HSE

Health & Safety

Executive

Toxicology
of substances
in relation
to major hazards

Acrylonitrile

This document
contains
L 41 pages
Toxicology of substances in relation
to major hazards

Acrylonitrile
by RM Turner andS Fairhurst

Contents

Summary 1

Introduction 1

Toxicological data available in humans 1

Toxicological data available in animals 2

Derivation of dangerous toxic load 2

Tables

1 LC50 valuesfor acrylonitrilein animals 3

2 Single exposure inhalation studies in animals 4

References 10

London:
Her Majesty's Stationery Office
© Crown copyright 1989
First published 1989

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ISBN0 11 885523 9
SUMMARY The principaleffectsarising from a singleinhalation
exposure of animals to acrylonitrile vapourare sensory
This paper examines the dangerous toxic load (DTL) for irritation of the eyesand nose, skin reddening, and lung
acrylonitrile, in accordance withthe principles of oederna (2). Vomiting and incoordination were also
toxicological assessment described in the recent HSE reported in cats and dogs(34). Mortality resultsfrom lung
publication Assessmentofthe Toxicity ofMajorHazard oedemaleading to respiratory distress and convulsions,
Substances(1). and deathsoccur aftera period of between several
hoursand a few days, the later deaths occurring
Thereis little reliable quantitative information on the particularly In guineapigs(3). Similarsigns oftoxicity,
effectsof a single exposure to acrylonitrile in humans, togetherwith headache, vertigo and tiredness, have
and manyof the acute inhalation studies in animals are been reported in humansreceiving an acute exposure to
ratherold and poorlyreported. Nevertheless, fromthe acrylonitrile(2). Liver tenderness and jaundice were also
data available it is suggested that for risk analyses the apparent in workersreceiving a sublethal exposure(5);
following relationship is used: fatty degeneration of the liver and focal kidneytubule
damagewere noted in a poorly reported acuteinhalation
DTL= 9 600 ppm mm. study in guinea pigs(6).

One case has beenreported of,a worker complaining of

INTRODUCTION lassitude and fatigue one year after a singleexposureto
acrylonitrile(5). However, in general the possibility of
This paper is a review of the available toxicological data long-term sequelae following an acute exposure has
on acrylonitrile, in orderto establish the most appropriate beenpoorlyinvestigated.
toxicityvaluesfor land-use planning decision-making. It
should be read in conjunction withthe above-mentioned Acrylonitrile expresses genotoxic activity in vitro, and is
HSE publication which provides the general framework carcinogenic in animalsand possiblyin hurnans(27).
within which this evaluation ofthe toxicity of acrylonitrile Teratogenicity has also been reported in animals,in a
wascarriedout(1). repeated inhalation studyin rats and in singleor
repeated oral admihistration studiesin rats and
Acrylonitrile (OH2 = CHCN) is a clear colourless or hamsters, although these effects occurredonly at dose
slightlyyellow volatile liquidunder normal conditions of levels close to orat those producing maternal toxicity(2).
temperature and pressure. Somephysicochernical However, fromthe data available it is not possible to
properties of acrylonitrile are shown below(2). describe in a reliable mannerrelationships between
singleinhalation exposures to acrylonitrile and possible
carcinogenic, mutagenic or teratogenic effects in
Property Value humans. Therefore, the dangerous toxic load for
acrylonitrile has been derivedprimarily from an
assessment of the data relating to the well-recognised
Molecularweight 53.06
effectsseen in animals and humans arising soon aftera
single inhalation exposureto acrylonitrile vapour.
Boiling point at 1.0133 x 1 o Pa 350.3°K
TOXICOLOGICALDATA AVAILABLEIN HUMANS
Freezing point at 1 .0133 x 1o Pa 189.5°K

1.33 x 1Q4 Pa Although there has beena numberof reports of

Vapour pressure at 296.6°K accidental fatalitiesor serious toxic effectsin humans
resulting fromsingle inhalation exposures to acrylonitrile,
Density at 298°K 0.8
very little information exists on the associated exposure
levels(78). The only quantitative data are containedin an
Watersolubility at 239°K 73.5 kg/rn3
anecdotal reportof workersexposedto 16-100 ppm
acrylonitrile for 20-45 minutes(9).Thesemen
Conversion factorfor vapourat 1 ppm = 2.2 mg/rn3 experienced sensoryirritation of the eyes, nose, throat
298°K, 1.0133 x io
Pa
and respiratory tract, itching of the skin, dull headache,
and a feeling of apprehension and nervous irritability.

