exposures symptoms
TWA range: 0.002-0.06 mg/m3 (0.0003-0.01 ppm)

From Table 1 ACGIH®, 2017

TABLE 3: Human respiratory cohort studies

† None of these workers with positive reaction were ‘currently’ exposed.


‡ May include “currently” exposed, previously exposed workers or both.

13
4.0 Health effects

The SCOEL review of phthalic anhydride noted that there was no data on the
reproductive and developmental toxicity potential in humans (SCOEL, 2011).

Animals
The ECHA REACH dossier on phthalic anhydride summarised the acute
inhalation toxicity potential in experimental animals:

“(4-hour) LC50 > 2.14 mg/L (aerosol (highest technically feasible


concentration)) – following exposure, the clinical signs observed for the
surviving animals included hypoactivity, abnormal respiration, reduced fecal
volume, ocular discharge and facial and/or anogenital staining. However
they recovered by Day 14. Although three animals lost weight by Day 7, all
surviving animals gained body weight over the 14-day observation period.
Gross necropsy of the decedent revealed discoloration of the lungs and
liver. No gross abnormalities were noted for any of the euthanized animals
when necropsied at the conclusion of the 14-day observation period.” (ECHA
REACH, 2018a).

The NICNAS review phthalic anhydride summarised the acute dermal toxicity
potential in experimental animals:

“The chemical was reported to have low acute toxicity via the dermal route
(LD50 in rats is > 2000 mg/kg bw).

“In a non-guideline study (REACH), five albino rabbits/sex/dose were


exposed to 10000 mg/kg bw as a 50 % suspension in water for 4 hrs with
wrapping. There were no mortalities and the local signs of mild erythema
and oedema observed on removal of the wrapping, recovered on the same
day. An LD50 > 10000 mg/kg bw was determined.

“In another non-guideline study (IUCLID 2000, REACH) in rabbits, severe


skin irritation was seen following a 24 hour exposure (refer to Skin irritation
section). An LD50 > 3160 mg/kg bw was reported.” (References as cited in
NICNAS, 2012).

The SCOEL review of phthalic anhydride summarised the skin and eye irritation/
corrosion potential in experimental systems:

“A PA solution (50%) in oil did not irritate rabbit ears after 20 hours of
exposure (DFG 1986/1987). PA (0.5 g/patch) did not cause skin irritation
on rabbits when applied by the semi-occlusive or occlusive method over a
period of 1 or 4 hours. The results were assessed at 1, 24, 48 and 72 hours, or
7 days later (Potokar et al 1985). PA did not produce irritation to the skin of
rabbits when exposed for 24 hours at 500 mg/animal (Bomhard et al 1996).
In another study 500 mg/animal for 24 hours having the test substance
moistened, slight irritation was reported (BioFax 1970).

“One drop of PA (5%) in polyethylene glycol 400 was slightly irritating


to rabbit eyes, while a 0.5% solution was not irritating (DFG 1986/87).
In an experiment with rabbits, the irritant effects of PA on the skin and eyes
correlated with each other. PA was found to be a mild skin irritant, but a
moderate eye irritant (Gad et al 1986). Introduction of PA into the eye at
50mg/animal caused irritation and a temporary corneal clouding in rabbits
(Bomhard et al 1996). In a study with a follow-up period of only 3 days and
an application of 100 mg/animal, the pronounced effects (71-81/110) were
not reversible (BioFax 1970).” (References as cited in SCOEL, 2011).

14
4.0 Health effects

The SCOEL review of phthalic anhydride summarised the potential for respiratory
sensitisation in experimental systems:

“Guinea pigs were sensitized by inhalation of PA dust at 500, 1 000, 5 000 g/


m3 (0.08, 0.2, 0.8 ppm), for 3 hours/day for 5 consecutive days. A PA-guinea
pig serum albumin (GPSA) challenge after 2 weeks elicited an immediate
onset of respiratory reactions, determined by plethysmography, in animals
exposed to all 3 levels of dust. The inhalation challenge with PA dust (5 000
g/m3 (0.8 ppm)) did not cause an immediate response, but the animals had
significant number of haemorrhagic lung foci. No foci were seen in the lungs
of PA-GPSA challenged animals. IgG-PA-GPSA antibodies were detected in
sera of all the PA-exposed animals, and the dose-response relationship was
highly significant (Sarlo et al 1994). A single intradermal injection of phthalic
anhydride (0.3 M) to guinea pigs was followed by the production of specific
IgG (Welinder et al 1995). After intradermal injection of hexahydrophthalic
anhydride to guinea pigs, the provocation with a phthalic anhydride
conjugate caused reactions in the respiratory passages (Zhang et al 1997).

“A single intradermal injection of a 0.3% PA solution in acetone/oil to guinea


pigs did not cause any pulmonary effect on inhalation provocation (44 mg/
m3 (7.5 ppm)) at 22 days. Another test in guinea pigs comprised intradermal
injection of 0.03, 0.1 or 0.3 % PA in corn oil with consequent inhalation
provocation with 11-29 mg/m3 (1.8-4.8 ppm) in argon or 9-48 mg/m3 (1.5-7.9
ppm) in dry air. Intradermal injection of 0.5 % solution and provocation with
11-29 mg/m3 (1.8-4.8 ppm) in argon resulted in respiratory effects. At the
lower concentrations, 0.03 and 0.1 % local irritant effects were seen in both
test and control animals (Blaikie et al 1995).

