Arlasolve DMI
File No: STD/1052
12 May 2004
NATIONAL INDUSTRIAL CHEMICALS NOTIFICATION AND ASSESSMENT SCHEME
(NICNAS)
FULL PUBLIC REPORT
Arlasolve DMI
This Assessment has been compiled in accordance with the provisions of the Industrial Chemicals (Notification and
Assessment) Act 1989 (Cwlth) (the Act) and Regulations. This legislation is an Act of the Commonwealth of Australia.
The National Industrial Chemicals Notification and Assessment Scheme (NICNAS) is administered by the Department
of Health and Ageing, and conducts the risk assessment for public health and occupational health and safety. The
assessment of environmental risk is conducted by the Department of the Environment and Heritage.
For the purposes of subsection 78(1) of the Act, this Full Public Report may be inspected at:
Library
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CANBERRA ACT 2600
AUSTRALIA
To arrange an appointment contact the Librarian on TEL + 61 2 6279 1161 or + 61 2 6279 1163.
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free of charge, by contacting NICNAS. For requests and enquiries please contact the NICNAS Administration
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Director
Chemicals Notification and Assessment
TABLE OF CONTENTS
FULL PUBLIC REPORT....................................................................................................................................... 4
1. APPLICANT AND NOTIFICATION DETAILS ................................................................................... 4
2. IDENTITY OF CHEMICAL ................................................................................................................... 4
3. COMPOSITION ...................................................................................................................................... 5
4. INTRODUCTION AND USE INFORMATION..................................................................................... 5
5. PROCESS AND RELEASE INFORMATION ....................................................................................... 5
5.1. Distribution, Transport and Storage ............................................................................................... 5
5.2. Operation Description..................................................................................................................... 5
5.3. Occupational exposure.................................................................................................................... 6
5.4. Release............................................................................................................................................ 6
5.5. Disposal .......................................................................................................................................... 7
5.6. Public exposure............................................................................................................................... 7
6. PHYSICAL AND CHEMICAL PROPERTIES ...................................................................................... 7
7. TOXICOLOGICAL INVESTIGATIONS ............................................................................................. 10
7.1. Acute toxicity ?oral ..................................................................................................................... 10
7.2. Acute toxicity - intravenous.......................................................................................................... 11
7.3.1 Irritation ?skin ............................................................................................................................. 12
7.3.2 Irritation ?skin ............................................................................................................................. 13
7.4. Irritation ?External auditory canal............................................................................................... 13
7.5.1 Irritation - eye ............................................................................................................................... 14
7.5.2 Irritation - eye ............................................................................................................................... 14
7.5.3 Irritation - eye ............................................................................................................................... 15
7.6.1 13-Week repeat dose oral toxicity ................................................................................................ 15
7.6.2. 13-Week repeat dose oral toxicity ................................................................................................ 17
7.7. 8-day repeat dose oral toxicity...................................................................................................... 19
7.8.1 Genotoxicity - bacteria ................................................................................................................. 20
7.8.2 Genotoxicity - bacteria ................................................................................................................. 20
7.9. Genotoxicity ?in vitro cytogenics assay ...................................................................................... 21
7.10T. 14-day Ocular toxicity - intravenous ....................................................................................... 23
7.11T. Skin sensitisation ?human volunteers .................................................................................... 23
7.12T. 1 Developmental toxicity ......................................................................................................... 24
7.12T. 2 Developmental toxicity ......................................................................................................... 25
7.13T. Oral tolerance of teeth cleaning gels containing Notified Chemical ?Human....................... 26
7.14T. Absorption after percutaneous admninistration. ..................................................................... 27
7.15T. Skin penetration enhancement. ............................................................................................... 27
7.16T. In Vitro Blood Compatability ................................................................................................. 28
8. ENVIRONMENT .................................................................................................................................. 30
8.1. Environmental fate........................................................................................................................ 30
8.1.1. Ready biodegradability ............................................................................................................ 30
8.1.2. Bioaccumulation ...................................................................................................................... 30
8.1.3 Fugacity model......................................................................................................................... 30
8.2. Ecotoxicological investigations .................................................................................................... 31
8.2.1. Acute toxicity to fish................................................................................................................ 31
8.2.3. Algal growth inhibition test ..................................................................................................... 32
8.2.4. Inhibition of microbial activity ................................................................................................ 32
9. RISK ASSESSMENT ............................................................................................................................ 33
9.1. Environment ................................................................................................................................. 33
9.1.1. Environment ?exposure assessment........................................................................................ 33
9.1.2. Environment ?effects assessment ........................................................................................... 33
9.1.3. Environment ?risk characterisation ........................................................................................ 33
9.2. Human health................................................................................................................................ 33
9.2.1. Occupational health and safety ?exposure assessment ........................................................... 33
9.2.2. Public health ?exposure assessment ....................................................................................... 35
9.2.3. Human health - effects assessment .......................................................................................... 35
9.2.4. Occupational health and safety ?risk characterisation ............................................................ 36
9.2.5. Public health ?risk characterisation ........................................................................................ 37
10. CONCLUSIONS ?ASSESSMENT LEVEL OF CONCERN FOR THE ENVIRONMENT AND
HUMANS ........................................................................................................................................................ 37
10.1. Hazard classification..................................................................................................................... 37
10.2. Environmental risk assessment..................................................................................................... 37
10.3. Human health risk assessment ...................................................................................................... 37
10.3.1. Occupational health and safety ........................................................................................... 37
10.3.2. Public health........................................................................................................................ 37
11. MATERIAL SAFETY DATA SHEET............................................................................................. 37
11.1. Material Safety Data Sheet ........................................................................................................... 37
11.2. Label ............................................................................................................................................. 37
12. RECOMMENDATIONS .................................................................................................................. 37
12.1. Secondary notification .................................................................................................................. 37
13. BIBLIOGRAPHY ............................................................................................................................. 37
FULL PUBLIC REPORT
Arlasolve DMI
1. APPLICANT AND NOTIFICATION DETAILS
APPLICANT(S)
Symex Holdings Limited
14 Woodruff Street
PORT MELBOURNE VIC 3207
and
Uniqema Australia Pty Ltd
c/o Blake Dawson Waldron
Level 39, 101 Collins Street
Melbourne VIC 3000
NOTIFICATION CATEGORY
Standard: Chemical other than polymer (more than 1 tonne per year).