1
TOXICOLOGICAL DATA AVAILABLEIN ANIMALS SLOT in humans, basedon data fromthe moresensitive
animal species,is:
The toxicityof acrylonitrile following a single inhalation
40 ppm for 4 hours.
exposure has been studied in several animalspecies
(3,4,6,10-14). Thesestudiesare summarised in Table 2. Derivation of dangerous toxic load equation
Someindication ofspeciesvariation in susceptibility is
givenby the approximate LC50 values and associated Fromthe studiesavailable, the relationship between
exposure timesshown in Table 1.
atmospheric concentration, exposure time and a toxic
loadconstantis best explored by investigating the data
Many ofthe animal studies have used relatively long from rats exposed to variousconcentrations of
exposure times, in the range 1-8 hours, and there are no
data on the effects ofexposure for periodsof lessthan acrylonitrile for periodsof between 30 mInutes and
30 minutes. 8 hours(3). Examination ofthese data by the method of
Maximum Likelihood(15)or by a simplegraphical plot of
the LC50 values from each exposure period, indicates a
valueof approximately 1 forthe exponent n, producing
DERIVATION OF 'DANGEROUS TOXICLOAD'
the expression: toxic load ct. Otherworkershave
deriveda similarvaluefor n from thesedata(16).
Estimation of one set ofexposure conditions
producing the HSE land-use planning SLOT A value of n 1.3 is obtained by Maximum Likelihood
(Specified Level of Toxicity)
analysisof the data from anotherstudy In rats(10).
From animal studies, the dog appearsto be the most Although this valuemust be consideredimprecise,given
the small numberof differentsets of experimental
sensitive speciesofthose tested. Unfortunately the
conditions used, it appearsto providesome additional
studies in dogs are reported only in brief detail, and
involve smallgroup sizes and somewhatirregular supportfor the toxic loadrelationshIp derivedabove.
patterns of mortality(34). Nevertheless, severe toxic The only otherstudyproviding data from which the toxic
effects, including respiratory distress and convulsions,
load relationship couldbe examined is an Inhalation
were produced by exposure of dogs to 65 ppm and
above for4 hours, and to 75 ppm and above for 7 hours. studyin mice(13). However, from the overallpattern of
Within the smallgroup sizes used,the lowest mortality and otherInformation in the report, thereis
some doubtconcerning the accuracy of the tabulated
concentrations at which deaths occurred were also
65 ppm for 4 hours (1/2 deaths) and 75 ppm for 7 hours mortality valuefor the 30-minute exposure to 680 ppm
(3/4 deaths). Mostof the dogs exposedto 100-110 ppm acrylonitrile. This concern, togetherwith the overallsmall
for 4 hourswere in a coma at the end of the exposure quantityof data produced bythis study, suggeststhat
any n valuederivedfrom the resultsquoted wouldnot be
period. A similardegree of susceptibility was indicated in
reliable.
other studies whereone of three Rhesusmonkeys died
following exposure to 75 ppm for 7 hours, and a 4-hour
Therefore, on balancethe available experimental
exposure LC50 in mice was givenas 136 ppm, evidence indicates that an appropriate toxic load
suggesting that somedeathsmay have occurred in this
equation for acrylonitrile is:
particular speciesand strain at exposure concentrations
of lessthan 100 ppm for4 hours(46). toxic load= ct.