“Three weeks after a 5-day exposure to 0.5 mg/m3 (0.08 ppm) for 6 hours/
day, the provocation treatment with 0.5 mg/m3 (0.08 ppm) also caused an
increase in haemorrhagic foci in the lungs of rats, which was assessed to be
a sign of airway sensitization.

“In a Japanese study, rabbits were sensitized subcutaneously to a PA- RSA (rat
serum albumin) conjugate. High titres of IgG against PA-RSA were found, but
also against PA-HSA and HSA. IgG-PA-HSA antibodies had cross-reactivity
with HHPA-HSA, MHHPA-HSA, and MTHPA-HSA. After purification of specific
IgG-PA, the levels of specific IgG to other conjugates were unchanged. Two
types of IgG antibody production were suspected, one to PA hapten alone
and the other to new antigenic determinants on HSA (Hatanaka et al 1997).

“When monkeys were exposed parenterally to PA-MSA (monkey serum


albumin), PA dissolved in ethanol saline, MSA, or ethanol-saline alone,
sensitization was observed only with PA-MSA. The presence of new antigenic
determinants formed by PA on protein carriers was essential for the parenteral
sensitization (Biagini et al 1988).” (References as cited in SCOEL, 2011).

The OECD SIDS review of phthalic anhydride summarised the reproductive and
developmental toxicity potential in experimental animals:

“There was no fertility study with phthalic anhydride available. No evidence


of toxicity to reproductive organs was observed in comprehensive
carcinogenicity studies in rats and mice, as no treatment-related changes
were observed for any reproductive organ investigated during macroscopic
and microscopic examination (NOAEL, rat: 1000 mg/kg bw/day; NOAEL,
mouse (time-weighted average): 3430 (f), 4670 (m) mg/kg bw/day).
Following i.p. injection, an exposure route which is of unknown relevance
for the normal human situation, of doses in the lethal range, developmental

15
4.0 Health effects

toxicity was found in mice in a poorly reported study. However, the chemical
is quickly hydrolyzed to phthalic acid after oral, dermal or inhalation exposure.
Phthalic acid was investigated in a developmental toxicity feeding study
in rats and gave no evidence of embryotoxicity, or fetotoxicity at a non-
maternally toxic dose level (1.25 % in feed = approximately 1000 mg/kg bw/
day = NOAEL for maternal toxicity). Significant decreases in the weight of
male fetuses and in the numbers of ossified centers of the caudal vertebrae
were, however, found in the 5.0 % group, where maternal toxicity was also
observed (NOAEL, developmental toxicity: 2.5 % in feed = approximately
1700 mg/kg bw/day). Based on the data of phthalic acid, the hydrolysis
product of phthalic anhydride, it is concluded that, in the absence of
maternal toxicity, phthalic anhydride is not a developmental toxicant.”
(References as cited in OECD SIDS, 2005).

4.2 Cancer
The International Agency for Research on Cancer (IARC) Monographs on the
Evaluation of Carcinogenic Risks to Humans do not include an evaluation of the
carcinogenic potential of phthalic anhydride.

The US National Toxicology Program (NTP) Report on Carcinogens (RoC),


Fourteenth Edition does not include an evaluation on the carcinogenic potential
of phthalic anhydride.

The NZ EPA has not classified phthalic anhydride as a 6.7A or 6.7B substance
– substances that are known or presumed, or suspected human carcinogens
respectively (EPA, 2018).

Humans
The SCOEL review of phthalic anhydride summarised the carcinogenic potential
in exposed workers:

“In a case-control study, lung cancer mortality was investigated in a plant


producing acetylene and PA. After control for age and smoking, the odds
ratio for lung cancer mortality among the 43 subjects exposed in the factory
was 5.6 (95%CI 1.9-16.2). The corresponding odds ratio for 99 referents from
other work environments in the region was 1.7 (95%CI 0.9-3.5). There was,
however, also exposure to potential confounders, phthalates and soot (Riboli
et al 1983).” (References as cited in SCOEL, 2011).

The SCOEL review of phthalic anhydride noted that there was not data available
on the mutagenic or genotoxic potential in humans (SCOEL, 2011).

Animals
The SCOEL review of phthalic anhydride summarised the carcinogenic potential
in experimental animals:

“Long-term feeding studies on rat and mouse have not disclosed any
evidence of carcinogenic effects of phthalic anhydride (HSE 1996, DFG 2001,
Haseman et al 1987, Kluwe 1986, Kluwe et al 1982, Shelby & Stasiewicz 1984).
There was no effect of PA in cell transformation tests performed in embryo
cells of Syrian hamsters (LeBoeuf et al 1996). Neither did a transformations
test with A-31-1-13 BALB/c-T-3T3 cells show any effect (Matthews et al 1993).