EXEMPT INFORMATION (SECTION 75 OF THE ACT)
Data items and details claimed exempt from publication:
Spectral data
?br>
Import volume
?br>
Client details
?br>
VARIATION OF DATA REQUIREMENTS (SECTION 24 OF THE ACT)
No variation to the schedule of data requirements is claimed.
PREVIOUS NOTIFICATION IN AUSTRALIA BY APPLICANT(S)
Johnson & Johnson Pacific Pty Ltd hold a Commercial Evaluation Chemical permit for this chemical
at the time of this assessment.
NOTIFICATION IN OTHER COUNTRIES
2. IDENTITY OF CHEMICAL
CHEMICAL NAME
1,4:3,6-dianhydro-2,5-di-O-methyl-D-glucitol
OTHER NAME(S)
Dimethyl isosorbide
Arlasolve DMI
CAS NUMBER
5306-85-4
MOLECULAR FORMULA
C8H14O4
STRUCTURAL FORMULA
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H3CO O
O OCH3
MOLECULAR WEIGHT
174.2
METHODS OF DETECTION AND DETERMINATION
The notified chemicals has been characterised using NMR, IR, and MS. Analytical techniques such
as gas chromatography could be used for its detection and determination.
3. COMPOSITION
DEGREE OF PURITY
96%
4. INTRODUCTION AND USE INFORMATION
MODE OF INTRODUCTION OF NOTIFIED CHEMICAL (100%) OVER NEXT 5 YEARS
The notified chemical will be introduced as a component of finished personal care product, and in the
future, as a raw ingredient for reformulation by local manufacturers.
MAXIMUM INTRODUCTION VOLUME OF NOTIFIED CHEMICAL (100%) OVER NEXT 5 YEARS
Year 1 2 3 4 5
Tonnes 1-10 1-10 1-10 1-10 1-10
USE
The notified chemical is used as a skin emollient in personal care products at concentrations up to
25%.
5. PROCESS AND RELEASE INFORMATION
5.1. Distribution, Transport and Storage
PORT OF ENTRY
Not known
IDENTITY OF MANUFACTURER/RECIPIENTS
TRANSPORTATION AND PACKAGING
The notified chemical will imported in 200L drums and/or 20L pails. It will also be imported as a
component of packaged personal care products.
5.2. Operation Description
Importation
The notified chemical will be imported neat in 200 L drums or 20 L pails. It will also be imported as a
component of packaged personal care products. Following importation, the notified chemical or
product containing it will be delivered to the notifiers' sites for reformulation or distribution to
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customers.
Reformulation
The drums/pails containing the notified chemical will be transferred from storage to the manufacturing
area. The notified chemical is then either decanted or pumped into the mixer where it is combined
with other ingredients of the cosmetic product. The mixing vessels used in this process may by open
or closed depending on the formulation being prepared.
The final product containing the notified chemical at concentrations up to 25% is then transferred to
the packaging line where it is packaged in plastic and glass containers and distributed for sale.
End-use
The products containing the notified chemical will be sold through retails outlets to consumers or
distributed to personal care salons such as hairdressers, cosmetologists or sunless tanning studios. In
some cases retail workers may demonstrate the products at the point-of-sale.
5.3. Occupational exposure
Number and Category of Workers
Category of Worker Number Exposure Duration Exposure Frequency
Importation 10 4 hours/day 40 days/year
Storage & Transport 100 6 hours/day 240 days/year
Formulation Preparation 200 6 hours/day 240 days/year
Point of Sale 1000 6 hours/day 240 days/year
Exposure Details
Importation, Transport and Storage
Workers involved in the importation, storage, and transport of the notified chemical or products
containing it are not expected to be exposed to the notified chemical except in the event of an accident
where the packaging may be breached.
Formulation
Dermal exposure to the notified chemical (96%) may occur during reformulation during transfer of the
notified chemical from drums and pails to the mixing vessel. Following reformulation any exposure
will be to products containing up to 25% notified chemical and may occur during packaging and
unitising of finished consumer products.
Retail
Retail workers involved in the shelf filling and sale of the final consumer product are not expected to
be exposed to the notified polymer except in cases of an accident where the packaging may be
breached. Sales representatives demonstrating the products will be dermally exposed to the products
containing 0.1 ?25% through application of the products to potential consumers or themselves.
End-Use
Dermal, and inadvertent ocular exposure may occur in those professions where the services provided
involve the application of personal care products. Examples include hairdressers, cosmeticians, and
beauticians. Inhalation exposure may also occur during the use of products which are applied as a
spray.