None ofthese sets of data is suitable for evaluation by Dangeroustoxic load valuefor acrylonitrile
methods such as probitanalysis, and considerable
uncertainty in derivingappropriate valuesin this Using the toxic load relationship givenabove, and the
assessment is created by the use of very smallgroup prediction of 40 ppm for4 hoursas one set of exposure
sizes and relatively longexposure periodsin the studies conditions producing the land-use planning SLOT, the
producing the most sensitive responses. In the absence dangerous toxic load Is:
ofquantitative information on the levels of acrylonitrile
producing severe toxic effects and deaths in humans, a DTL = 9 600 ppm mm.
cautious but reasonable estimate of one set of exposure
conditions predicted to produce the land-use planning Someexamples of exposure conditions producing this

2
DTLare given below. Table 1 LC50 valuesfor acrylonitrile in animals

Exposureperiod (mm) Duration Approximate

Species of LC50 values Reference
exposure (ppm)
5 10 30 60 120 240 (hours)

Atmospheric Rat 0.5 2500-3000 10

concentration 1920 960 320 160 80 40
1 1911 3
(ppm)
2 727 3
1000 10

In the caseof acrylonitrile, because of the nature ofthe 4 214 6

available toxicological information, it has been necessary 339 3
to base the predictions of the atmospheric 500-1000 11,12
concentrations producing the DTLat short exposure 8 268 3
timeson extrapolation from the concentration at the
relatively longexposure period of 4 hours. It shouldbe Mouse 1 400-770 13
acknowledged that this distance of extrapolation in itself 2 400 13
introduces considerable uncertainty into the prediction of 4 136 6
DTLconditions at the shortestexposure times. Guinea pig 4 450 6
550 3

Rabbit 4 135-260 3
Cat 4 275-600 3
Dog 7 50-75 4

3
TABLE 2 SINGLE EXPOSURE INHALATION STUDIES IN ANIMALS

Species Exposure Observations

characteristics conditions

Rat3 Exposure ranged from Observation period was not given. The mortality
Osborne—Hendel 90—2445 ppm for periods of results were:—
mean 295 g 30 minutes to 8 hours.
30 minutes exposure
16 per group
665 ppm 0/16
1270 ppm 0/16
1490 ppm 0/16
2445 ppm 0/16

1 hour exposure

665 ppm 0/16

1270 ppm 0/16
1490 ppm 4/16
2445 ppm 13/16

2 hours exposure

305 ppm 0/16

595 ppm 1/16
1260 ppm 16/16

4 hours exposure

130 ppm 0/16

315 ppm 5/16
635 ppm 16/16

8 hours exposure

90 ppm 0/16
135 ppm 0/16
210 ppm 1/16
270 ppm 7/16
320 ppm 15/16

Probit analysis of these data gives the following

LC50 values:—

1 h exposure : 1911 ppm

2 h exposure : 727 ppm

4 h exposure : 339 ppm

8 h exposure : 268 ppm

Overall, the data fit a relationship of:—

toxic load ct
where n 1

4
TABLE 2 SINGLE EXPOSUREINHALATION STUDIES IN ANIMALS

Species Exposure Observations

characteristics conditions

For each exposure period, signs of toxicity ranged

from irritation of the mucous membranes at lower
concentrations to flushing or reddening of the
skin, rapid, shallow breathing, dyspnoea,
convulsions and coma at higher concentrations. All
decedents died within 14 hours post—exposure. Few
toxic signs were evident at 24 hours post—exposure.

Rat'0 Exposures ranged from Observation period was not given. The mortality
Wistar 650—3000 ppm for periods results were:—
male of 10 minutes to 3 hours.
200—300 g 10 minutes exposure

3—6 per group 2400 ppm 0/3

30 minutes exposure

1600 ppm 0/3

2600 ppm 1/3
3000 ppm 6/6

2 hours exposure

950 ppm 1/3

1100 ppm 3/3

3 hours exposure

650 ppm 1/3

Rat6 4 hours exposure to each A very briefly reported study, with no raw data
of six unspecified given. IC50 214 ppm
2 per group concentrations

Rat'1 12 500 or 1000 ppm for A very briefly reported study. 114—day observation
Sherman 4 hours, period. The mortality results were:—
males and females
100—150 g 500 ppm 0/6
1000 ppm 6/6
6 per group

Rat4 25, 50, 75 or 100 ppm for Half the animals were sacrificed immediately
Wistar 7 hours, post—exposure. Accurate mortality data therefore
130 g cannot be derived from this study, although 4 rats
died at 100 ppm. Very little cyanide and
20 per group cyanmethaemoglobin was found in the blood.