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4.0 Health effects

“An in vivo study with male F344 rats, 15000 mg of PA/kg food was administered
orally for 1 and 2 weeks. The formation of 8-hydaroxydeoxyguanosine in the
DNA of liver and kidney. There were no differences between rats given PA and
controls (Takagi et al 1990).” (References as cited in SCOEL, 2011).

The OECD SIDS review of phthalic anhydride summarised the genotoxic potential
in in vitro experimental systems:

“Phthalic anhydride was not mutagenic in the Ames test with and without
metabolic activation (OECD TG 471). Chromosomal aberrations were induced
in mammalian cells in vitro at the highest phthalic anhydride concentrations
(10 mM) only in the absence of S9 mix with concomitant marked cytotoxicity
and compound precipitate. In vivo studies are not available. Overall, it can
be concluded that phthalic anhydride is genotoxic in vitro at extremely
high, cytotoxic concentrations, and only in the absence of a metabolic
activation system. This genotoxic effect is not expected to be relevant under
in vivo conditions, where phthalic anhydride is rapidly hydrolyzed to the
nongenotoxic phthalic acid.” (References as cited in OECD SIDS, 2005).

The SCOEL review of phthalic anhydride noted an in vivo micronucleus test in


F344 rats, where phthalic anhydride gave a negative result (Heddle et al., 1991
as cited in SCOEL, 2011).

4.3 Absorption, distribution, metabolism and excretion


The SCOEL review of phthalic anhydride noted that dermal absorption of
phthalic anhydride was “minute”, based on the dermal LD50 in rabbits reported
at 10,000 mg/kg b.w. (BioFax, 1970 as cited in SCOEL, 2011), and summarised the
toxicokinetics in exposed workers:

“Pfäffli (1986) followed the excretion of phthalic acid in workers exposed


to PA by taking urine samples pre-shift, on-shift, post-shift, in the evening,
and on the following morning. At low atmospheric exposure to PA (150 g/
m3, range 30-330 g/m3 (0.02 ppm, range 0.005-0.05 ppm)) the pre-shift
phthalic acid concentrations were on the same level as those found in the
urine samples of occupationally unexposed people (0.34, range 0.02-0.89
mol/mmol creatinine). In workers exposed to higher concentrations (1 630
g/m3, SD 130 g/m3 (0.3 ppm, SD 0.02 ppm)), the pre-shift phthalic acid
excretion was 1.02 (SD 0.25) mol/mmol creatinine indicating an accumulation
of phthalic acid in urine. At high exposure, 10 500 g/m3 (1.7 ppm), the pre-
shift urinary concentration increased to 4.8 mol/mmol creatinine, which was
about 14 times higher than in workers with low exposure. No conjugation of
phthalic acid to glucuronide was observed (Pfäffli 1986).

“The half-time of phthalic acid in urine of PA-exposed workers was shown to


be about 14 hours (Pfäffli 1986). The halftime for the dicarboxylic acid of PA
in urine was 14 hours.” (References as cited in SCOEL, 2011).

17
5.0
Exposure
standards
IN THIS SECTION:

5.1 Other exposure standards


5.2 ACGIH®
5.3 SCOEL
5.4 DECOS
5.5 DFG
5.6 New Zealand

18
5.0 Exposure standards

5.1 Other exposure standards


Table 4 below shows the phthalic anhydride exposure standards from around
the world, as published by the Institute for Occupational Safety and Health
of the German Social Accident Insurance (IFA, 2018).

JURISDICTION OR 8-HOUR LIMIT SHORT-TERM LIMIT


ADVISORY BODY VALUE VALUE

ppm mg/m3 ppm mg/m3

Australia 1 6.1

Austria 11 21

Belgium 1 6.2

Canada – Ontario 1

Canada – Québec 1 6.1

Denmark 1 2

Finland 0.2

France 6

Hungary 1 1

Ireland 4 122

Japan – JSOH 0.333 23

Latvia 1

 New Zealand 1 6.1

People’s Republic of China 14

Poland 1 2

Romania 0.3 5
2 5
0.85,6
55,6

Singapore 1 6.1

South Korea 1 6

Spain 7
1 6

Sweden 0.03 0.2 0.066 0.46

Switzerland 11 11

USA – NIOSH 1 6 TABLE 4:


USA – OSHA 2 12 Exposure standards
for phthalic anhydride
UK 4 12
from around the world

It is noted that the only organisations from whom we got information as to how
and why they recommended occupational exposures standards on phthalic
anhydride were ACGIH®, SCOEL, DECOS and DFG.

1
Inhalable aerosol.
2
15 minutes reference period.
3
Occupational exposure limit ceiling: Reference value to the maximal exposure concentration of the substance during a working day.
4
Ceiling limit value.
5
Inhalable fraction and vapour.
6
15 minutes average value.
7
sen.