5.4. Release
RELEASE OF CHEMICAL AT SITE
The notified chemical will not be manufactured in Australia but will be reformulated into personal
skin care products. Waste notified chemical will be generated during reformulation via:
- Spills up to 1% maximum 100 kg,
- Import container residues up to 1% maximum 100 kg,
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- Process Equipment cleaning up to 1.5% maximum 150 kg.
RELEASE OF CHEMICAL FROM USE
Approximately 1% of the contents of the end-product container will remain in it when it is disposed
of to landfill, generally in domestic rubbish. This equates to approximately 100 kg of notified
chemical annually. Since the notified chemical is a component in skin care products ultimately the
majority of the notified chemical will be washed into the sewer.
5.5. Disposal
Reformulation solid wastes, including spills and import containers and any residues present, will be
disposed of to landfill. This represents up to 200 kg per year of the notified chemical. A further 100
kg will be disposed of to landfill in end-user containers.
The process equipment cleaning effluent containing 1.5% (150 kg) of notified chemical will be
disposed of to sewer. Approximately 95.5% of the notified chemical will end up in the sewer due to
use of the end-product. A total of 97% of the imported volume of notified chemical will go to sewer, ie
up to 9700 kg per annum.
5.6. Public exposure
Personal care products containing the notified polymer at concentrations of up to 25% are for sale to
the general public. Members of the public will make dermal contact and possibly accidental ocular
contact with products containing the notified polymer. In most cases exposure is expected to be
limited to 1-10 grams of product, 1-2 times per day. Inhalation exposure may occur during use of
spray products.
6. PHYSICAL AND CHEMICAL PROPERTIES
Appearance at 20oC and 101.3 kPa Colourless liquid with a mild odour
234-242 oC
Boiling Point
Not stated
METHOD
Remarks From MSDS
TEST FACILITY Not stated
1160 kg/m3 at 25oC
Density
METHOD Not stated
Remarks From MSDS
TEST FACILITY Not stated
0.013 kPa at 25oC
Vapour Pressure
The estimation method, MPBPWIN in the EPIWIN package, uses the composition
METHOD
and structure of the chemical to estimate its melting point, boiling point and vapour
pressure.
Remarks Antoine method ?VP= 0.104 mm Hg
Modified Grain method ?VP= 0.094 mm Hg
Mackay method ?VP= 0.104 mm Hg
Mean of results ?VP = 0.1 mm Hg
These results indicate that the notified chemical is volatile (Mensink, 1995).
TEST FACILITY Not stated
1?03 g/L at 25oC
Water Solubility
Estimation method
METHOD
Remarks The estimation method, WSWIN in the EPIWIN package, uses the composition
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and structure of the chemical to estimate its water solubility. As this value is
derived from the log Pow of ?.6, which was estimated by the fragment method,
the result is relatively reliable.
This estimation indicates that the notified chemical is readily soluble (Mensink,
1995).
TEST FACILITY Not stated.
Not attempted.
Hydrolysis as a Function of pH
The notified chemical is not expected to hydrolyse in the
environmental pH range 4-9.
Log Pow = -2.1 at 20oC
Partition Coefficient (n-octanol/water)
Fragmentation technique (part of OECD TG 117)
METHOD
Remarks This method entails the addition or subtraction of known structures and their
fragmental constants to produce the structure of the test chemical, and
consequently its partition coefficient.
This result indicates that the notified chemical will partition into water.
TEST FACILITY Brixham Environmental Laboratory, 1993a.
log Pow = -1.6 at 20oC
Partition Coefficient (n-octanol/water)
Estimation method.
METHOD
Remarks The estimation method, KOWWIN in the EPIWIN package, uses the composition
and structure of the chemical to estimate its partition coefficient by the fragment
method.
TEST FACILITY Not stated.
log Koc = 1 (temperature not specified)
Adsorption/Desorption
Estimation method.
METHOD
Remarks The estimation method, KOCWIN in the EPIWIN package, uses the composition
and structure of the chemical to estimate its adsorption/desorption coefficient.
A Koc of 10 indicates that the notified chemical is very highly mobile. (McCall et
al, 1981).
TEST FACILITY Not stated.
Not attempted.
Dissociation Constant
The notified chemical does not contain any groups that
would dissociate.
Not applicable as chemical is liquid.
Particle Size
>110oC
Flash Point
ASTM D3278-73
METHOD
Remarks From MSDS
TEST FACILITY Not stated
Not flammable. Combustible.