5
TABLE 2 SINGLE EXPOSURE INHALATION STUDIES IN ANIMALS

Species Exposure Observations

characteristics conditions

Mouse1 Exposures ranged from A briefly reported study wIth 8 10—day observation
273—2636 ppm for periods period. The mortality results were:—
6 per group of 30 minutes to 2 hours.
30 minutes exposure

273 ppm 0/6

680 ppm 5/6
2636 ppm 5/6

1 hour exposure

409 ppm 1/6

773 ppm 6/6

2 hours exposure

409 ppm 3/6

All deaths occurred within 24 hours post—exposure,

preceded by rapid, shallow breathing, then
dyspnoea, apnoea, convulsions and prostration.

The reliability of the entry of 5/6 deaths at 680

ppm for 30 minutes is questionable In view of the
other data in this paper.

Mouse6 4 hours exposure to each A very briefly reported study, with no raw data
of six unspecified given. LC50 136 ppm.
2 per group concentrations.

Guinea pig3 100—1160 ppm for 4 hours. Total observation period was not given. The
mortality results were:—
8—16 per group
100 ppm 0/16
265 ppm 0/8
575 ppm 5/8
1160 ppm 8/8

Guinea pigs responded somewhat differently to other

species examined by these workers. The toxic
effects observed were concentration—dependent
irritation of the mucous membranes, and deaths due
to pulmonary oedema, occurring at 3—6 days
post—exposure.

6
TABLE 2 SIIIGLE EXPOSURE INHALATION STUDIES IN ANIMALS

Species Exposure Observations

characteristics conditions

Guinea pig6 4 hours exposure to each A very briefly reported study with no raw data
of six unspecified given. LC50 450 ppm
2 per group concentrations.
Necropsy of the decedents revealed oedema and focal
haemorrhage of the lung, brain and CNS, and
congestion of several other organs. In the
survivors examined at 7—14 days post—exposure the
principal findings were respiratory tract
inflammation, fatty degeneration in -the liver, and
some kidney tubule epithelium damage.

Rabbit3 100—580 ppm for 4 hours. Observation period not given. The mortality
results were:—
2—3 per group
100 ppm 0/3
135 ppm 0/2
260 ppm 2/2
580 ppm 2/2

Signs of toxicity ranged from irritation of the

mucous membranes at lower concentrations to
flushing or reddening of the skin, rapid, shallow
breathing, dyspnoea, convulsions and coma at higher
concentrations. All decedents died within 5 hours
post—exposure.

Rabbit'4 5 rabbits exposed All rabbits died between 1 and 3 hours after
Chinchilla individually, head—only, to commencement of exposure.
3 kg 264—500 ppm until death.

11 animals 3 rabbits exposed All rabbits survived, showing no signs of

in total individually via depilated toxicity.
skin only, to 454—1909 ppm
for 2—4 hours.

3 rabbits exposed All rabbits died between 2 and 4 hours after

individually, via depilated commencement of exposure.
skin only, to 20,000—30,000
ppm until death.

Cat3 100—600 ppm for 4 hours. Observation period not given. The mortality
results were:—
2—4 per group
100 ppm 0/4
275 ppm 0/2
600 ppm 2/2

7
TABLE 2 SINGLE EXPOSURE INHALATION STUDIES IN ANIMALS

Species Exposure Observations

characteristics conditions

Mucous membrane Irritation seen at 100 ppm. At the

higher concentrations vomiting, howling and
convulsions were observed. The two deaths at 600
ppm occurred within 1
hours post—exposure.

Dog3 30—165 ppm for 4 hours. Observation period was not given. The mortality
males and females results were:—
5—12 kg
30 ppm 0/3
2—3 per group 65 ppm 1/2
100 ppm 0/3
110 ppm 2/3
165 ppm 2/2

Salivation was the only effect seen at 30 ppm. At

65 ppm and above, severe effects were produced:
rapid, shallow breathing, dyspnoea, convulsions,
coma and hind leg paralysis. Deaths occurred In
3—72 hours. Survivors showed signs of toxicity for
several days post—exposure.