19
5.0 Exposure standards

5.2 ACGIH®
The American Conference of Governmental Industrial Hygienists (ACGIH®) 2017
review of phthalic anhydride recommended a TLV-TWA of 0.002 mg/m3 (0.0003
ppm) and a TLV-STEL of 0.005 mg/m3 (0.0009 ppm), measured as inhalable
fraction and vapour, with Skin, RSEN and DSEN notations for occupational
exposure to minimise the potential for the induction of sensitisation. The ACGIH®
noted that phthalic anhydride is a respiratory tract irritant and sensitiser with
immediate, late or dual type asthma, conjunctivitis, rhinitis, chronic bronchitis,
urticaria, and allergic dermatitis. The Skin notation was assigned based on animal
studies indicating that phthalic anhydride can induce respiratory sensitisation via a
T helper 2 (Th2) cytokine phenotype response after dermal application of phthalic
anhydride (Dearman et al., 2000, 2002; Goutet et al., 2012; Mori et al., 2012; van
Och et al., 2002 as cited in ACGIH®, 2017). The RSEN notation was assigned based
on both animal studies (Sarlo et al., 1994; van Och et al., 2002 as cited in ACGIH®,
2017) and human experience (Barker et al., 1998 as cited in ACGIH®, 2017). The
DSEN notation was assigned based on animal studies and human experience
involving both phthalic anhydride provoked IgE Type 1 contact urticaria (Baader,
1955; Menschick, 1955; Gutierrez-Fernandez et al., 2007 as cited in ACGIH®,
2017), and Type IV delayed sensitisation (Gad, 1988; Gach et al., 2005 as cited
in ACGIH®, 2017). The ACGIH® assigned an A4, Not Classifiable as a Human
Carcinogen notation for phthalic anhydride, based on the lack of carcinogenic
response in animal studies after chronic dietary exposure (Kluwe et al., 1982 as
cited in ACGIH®, 2017). The ACGIH® noted that occupational exposure should be
kept as low as possible below the recommended TLV®, because the TLV® may
not protect against an allergic reaction in sensitised individuals (ACGIH®, 2017).

The rationale for their conclusions included that:

“The TLV-TWA value is intended to protect against the induction of


sensitization and is based on worker studies that indicate average exposures
below 0.01 mg/m3 (0.002 ppm) rarely result in sensitization (Barker et al.,
1998). Phthalic anhydride exposures have been linked to high incidence rates
of respiratory disease in some occupational settings (Nielsen et al., 1988,
1991; Wernfors et al., 1986). The sensitizing capacity of phthalic anhydride has
been shown to be as low as 0.4 mg/m3 (0.07 ppm) TWA8hr in human studies
(Kim et al., 2009; Nielsen et al., 1988; Wernfors et al., 1986) and 0.5 mg/m3
(0.08 ppm) (the lowest concentration tested) in an animal assay (Sarlo et al.,
1994). Peak exposures may be important in the development of occupational
asthma from acid anhydrides (van Tongeren et al., 1995). Accordingly, a
TLV-STEL of 0.005 mg/m3 (0.0009 ppm) measured as inhalable fraction and
vapor is recommended to keep exposures below short-term exposures found
in studies with high asthma prevalence (Barker et al., 1998; Nielsen et al.,
1988; Wernfors et al., 1986).” (References as cited in ACGIH®, 2017).

5.3 SCOEL
The Scientific Committee on Occupational Exposure Limits (SCOEL) 2011 review
of phthalic anhydride concluded:

“Phthalic anhydride (PA) causes irritation and sensitization of the eyes and
the respiratory tract. OA induces allergic rhinoconjuctivitis and asthma. From
a health-based point of view, the allergic respiratory effects, being persistent,
are the most severe effects of PA. It is not always possible to separate irritant
and allergic effects. IgE-mediated asthma and rhinitis has been proven, but
other unknown mechanisms may be involved. Experimental animal studies
have demonstrated a weak skin sensitizing effect and skin sensitization has
been reported in humans.

20
5.0 Exposure standards

“Human data on dose-response is poor. Based on the available scientific


data, it is not possible to identify a NOAEL, nor a LOAEL for PA. Among
workers exposed to 8-hour TWA levels of PA below 0.1 mg/m3 (0.02 ppm)
(0.1 being the detection limit of the PA assay) rhinitis, conjunctivitis and
rhinoconjunctivitis occurred in a substantial proportion of exposed, whereas
no cases of asthma were found. Whether the symptoms were irritant or
allergic is uncertain (Nielsen et al 1988). Available experimental animal data
are not of any further help in the assessment of a NOAEL or LOAEL.

“Peak exposures are likely to be important inducers of sensitization.


The recommendation of a STEL would, therefore be advisable, but a
scientifically based value is impossible to assess based on available data.

“Studies available do not indicate genotoxic, mutagenic or carcinogenic


effects of PA.

“Data do not indicate significant absorption through the skin.” (SCOEL, 2011).