Flammability Limits
No data available
Autoignition Temperature
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None known
Explosive Properties
None
METHOD
Remarks
TEST FACILITY None
Reactivity
Remarks Can react with oxidising agents
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7. TOXICOLOGICAL INVESTIGATIONS
Endpoint and Result Assessment Conclusion
Rat, acute oral LD50 6530.8 mg/kg bw - low toxicity
Rat, acute intravenous (1) LD50 5836 mg/kg bw (both sexes)
Rat, acute intravenous (2) LD50 5369 mg/kg bw (both sexes)
Mouse, acute intravenous (1) LD50 6895 mg/kg bw (both sexes)
Mouse, acute intravenous (2) LD50 5416 mg/kg bw (both sexes)
Rat, 14-day ocular toxicity Low acute ocular toxicity
NOAEL (systemic toxicity) 630 mg/kg/day
Rabbit, skin irritation (1) very slightly irritating
Rabbit, skin irritation (2) non-irritating
Rabbit, ear irritation non-irritating
Rabbit, eye irritation - 40%, 100% inconclusive
Rabbit, eye irritation ?60%, 80% slightly-irritating
Rabbit, eye irritation ?100% slightly-irritating
Rat, repeat dose oral toxicity - 90 days. NOAEL 375 mg/kg/bw day
Beagle, repeat dose oral toxicity - 90 days NOAEL 100 mg/kg/bw day
Rabbit, repeat dose oral toxicity - 8 days NOAEL 300 mg/kg/bw day
Genotoxicity - bacterial reverse mutation (1) non mutagenic
Genotoxicity - bacterial reverse mutation (2) non mutagenic
Genotoxicity ?in vitro human lymphocyte non genotoxic
chromosome aberration
Skin sensitisation ?human volunteers No evidence of sensitisation
Developmental toxicity - rabbit NO(A)EL 300 mg/kg/bw/day
No evidence of maternal or foetal toxicity
Developmental toxicity - rat NO(A)EL 300 mg/kg/bw/day
No evidence of maternal or foetal toxicity
Oral tolerance, human No treatment related effects up to 25%
Rat, percutaneous absorption 32% absorbed in 12 hours
Mouse, skin penetration enhancement Enhanced absorption of glycerol
7.1. Acute toxicity ?oral
TEST SUBSTANCE Notified chemical
OECD TG 401 Acute Oral Toxicity.
METHOD
Species/Strain Rat/Holtsman
Vehicle Distilled water
Remarks - Method
RESULTS
Group Number and Sex Dose Mortality
of Animals mL/kg bw
I 5M 10.0 (11600 mg/kg) 5
II 5M 6.81 (7899.6 mg/kg) 5
III 5M 4.64 (5382.4 mg/kg) 0
IV 5M 3.16 (3665.6 mg/kg) 0
V 5M 2.15 (2494 mg/kg) 0
VI 5M 1.47 (1705.2 mg/kg) 0
LD50 5.63 mL/kg bw (6530.8 mg/kg bw)
Signs of Toxicity Within five to 10 minutes following oral administration of the test
substance, the animals at each dosage level appeared depressed and
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showed lacrimation, laboured respiration, tachycardia, and ataxia. The
above listed gross signs of systemic toxicity continued throughout the
remainder of the day in animals dosed with the lowest dosage level (1.47
mL/kg bw). Within one hour or less following dosage and generally
throughout the remainder of the day, remaining animals showed the
following additional signs: chromodacryorrhoea, slow and laboured
respiration, and depressed or placement, righting, and pain reflexes.
Animals at the three higher dosage levels also showed bloated abdomens.
Death was immediately preceded by coma and a profuse bloody
discharge from the eyes. Animals at the lower two dosage levels
exhibited normal appearance and behaviour at 24 hours after dosage and
thereafter. At 24 hours the remaining survivors appeared depressed and
showed a bloody discharge around the eyes and laboured respiration,
while those at 4.64 and 6.81 mL/kg levels also showed bloated
abdomens, tachycardia, and depressed or absent placement and righting
reflexes. These animals gradually recovered within an additional one to
three days after which they appeared normal.
Effects in Organs Gross autopsies performed upon the animals that died showed
hyperaemic and inflated lungs, slight irritation of the small intestine and
congested kidneys and adrenals. In addition the blood appeared to have a
thin consistency and did not clot readily. No gross pathological findings
were observed at autopsy of the surviving animals.
Remarks - Results
The notified chemical is of low toxicity via the oral route.
CONCLUSION
TEST FACILITY Hazleton Laboratories (1957)
7.2. Acute toxicity - intravenous
TEST SUBSTANCE Notified chemical.
METHOD
Species/Strain Rat-Sprague Dawley
Mouse- Swiss Webster
Vehicle 0.9% sodium chloride solution
Remarks - Method 14 day study period
RESULTS
Group Conc. Dose Number and Sex LD50
(% v/v) (mg/kg) of Animals (both sexes)
Rat I 20 3160 10M/10F 5836
3980 10M/10F
5010 10M/10F
6310 10M/10F
7940 10M/10F
Rat II 40 3160 10M/10F 5369
3980 10M/10F
5010 10M/10F
6310 10M/10F
7940 10M/10F
Mouse I 20 4470 10M/10F 6895
5620 10M/10F
7080 10M/10F
8910 10M/10F
11200 10M/10F
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Mouse II 40 2820 10M/10F 5416
3550 10M/10F
4470 10M/10F
5620 10M/10F
7080 10M/10F
LD50 All of the 14-day LD50 values in both sexes of mice and rats for 20%
and 40% notified chemical indicate a low order of intravenous toxicity in
both rats and mice.
Signs of Toxicity - Local Following a single toxic intravenous dose of the notified chemical, both
sexes of rats and mice displayed initial stimulation, demonstrated by
rapid shallow breathing and rapid heartbeat. This was followed by a
prolonged depression phase characterised by loss of righting reflex,
laboured respiration, narcosis and death. Death was attributed to
respiratory depression. A few rats and mice chewed the tips of their tails
off, which was probably a response to irritation induced by notified
chemical that had leaked from the vein into the tissues of the tail.
Other signs of toxicity seen only in rats were lacrimation, coolness to the
touch, and white froth around the mouth and nose. Several rats had
bloody urine, and small dull spots on the eyeball surface were seen in
about 14 of 119 survivors. A dose related decrease in bodyweight gain
was noted in rats which was probably related to the lack of feeding
during long period of narcosis or decreased motor activity. Several mice
had urine stained abdomens and a few had small patches of fur missing
from the top of their heads.