Dog4 Three groups of 4—5 dogs Dogs were observed for 7—10 days post—exposure.
were exposed to 50—100 ppm For the 7—hour exposures, the mortality results
14 animals for 7 hours. One dog was were:—
in total exposed to 100 ppm for 1
hour. 50 ppm 0/4
75 ppm 3/4
100 ppm 5/5

The one dog exposed to 100 ppm for 1 hour also

died.

Dogs exposed to 75 or 100 ppm showed vomiting,

incoordination, respiratory distress and
convulsions. Cyanide and cyanmethaemoglobln were
detected in the blood of dogs at all three exposure
levels.

-
Monkey3 65 or 90 ppm for LI Observation period not given. No deaths. Only
Rhesus hours. slight signs of toxicity were observed: mucous
males and females membrane irritation, increased respiratory rate.
4.2—4.8 kg -

2-4 per group

8
TABLE 2 SINGLE EXPOSUREINHALATION STUDIES IN ANIMALS

Species Exposure Observations

characteristics conditions

Monkey4 75 ppm for 7 hours. Monkeys were observed for 7—10 days post—exposure.
Rhesus One died. All 3 animals had appreciable levels of
cyanide and cyanmethaemoglobin in the blood.
3 animals

9
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1 TurnerR M and Fairhurst S. Assessment of the American-made rubber md Med 194817 199-207.
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Inspector ReportNo 211989. 10 Appel K E, PeterH and Bolt H M. Effect of
potential antidotes on the acutetoxicity of acrylonitrile
2 WHO International Programme on Chemical mtArch Occup EnvironHealth1981 49 157-163.
Safety Environmental Health Criteria 28: Acrylonitrile
World Health Organisation, Geneva, 1983. 11 Carpenter C P, Smyth H F and Pozzani U C. The
assayof acutevapourtoxicity, and the grading and
3 Dudley H C and Neal P A. Toxicology of interpretation of results on 96 chemIcal compounds
acrylonitrile (vinylcyanide). I. A studyof the acute JIndHyg Toxicol 194931 343-346.
toxicityJ md Hyg Toxicol 194224 27-36.
12 Smyth H F and CarpenterC P. Furtherexperience
4 BriegerH, Rieders F and Hoders W A. withthe range finding test in the Industrial toxicology
Acrylonitrile: spectrophotometric determination, acut& laboratory J md Hyg Toxicol 1949 30 63-68.
toxicity, and mechanism of action md HygOccup Med
19526 128-140. 13 McOmieW A. Comparative toxicityof
methacrylonitrile and acrylonitrile J mdHyg Toxlcol 1949
5 Wilson R H. Health hazards encountered in the 31113-116.
manufacture of synthetic rubber JA MA 1944 124 701-
703. 14 Rogaczewska 1, Absorption of acrylonitrile
vapours throughthe skin in animals Med Prac 197526
6 Knobloch K, Szendzikowski S, Czajkowska T and 459-465 HSE translation no. 12869.
Krysiak B, Experimental studies of the acute and
subacute toxicityof acrylonitrile Med Prac 1971 22 257- 15 Finney D J. ProbitanalysisCambridge University
269. Press, London, 1977.

7 IARC Monographs on the Evaluation of the 16 Ten Berge W F, ZwartA and Appelman L M.
Carcinogenic Risk of Chemicals to Humans. Volume 1: Concentration-time mortalityresponse relationship of
Some Monomers, Plastics and Elastomers, and irritant and systemically acting vapoursand gases
Acrolein. International Agencyfor Research on Cancer, JHazMaterl98613301-309,
Lyon, 1979, 73-113.

8 EPA. Health HazardAssessment Documentfor

Acrylonitrile EPA 600/8-82-007F. NTIS PB84-l49152,
Springfield, VA, USA, 1983.

Printed in the UKfor HMSO M3 12/89

10
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