5.4 DECOS
The Dutch Expert Committee on Occupational Standards (DECOS) review of
cyclic acid anhydrides concluded that the induction of allergenic sensitisation
was the critical adverse health effect against which workers should be protected,
because it is an irreversible change associated with a higher risk of developing
allergic reactions. DECOS did not find clear data suggesting that irritation
occurred below exposure levels at which allergic hypersensitivity had also been
reported, indicating that by preventing hypersensitivity, irritation to the airways
and lungs would also be prevented. The choice of effect parameter was allergic
IgE-mediated sensitisation as DECOS considered this parameter to be the best
basis for deriving health-based recommended occupational exposure limits
(HBR-OEL) (DECOS, 2010).

However, for phthalic anhydride DECOS found that work-related respiratory


symptoms were reported at average full-day exposures of up to 0.4 mg/m3
(0.07 ppm) combined with peak exposures of up to 13 mg/m3 (2.1 ppm), with the
variation in exposure levels giving uncertainty to what was the average full-shift
working day exposure. The Committee considered the available data was not
suitable for deriving a health-based recommended OEL or reference value, so
abstained from giving a recommendation (DECOS, 2010).

The DECOS procedure was based on the premise that a threshold level does exist
for allergic sensitisation by inhaled allergens, but the threshold level will often
be too low to discern using the techniques presently available and so reference
values, concentration levels that correspond to predefined accepted levels of risk
of allergic sensitisation, would need to be determined (DECOS, 2010).

5.5 DFG
The Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)
2009 review of phthalic anhydride recommended no MAK value, no Peak
limitation; Sensitisation notation “Sa”; no Carcinogenicity Category; no
Pregnancy risk classification (DFG, 2009).

The DFG decision was based on the following rationale:

“Phthalic anhydride is sensitizing and locally irritating to the respiratory


passages in humans. A skin sensitizing effect has been demonstrated in
animal studies. Cases of skin sensitization have been reported in humans.
Based on the effects in humans and the results of animal studies, the
designation with “Sa” is retained.

21
5.0 Exposure standards

“In 1992 the MAK value for phthalic anhydride was lowered to 1 mg/m3 (0.2
ppm). In 1995 it was demonstrated that the MAK value of 1 mg/m3 (0.2 ppm)
significantly reduces the extent of sensitization. Since then, no new data on
effects in humans have been reported which would substantially change
this assessment. However, sensitizing and irritating effects in the respiratory
passages cannot always be differentiated. In an inadequately documented
animal study, the inhalative exposure to 0.5 mg phthalic anhydride/m3 (0.08
ppm) caused effects in the lungs which were interpreted to be allergenic
to the respiratory tract. Data on the irritative effects in humans and chronic
toxicity in animal studies are lacking; therefore, phthalic anhydride is
classified in Section IIb of the List of MAK and BAT Values. The previous
MAK value, the assignment to Peak limitation category I, and the
classification in Pregnancy risk group D are withdrawn.

“There are no data available on absorption through the skin. The epicutaneous
application did not cause toxic effects in animal studies. Therefore, the
substance is not designated with an “H”.

“There are no data available that would justify a classification in one of the
categories for germ cell mutagenicity.” (DFG, 2009).

5.6 New Zealand


WorkSafe’s WES for phthalic anhydride has been unchanged since adoption
in 1994.

The toxicological database reviewed above indicates that phthalic anhydride is


locally and systemically toxic to humans (eg causing respiratory tract, eye and
skin irritation, respiratory tract and skin sensitisation, asthma) and locally and
systemically toxic to laboratory animals (eg causing respiratory tract, skin and
eye irritation, and respiratory tract and skin sensitisation).

Based on the aforementioned documentation, and in particular the findings listed


below, WorkSafe considers its current WES-TWA of 1 ppm (6.1 mg/m3) with a sen
notation for phthalic anhydride, to be inadequate to manage health risks from
possible workplace exposure:
–– The current WES-TWA of 1 ppm phthalic anhydride is higher than the levels
reported to induce respiratory sensitisation or occupational asthma in
exposed workers.
–– Phthalic anhydride has the potential to induce respiratory sensitisation
in exposed workers, and this endpoint forms the basis for the ACGIH®
recommended TLV-TWA and TLV-STEL (ACGIH®, 2017). SCOEL, DECOS and
DFG consider phthalic anhydride to be either a respiratory and skin sensitiser
(SCOEL, 2011; DECOS, 2010), or a skin sensitiser (DFG, 2009). Allergic
sensitisation is considered an irreversible change (DECOS, 2010). A sen
notation is warranted.
–– Studies in workers have indicated that average exposures to phthalic
anhydride below 0.01 mg/m3 (0.002 ppm) were rarely associated with
sensitisation (Barker et al. 1998 as cited in ACGIH®, 2017).
–– Human studies have reported that phthalic anhydride has a sensitising
capacity at 0.4 mg/m3 (0.07 ppm) TWA8hr (Kim et al., 2009; Nielsen et al.,
1988; Wernfors et al., 1986 as cited in ACGIH®, 2017) with high incidence rates
for respiratory disease in some occupational settings (Nielsen et al., 1988;
Wernfors et al., 1986 as cited in ACGIH®, 2017).