Remarks - Results No marked difference in toxicity between 20% and 40% solutions.
The notified chemical is of low toxicity via the intravenous route.
CONCLUSION
TEST FACILITY ICI Americas Inc (1981a)
7.3.1 Irritation ?skin
TEST SUBSTANCE Notified chemical
Primary irritation to the rabbit skin was tested and scored in accordance
METHOD
with the procedure outlined in Association of Food and Drug Officials,
US (1959)
Species/Strain Rabbit/New Zealand White
Number of Animals 30
Vehicle Water
Observation Period 72 hours
Type of Dressing Occlusive
Remarks - Method 6 rabbits were used, three with skin intact and three with the skin
abraded. Dermal scores were at 24h and 72h only.
RESULTS
Lesion Mean Score* Maximum Value Maximum Maximum Value at
Duration of Any End of
Effect Observation
Period
Erythema/Eschar 0.083 1 <72 0
Oedema 0 0 - 0
*Calculated on the basis of the scores at 24and 72 hours for ALL animals.
Remarks - Results At 24 hours none of the three intact skin areas showed any irritation
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while one of the three abraded skin areas showed slight erythema. At 72
hours no irritation at all was observed on any of the skin tested.
The notified chemical is mildly irritating to skin.
CONCLUSION
TEST FACILITY Atlas Chemical Industries (1968a)
7.3.2 Irritation ?skin
TEST SUBSTANCE Notified Chemical
Primary irritation to the rabbit skin was tested and scored in accordance
METHOD
with the procedure outlined in Association of Food and Drug Officials,
US (1959)
Species/Strain Rabbit/New Zealand White
Number of Animals 30
Vehicle Water
Observation Period 72 hours
Type of Dressing Occlusive
Remarks - Method 6 rabbits were used for each material or preparation that was tested, three
with skin intact and three with the skin abraded.
RESULTS
Lesion Mean Score*. Maximum Maximum Maximum
Conc % Value Duration of Value at End
Any Effect of
Observation
Period
100 80 60 40 20
Erythema/Eschar 0 0 0 0 0 0 - 0
Oedema 0 0 0 0 0 0 - 0
*Calculated on the basis of the scores at 24 and 72 hours for EACH animal.
Remarks - Results All individual dermal irritation scores observed on each rabbit, with
intact or abraded skin, at 24 hours and 72 hours were zero.
The notified chemical is non-irritating to skin.
CONCLUSION
TEST FACILITY Atlas Chemical Industries (1963)
7.4. Irritation ?External auditory canal
TEST SUBSTANCE Notified chemical
The test substance (0.25 mL) was introduced into the external auditory
METHOD
canal so that it wet the integument from the external orifice to the
tympanaum. The two ears, after installation of the test material, were
taped together to in an upright position with masking tape to prevent the
ears from "flopping" independently when the rabbit shook its head. Tape
was removed at two hours and the canal observed for signs of irritation.
The canal was observed again at 24 and 72 hours. After five days each
rabbit was sacrificed and the auditory canal dissected from the external
orifice to the tympanum. The tissue was observed, grossly, for signs of
irritation.
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Species/Strain Rabbit/New Zealand White
Number of Animals 16
Vehicle Water
Observation Period 72 hours
Type of Dressing None
Remarks - Method 4 rabbits were used for each material or preparation that was tested. The
notified chemical was instilled into the right ear of each of the four
rabbits; Tween 80, in comparable concentration, was instilled into the left
ear of each of the same four rabbits and served as a control.
RESULTS
Remarks - Results No signs of irritation to the integument of the external auditory canal of
the was observed in any of the rabbits treated with the notified chemical
either undiluted or as a 40% w/v aqueous solution, or with Tween 80,
undiluted or as a 40% w/v aqueous solution. The dissection of the canal
revealed no visible signs of irritation to either the tympanum or the
integument of the canal.
The notified chemical is not irritating to the ear of rabbits.
CONCLUSION
TEST FACILITY Atlas Chemical Industries (1963)
7.5.1 Irritation - eye
TEST SUBSTANCE Notified chemical
Primary irritation to the rabbit eye was tested and scored in accordance
METHOD
with the procedure outlined in Association of Food and Drug Officials,
US (1959)
Species/Strain Rabbit/New Zealand White
Number of Animals 4F/7M, 5F4M
Observation Period 7 days
Remarks - Method Results were interpreted using the methods of Kay and Calandra (1962)
and Larrick (1963).
RESULTS
Concentration % Methods of interpretation
Kay and Calandra Conclusion Larrick Conclusion
100 Cannot be classified None 4/6 positive Positive test
100 Non-irritating Non-irritating 0/6 positive Negative test
40 Non-irritating Non-irritating 0/6 positive Negative test
Remarks - Results Testing of undiluted test substance on the cornea and mucosa of the
rabbit eye produced a range of irritation so varied (scores ranging from 0
to 64 at 24 hours) that a retest was indicated. The notified chemical was
retested undiluted and as a 40% w/v aqueous solution, each on 6
unwashed eyes and 3 receiving a wash 2 seconds after instillation. In all
tests whether made with undiluted or the 40% w/v aqueous solution, no
irritation was observed.