22
5.0 Exposure standards

–– Peak exposures may be important in the development of occupational asthma


from acid anhydrides (van Tongeren et al., 1995 as cited in ACGIH®, 2017;
Barker et al., 1998).
–– The Health Council of the Netherlands works on the premise that threshold
levels exist for allergic sensitisation by inhaled allergens (DECOS, 2008), but
the data for phthalic anhydride was inadequate to quantitatively derive such
a threshold (DECOS, 2010).
–– Any threshold level for allergic sensitisation by inhaled allergens may not
be protective once an individual has become sensitised (ACGIH®, 2017), and
cross-sensitivity may occur with other related substances (ACGIH®, 2017).
–– The odour threshold for phthalic anhydride was reported at 0.053 ppm
(ACGIH®, 2017) and may not be protective.
–– Phthalic anhydride particulate and vapour together may contribute to the
total inhalation exposure in any workplace due to the physicochemical nature
of the substance.

23
6.0
Analytical
methods for the
assessment of
airborne phthalic
anhydride

24
6.0 Analytical methods for the assessment of airborne phthalic anhydride

No current analytical methods


would appear to be available
that can determine the
airborne concentration of
phthalic anhydride at levels
likely to be protective of
worker health.

A common method to measure phthalic anhydride exposure is using OSHA


Method ORG-90 (OSHA, 1991).

Using this method, an air sample of up to 75 litres at a flow rate of 1 L/min is


collected through an open-face sampling device containing two glass fibre filters,
each coated with 3,4-dimethoxybenzylamine. The samples are extracted using
acetonitrile/dimethyl sulfoxide and analysed by reverse phase high-performance
liquid chromatography with UV (ultraviolet) detection.

The method has a reported reliable quantitation limit of 0.008 ppm (0.05 mg/m3).
It is acknowledged that this could not quantify samples at airborne concentrations
below 0.002 ppm, which is the proposed 8-hour TWA.

There would not appear to be any options available for real-time determination
of phthalic anhydride using sensor technology.

25
7.0
Discussion and
recommendations

26
7.0 Discussion and recommendations

WorkSafe considers its current


WES-TWA of 1 ppm (16.1 mg/m3)
with a sen notation for phthalic
anhydride to be inadequate to
protect workers exposed in the
workplace, based on current
knowledge.

It is proposed that WorkSafe:


1. adopt a WES-TWA for phthalic anhydride at 0.002 ppm (0.01 mg/m3)
inhalable fraction and vapour
2. adopt a skin notation for phthalic anhydride, and
3. maintain the sen notation for phthalic anhydride.

It is acknowledged that currently there are no available analytical methods


that would allow determination of airborne levels of phthalic anhydride at
the proposed WES-TWA. WorkSafe recommends substituting for alternative
substances so far as is reasonably practicable.

Conclusions of the ACGIH®, SCOEL, DECOS and DFG reviews are summarised below:
–– the current WES-TWA of 1 ppm phthalic anhydride is higher than the levels
reported to induce respiratory sensitisation or occupational asthma in
exposed workers
–– phthalic anhydride has the potential to induce respiratory sensitisation
in exposed workers, and this endpoint forms the basis for the ACGIH®
recommended TLV-TWA and TLV-STEL. SCOEL, DECOS and DFG consider
phthalic anhydride to be either a respiratory and skin sensitiser, or a skin
sensitiser. Allergic sensitisation is considered an irreversible change. A sen
notation is warranted
–– studies in worker have indicated that average exposures to phthalic anhydride
below 0.01 mg/m3 (0.002 ppm) were rarely associated with sensitisation
(Barker et al. 1998 as cited in ACGIH®, 2017)
–– as no threshold level for allergic sensitisation by phthalic anhydride has been
established, exposure at the proposed WES-TWA of 0.002 ppm (0.01 mg/m3)
inhalable fraction and vapour may pose some risk to exposed workers, so any
exposures should be minimised;
–– skin penetration resulting in systemic toxicity can occur in experimental
animals exposed to phthalic anhydride, with evidence of the development
of a T helper 2 cytokine phenotype response associated with respiratory
sensitisation. A skin notation is justified.

27
Appendices
IN THIS SECTION:

Appendix 1: Glossary
Appendix 2: HSNO health-related hazardous substance classifications
Appendix 3: References

28
Appendices

Appendix 1: Glossary

TERM MEANING

95% CI 95% Confidence Interval.

AA-HSA Acid anhydride human serum albumin.

ACGIH® The American Conference of Governmental Industrial Hygienists (ACGIH®) is a member-based


organisation, established in 1938, that advances occupational and environmental health. Examples
of this include their annual edition of the TLVs® and BEIs® book and work practice guides. Store at:
www.acgih.org/store

CI Confidence Interval.

DECOS Dutch Expert Committee on Occupational Standards. A committee of the Health Council of the
Netherlands. The latter was established in 1902 as an independent scientific advisory body with a
remit: “to advise the government and Parliament on the current level of knowledge with respect to
public health issues and health (services) research...” (Section 22, Health Act).

DFG Deutsche Forschungsgemeinschaft (German Research Foundation), the Permanent Senate


Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area, Federal
Republic of Germany. The science-based MAK values are recommended to the German Minister of
Labour and Social Affairs for possible adoption under the German Hazardous Substances Ordinance.

DNA Deoxyribonucleic acid.

DSEN A notation indicating the substance is a dermal sensitiser. DSEN is used in place of SEN when specific
evidence of sensitisation by the dermal route is confirmed by human or animal data. An ACGIH® term.

ECHA The European Chemicals Agency (an agency of the European Union).

EPA The New Zealand Environmental Protection Authority.

FEV1 Forced expiratory volume in 1 second.

GPSA Guinea pig serum albumin.

“H” DFG MAK designation: danger of percutaneous absorption.

Hapten Haptens are small-molecular-weight compounds that evoke an immune response only when they are
attached to carrier proteins.

HBR-OEL Health-based recommended exposure limit. European Union term.

HHPA Hexahydrophthalic anhydride.

HSA Human serum albumin.

HSNO Hazardous Substances and New Organisms Act 1996, New Zealand.

IARC International Agency for Research on Cancer, World Health Organisation.

IFA Institut für Arbeitsschutz der Deutschen Gestzlichen Unfallversicherung (Institute for Occupational
Safety and Health of the German Social Accident Insurance).

IgE Immunoglobulin E.

IgG Immunoglobulin G.

IgG4 Immunoglobulin G subclass 4.

i.p. Intraperitoneal.

IU/mL International Units per Millilitre.

JSOH Japan Society for Occupational Health.

LC50 Lethal Concentration 50%: Concentration resulting in 50% mortality.

LD50 Lethal Dose 50%: Dose resulting in 50% mortality.

29
Appendices

TERM MEANING

L/min Litres per minute.

MA Maleic anhydride.

MAK Maximale Arbeitsplatz-Konzentration, (maximum workplace concentration) is defined as the maximum


concentration of a chemical substance (as gas, vapour or particulate matter) in the workplace air
which generally does not have known adverse effects on the health of the employee nor cause
unreasonable annoyance (eg by a nauseous odour) even when the person is repeatedly exposed
during long periods, usually for 8 hours daily but assuming on average a 40-hour working week.

MEST Mouse-ear swelling test.

g/m3 Micrograms of substance per cubic metre of air.

mol Micromole or one millionth of a mole of a substance.

mg Milligram or one thousandth of a gram.

mg/kg b.w. Milligrams of substance per kilogram body weight.


or mg/kg bw

mg/kg b.w./day Milligram of substance per kilogram body weight per day (exposure rate).
or mg/kg bw/day
or mg/kg/day
or mg/kg bw/d

mg/L Milligrams per litre.

mg/m3 Milligrams of substance per cubic metre of air.

MHHPA Methyl hexahydrophthalic anhydride.

mM Millimolar – millimoles per litre, or thousandths of a mole per litre.

mmol Millimole or a concentration of one thousandth of a mole of a substance.

MSA Monkey serum albumin.

MTHPA Methyl tetrahydrophthalic anhydride.

NICNAS National Industrial Chemicals Notification and Assessment Scheme is the Australian government’s
regulatory body for industrial chemicals.

NIOSH The National Institute for Occupational Safety and Health is the United States federal agency
responsible for conducting research and making recommendations for the prevention of work-
related injury and illness.

NOAEL No Observed Adverse Effect Level.

NTP National Toxicology Program, US Department of Health and Human Services.

OECD Organisation for Economic Co-operation and Development.

OEL Occupational Exposure Limit (equivalent to a WES).

OSHA Occupational Safety and Health Administration, US Department of Labor.

PA Phthalic anhydride.

ppm Parts of vapour or gas per million parts of air.

RAST Radioallergosorbent test: a blood test using radioimmunoassay test to detect specific IgE antibodies.

REACH Registration, Evaluation, Authorisation and Restriction of Chemicals. An EU program and regulation.

RoC Report on Carcinogens.

RSA Rat serum albumin.

30
Appendices

TERM MEANING

RSEN A notation indicating the substance is a respiratory sensitiser. RSEN is used in place of SEN when
specific evidence of sensitisation by the inhalation route is confirmed by human or animal data.
An ACGIH® term.

“Sa” Sensitising to airways. A DFG MAK notation.

SCOEL The Scientific Committee on Occupational Exposure Limits is a committee of the European
Commission, established in 1995 to advise on occupational health limits for chemicals in the
workplace within the framework of Directive 98/24/EC, the chemical agents directive, and Directive
90/394/EEC, the carcinogens at work directive.

sen A substance that can ‘sensitise’ the skin or respiratory system, inducing a state of hypersensitivity
to it, so that on subsequent exposures, an allergic reaction can occur (which would not develop in
non-sensitised individuals). It is uncommon to become sensitised to a compound after just a single
reaction to it. A term WorkSafe also uses.

SEN A notation indicating the substance is a sensitiser. DSEN and RSEN are used in place of SEN when
specific evidence of sensitisation by the dermal or respiratory route, respectively, is confirmed by
human or animal data. An ACGIH® term.