Overall the study was inconclusive. However, based on the results of the
CONCLUSION
retests, the notified chemical is non-irritating to the eye
TEST FACILITY Atlas Chemical industries Inc. (1964a)
7.5.2 Irritation - eye
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TEST SUBSTANCE Notified chemical
Primary irritation to the eye mucosa of the rabbit was tested and scored in
METHOD
accordance with the procedure outlined in AFDO, US (1959)
Species/Strain Rabbit/New Zealand White
Number of Animals 9 (male and female ?relative numbers not clear)
Observation Period 7 days
Remarks - Method
RESULTS
Remarks - Results Tested on the eye mucosa of albino rabbits as an 80% and 60% w/v
aqueous solution, the notified chemical did not cause irritation to the
washed or unwashed eyes. All scores were zero.
The notified chemical is non-irritating to the eye.
CONCLUSION
TEST FACILITY Atlas Chemical industries Inc. (1964b)
7.5.3 Irritation - eye
TEST SUBSTANCE Notified chemical
Primary irritation to the eye mucosa of the rabbit was tested and scored in
METHOD
accordance with the procedure outlined in AFDO, US (1959)
Species/Strain Rabbit/New Zealand White
Number of Animals 4F/5M
Observation Period 7 days
Remarks - Method 0.1 mL instilled into eye- 6 unwashed, 3 washed for 2 seconds with 20
mL water.
RESULTS
Concentration (%) Condition of eye in Classification
regard to wash after Kay and Calandra Code of Federal No of eyes
instillation regulations Positive/No.
Tested
100 Unwashed Mildly irritating Negative 0/6
2 second wash Mildly irritating Negative 0/3
Remarks - Results The notified chemical, tested on the eye mucosa of albino rabbits as a
100% w/v aqueous solution, was classified as mildly irritating according
to the interpretation of Kay and Calandra.
The notified chemical is slightly irritating to the eye.
CONCLUSION
TEST FACILITY Atlas Chemical industries Inc. (1968)
7.6.1 13-Week repeat dose oral toxicity
TEST SUBSTANCE Notified chemical
OECD TG 408 Repeated Dose 90-Day Oral Toxicity Study in Rodents.
METHOD
Species/Strain Rat ?Sprague Dawley.
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Route of Administration Oral ?gavage/diet/drinking water.
Exposure Information Total exposure days: 13 weeks
Dose regimen: 7 days per week
Post-exposure observation period: None
Vehicle Water
Remarks - Method
RESULTS
Group Number and Sex Dose Mortality
of Animals mg/kg bw/day
I (control) 20M/20F 0 1M
II 20M/20F 30 0
III 20M/20F 100 0
IV 20M/20F 375 1M
Mortality and Time to Death
Two males died during the 13 week treatment period. One control male dies shortly after withdrawal of a
blood sample during week 12. A high dose male was found dead during week 13 of treatment with no
significant prior clinical history.
Clinical Observations
No clinical signs considered to be treatment related were noted during the 13 week treatment period.
Body Weights
There was no indication of a treatment related effect on body weights.
Laboratory Findings ?Clinical Chemistry, Haematology, Urinalysis
Clinical biochemistry
Isolated increases in serum glutamic pyruvic transaminase (SGPT) and serum glutamic oxaloacetic
transaminase (SGOT) levels were obtained at week 6 from 1 high-dose and 1 mid-dose female, and at week
12 from 1 high-dose male and SGPT levels for 2 mid-dose females when compared with controls. These
differences were however considered of doubtful toxicological significance given their small magnitude and
the inherent variability of these parameters.
Marginally increased levels of chloride were recorded for all females receiving 375 mg/kg/day, a large
proportion of females and 1 male receiving 100 mg/kg/day, and occasional males and females receiving 30
mg/kg/day. In light of the lack of disturbance in other electrolyte levels, the small magnitude of differences in
chloride levels, and the individual variability between sampling occasions, the toxicological significance of
these marginally higher chloride levels is uncertain.
Urinalysis
No changes in quantity and quality of urine voided by treated rats when compared with controls which could
be attributed to treatment with the test substance.
Haematology
There was no indication of any adverse treatment related changes in haematological results obtained from
control and DMI treated rats receiving the test substance at a level of 375 mg/kg/day.
Pathology ?Organ weights, Macroscopic changes, Histopathology
Organ weights
A small but statistically significant increase in absolute and relative liver weights among males and females
receiving 375 mg/kg/day compared to controls was recorded. Absolute and relative liver weights for other
treated rats were comparable with controls.
A small but statistically significant increase in absolute kidney weights is was also noted for males receiving
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375 mg/kg/day, with an associated increase in relative liver weights when compared with controls. Females
receiving 375 mg/kg/day and all other rats treated with lower doses showed no significant change in kidney
weights.
Macroscopic changes
Gross pathology examination of rats found dead during the course of the study revealed no consistent changes
that could be associated with treatment. Additionally, examination of those rats surviving to termination
revealed a low incidence of commonly occurring pathology changes with no indication of any disturbance
attributable to treatment.
Histopathology
Histopathological examination of controls and rats at 375 mg/kg/day revealed a low incidence of commonly
occurring changes which showed no evidence of any treatment related disturbance.
Remarks ?Results
The small increases in absolute and relative liver and kidney weights for males and females receiving 375
mg/kg/day were not associated with any morphological changes and therefore believed to be adaptive in
nature.
CONCLUSION
The No Observed (Adverse) Effect Level (NO(A)EL) was established as 375 mg/kg bw/day in this study,
based on the absence of any consistent effect on survival, clinical signs, growth rate, food intake, haematology,
clinical chemistry, urinalysis, gross pathology or histopathological findings. Small increase in liver and kidney
weights at the 375 mg/kg/day level is considered to be adaptive in nature. The NOEL was established as 100
mg/kg/day.
TEST FACILITY Bio-Research Laboratories Ltd. (1987a).
7.6.2. 13-Week repeat dose oral toxicity
TEST SUBSTANCE Notified chemical
OECD TG 409 Repeated Dose 90-Day Oral Toxicity Study in Non-
METHOD
Rodents.
Species/Strain Dog ?Canis familiaris (Beagle)
Route of Administration Oral ?gelatin capsule
Exposure Information Total exposure days: 13 weeks
Dose regimen: 7 days per week
Post-exposure observation period: None
Vehicle Water
Remarks - Method
RESULTS
Group Number and Sex Dose Mortality
of Animals mg/kg bw/day
I (control) 3M/3F 0 0
II 3M/3F 30 0
III 3M/3F 100 0
IV 3M/3F 700 0
Mortality and Time to Death
No deaths occurred during the course of the study.
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Clinical Observations
Brown or yellow and or white mucoid material in cage trays was noted on one or two occasions among 1
control female, 2 females receiving 30 mg/kg/day, 1 male and 1 female receiving 100 mg/kg/day, and 1 male
and 1 female receiving 700 mg/kg/day. This finding was also observed on three occasions in 1 female
receiving 100 mg/kg/day, four occasions in one female receiving 700 mg/kg/day, and on six occasions in one
male receiving 700 mg/kg/day. Rare occasions of sporadic vomiting was noted before or after the daily
treatment. Mucous deposition and vomiting were noted with a low incidence and showed no consistent
pattern attributable to the notified chemical.
Salivation during or shortly after treatment was noted once in 2 females receiving 100 mg/kg/day and on five
occasions in 1 female receiving 700 mg/. During week 12 salivation was also noted following ocular
administration of atropine for ophthalmoscopic examination, in all males receiving 30 mg/kg/day, 2 males and
1 female receiving 100 mg/kg/day and 1 male and 2 females receiving 700 mg/kg/day.
Body Weights
Negligible weight gain or a small weight loss over the 13-week treatment period compared with control
weights was observed in dogs treated at 700 mg/kg/day. This reduction in weight body weight gain was noted
from the second week of treatment and resulted in slightly lower weekly group mean body weights for the
high dose animals compared with controls or dogs receiving 30 mg/kg/day.
Similarly, dogs receiving 100 mg/kg/day showed marginally lower overall body weight gains, compared with
controls, for the 13 瓀eek treatment period. Weekly group mean body weights and overall body weight gains
for animals receiving 30 mg/kg/day were comparable with those of controls.
Food consumption and conversion ratios
A consistent small reduction in food intake was noted from week 2 of treatment in dogs treated with 700
mg/kg/day compared with controls. Males and females treated at this level also recorded a marked reduction
in food utilisation throughout the treatment period. Food conversion ratios for dogs receiving 100 mg/kg/day
were also slightly higher than controls for the first 8 weeks of the treatment period. These dogs, however, also
exhibited slightly higher pre-treatment values and showed overall values similar to that of controls and the 30
mg/kg/day group. The toxicological significance of food this result for the 100 mg/kg/day group is of
doubtful toxicological significance.
Ophthalmoscopy
No toxicologically significant ocular findings were observed.
Laboratory Findings ?Clinical Chemistry, Haematology, Urinalysis
Clinical biochemistry
Alkaline phosphatase levels were markedly higher in dogs treated at 700 mg/kg/day at weeks 7/8 and 12. A
marked increase in glutamic pyruvic transaminase (GPT) levels was also noted in 1 male and all females
receiving 700 mg/kg/day at weeks 7/8 and 12. A less marked increase was also noted for an additional two
males in the 700 mg/kg/day group. Increased glutamic oxaloacetic transaminase (GOT) values were also
noted at 7/8 and 12 for 2 high dose males as compared with controls. Increase GOT values were also noted at
weeks 7/8 and 12 for one male and at week 7 for one female as compared with controls and other treated dogs.
At weeks 7/8 and 12, a trend to slightly lower values for cholesterol, total protein, albumin and A/G ratio was
noted for females receiving 700 mg/kg/day compared to controls. One male receiving this dose level also
showed slightly lower total protein at week 12 and slightly lower albumin at weeks 7/8 and 12 compared with
controls.
Urinalysis
No changes in quantity and quality of urine voided by treated rats when compared with controls which could
be attributed to treatment with DMI.
Haematology
Haematology data obtained at weeks 7/8 and 12 revealed slightly lower red cell parameters for one male and 2
females receiving 700 mg/kg/day. Compared with controls. One additional female also showed slightly lower
red cell parameters at week 12 when compared with controls. The red cell parameters in affected individuals
were also slightly reduced when compared with pre-treatment values.
No other toxicologically significant haematological values were observed.
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Pathology ?Organ weights, Macroscopic findings, Histopathology
Organ weights
Increased absolute and relative liver weights were observed in dogs receiving 700 mg/kg/day compared with
controls. Liver weights were comparable with controls for other treated dogs. Higher relative and absolute
spleen weights were observed in females receiving 700 mg/kg/day while males receiving these levels tended
to show lower spleen weights. This parameter is however considered to be of doubtful toxicological
significance given the inherent variability in this parameter due to differences in the degree of exsanguination
(blood content), inconsistency with respect to sex, and absence of histopathological change.