SIDS Screening Information DataSet (OECD).

skin Skin absorption – applicable to a substance that is capable of being significantly absorbed into the
body through contact with the skin. A term WorkSafe also uses.

Skin A notation indicating the potential for significant contribution to the overall exposure, by the
cutaneous route, including mucous membranes and the eyes, by contact with vapours, liquids and
solids. An ACGIH® term.

TLV® Threshold Limit Value (see TLV-STEL and TLV-TWA below). An ACGIH® term. What TLVs® and BEIs®
are, how they are formulated, and the guidance on their use are found at: www.acgih.org/tlv-bei-
guidelines/policies-procedures-presentations

TLV-STEL TLV-Short-Term Exposure Limit; a 15 minute TWA exposure that should not be exceeded at any time
during a work day, even if the 8-hour TWA is within the TLV-TWA. An ACGIH® term.

TLV-TWA TLV – Time-Weighted Average; the TWA concentration for a conventional 8-hour workday and a
40-hour workweek, to which it is believed that nearly all workers may be repeatedly exposed to,
day after day, for a working lifetime without adverse effect. An ACGIH® term.

TMA Trimellitic anhydride.

TWA8hr Time-weighted average – 8-hour.

WES Workplace Exposure Standard – WESs are values that refer to the airborne concentration of
substances, at which it is believed that nearly all workers can be repeatedly exposed to, day after
day, without coming to harm. The values are normally calculated on work schedules of five shifts
of eight hours duration over a 40 hour week. A WorkSafe term.

WES-STEL The 15-minute time-weighted average exposure standard. Applies to any 15-minute period in the
working day and is designed to protect the worker against adverse effects of irritation, chronic or
irreversible tissue change, or narcosis that may increase the likelihood of accidents. The WES-STEL
is not an alternative to the WES-TWA; both the short-term and time-weighted average exposures
apply. Exposures at concentrations between the WES-TWA and the WES-STEL should be less than
15 minutes, should occur no more than four times per day, and there should be at least 60 minutes
between successive exposures in this range. A WorkSafe term.

WES-TWA The average airborne concentration of a substance calculated over an eight-hour working day.
A WorkSafe term.

31
Appendices

Appendix 2: HSNO health-related hazardous substance classifications


This is the full list of all health-related hazardous substances classifications that are listed by the NZ EPA,
including those that apply to this substance.

CLASSIFICATION CODE MEANING

Acutely toxic

6.1A Substances that are acutely toxic – Fatal

6.1B Substances that are acutely toxic – Fatal

6.1C Substances that are acutely toxic – Toxic

6.1D Substances that are acutely toxic – Harmful

6.1E Substances that are acutely toxic – May be harmful, aspiration hazard

Skin irritant

6.3A Substances that are irritating to the skin

6.3B Substances that are mildly irritating to the skin

Eye irritant

6.4A Substances that are irritating to the eye

Sensitisation

6.5A Substances that are respiratory sensitisers

6.5B Substances that are contact sensitisers

Mutagens

6.6A Substances that are known or presumed human mutagens

6.6B Substances that are suspected human mutagens

Carcinogens

6.7A Substances that are known or presumed human carcinogens

6.7B Substances that are suspected human carcinogens

Reproductive/developmental toxicants

6.8A Substances that are known or presumed human reproductive or developmental toxicants

6.8B Substances that are suspected human reproductive or developmental toxicants

6.8C Substances that produce toxic human reproductive or developmental effects on or via lactation

Target organ toxicants

6.9A Substances that are toxic to human target organs or systems

6.9B Substances that are harmful to human target organs or systems

Skin corrosive

8.2A Substances that are corrosive to dermal tissue (UN PGI)

8.2B Substances that are corrosive to dermal tissue (UN PGII)

8.2C Substances that are corrosive to dermal tissue (UN PGIII)

Eye corrosive

8.3A Substances that are corrosive to ocular tissue

Source: www.epa.govt.nz/industry-areas/hazardous-substances/rules-for-hazardous-substances/hazardous-
substances-classification-codes

32
Appendices

Appendix 3: References
American Conference of Governmental Industrial Hygienists (ACGIH®). (2017).
Phthalic anhydride. Documentation of the Threshold Limit Values and Biological
Exposure Indices. 7th Edition. Cincinnati, Ohio: ACGIH®.

From ACGIH®, Documentation of the Threshold Limit Values and Biological


Exposure Indices, 7th Edition. Copyright 2001. Reprinted with permission.

Barker et al. (1998). Risk factors for sensitisation and respiratory symptoms
among workers exposed to acid anhydrides: a cohort study. Occup Environ
Med, Vol. 55; pp 684-691. www.ncbi.nlm.nih.gov/pmc/articles/PMC1757519/pdf/
v055p00684.pdf

Deutsche Forschungsgemeinschaft (DFG). (2009). The MAK-Collection:


MAK Value Documentation, 2009: Phthalic anhydride. DFG; WILEY-VCH
Verlag GmbH & Co. KGaA, Weinheim. https://onlinelibrary.wiley.com/doi/
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33
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34
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