Macroscopic findings
Gross pathology examination of all dogs killed after 13 weeks of treatment revealed macroscopically observed
liver enlargement in 1 male receiving 700 mg/kg/day compared with controls. No other significant gross
pathology observations were made.
Histopathology
Histopathological evaluation revealed no evidence of treatment related effects.
Remarks ?Results
CONCLUSION
The NO(A)EL level is established as 100 mg/kg/day based on signs of general toxicity at 700 mg/kg/day. This
included reduced body weight gain, haematological and blood biochemistry changes and liver effects at 700
mg/kg/day.
TEST FACILITY Bio-Research Laboratories Ltd. (1987b).
7.7. 8-day repeat dose oral toxicity
TEST SUBSTANCE Notified chemical
METHOD
Species/Strain Rabbit/New Zealand White
Route of Administration Oral ?gavage
Exposure Information Total exposure days: 8 days
Dose regimen: Once daily for eight days
Post-exposure observation period: None
Vehicle Water
Remarks - Method
RESULTS
Group Number and Sex Dose Mortality
of Animals mg/kg bw/day
I 5F 300 0
Mortality and Time to Death
No premature deaths occurred during the course of the study.
Clinical Observations
There were no changes in clinical condition observed during the dosing period or on the days of necropsy.
Body Weights
Slight retardation of mean bodyweight gain to slight bodyweight loss in some cases was observed during the
first five days of dosing, however this is considered usual when dosing na飗e animals. Bodyweight gain
during the remainder of the dosing period was similar to that of the pre-dosing period. There was no effect of
treatment on bodyweight.
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Food consumption
Slight reduction in the food consumption of 3 of the five animals was observed over days 3 to 5 however this
was considered to be related to the dosing of na飗e animals rather than a direct effect of the notified chemical.
Food consumption for all five animals was similar to that during the pre-dosing period on the other days of the
study.
Necroscopy
There were no macroscopic abnormalities observed at necroscopy in any of the treated females.
Remarks ?Results
CONCLUSION
The NO(A)EL level is established as 300 mg/kg/day based the lack of evidence of toxicity at this dose level.
TEST FACILITY Toxicol. (1993a).
7.8.1 Genotoxicity - bacteria
TEST SUBSTANCE Notified chemical
Not stated
METHOD
Species/Strain S. typhimurium:
G46, TA1535, TA1537, TA 1538, TA98, TA100, D3052, C3076.
E. coli: WP2, WP2 uvrA-
Metabolic Activation System S9
Concentration Range in a) With metabolic activation: 0.1-1000 礸/plate.
Main Test b) Without metabolic activation: 0.1-1000 礸/plate.
Vehicle Water
Remarks - Method Positive controls are 2-acetylaminofluorene and Streptozotocin.
No mutagenic activity was observed at any concentration in any of the
RESULTS
strains tested.
The notified chemical was not mutagenic to bacteria under the conditions
CONCLUSION
of the test.
TEST FACILITY Not provided (RE Macmahon, 1979)
7.8.2 Genotoxicity - bacteria
TEST SUBSTANCE Notified Chemical
Maron and Ames (1983)
METHOD
Species/Strain S. typhimurium:
TA1538, TA1535, TA1537, TA98, TA100.
Metabolic Activation System Araclor 1254璱nduced liver S9
Concentration Range in a) With metabolic activation: 1.6 - 5000 礸/plate.
Main Test b) Without metabolic activation: 1.6 - 5000 礸/plate.
Vehicle Dimethyl sulphoxide
Remarks - Method
RESULTS
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Metabolic Test Substance Concentration (礸/plate) Resulting in:
Activation Cytotoxicity in Cytotoxicity in Precipitation Genotoxic Effect
PreliminaryTest Main Test
Absent
Test 1 None - No
Test 2 None - No
Test 3 None - No
Present
Test 1 None - Slight (TA 1535 only)
Test 2 None - No
Test 3 None - Slight (TA 1538 only)
Remarks - Results In the first experiment, a slight positive response was observed for TA
1535 in the presence of S9. Data obtained for strain TA1537 in the
absence of S9 was insufficient due to the level of contamination
observed. Data for strain TA 1538 (+S9) was discounted due to the lack
of response observed with the positive control 2-Aminoanthracene, in
this strain. It is believed the S9-mix was omitted from these plates during
pouring.
In the second experiment, the notified chemical gave a negative response
in both the presence and absence of an auxiliary metabolising system
(S9) in all strains, when tested to a maximum dose of 5000g/plate.
The notified chemical was not mutagenic to bacteria under the conditions
CONCLUSION
of the test.
TEST FACILITY Imperial Chemical Industries P.L.C. (1986)
7.9. Genotoxicity ?in vitro cytogenics assay
TEST SUBSTANCE Notified chemical
OECD TG 473 In vitro Mammalian Chromosomal Aberration Test.
METHOD
Species/Strain Human
Cell Type/Cell Line Lymphocyte
Metabolic Activation Aroclor 1254 Induced Rat liver ?S9
System
Vehicle Water
Remarks - Method
Metabolic Test Substance Concentration (礸/mL) Exposure Harvest
Activation Period Time
Absent
Test 1 34.45, 49.21, 70.30, 100.4, 143.5, 204.9, 292.8, 418.3, 20 hours 20 hours
597.5, 853.6*, 1219*, 1742*
Test 2 73.57, 98.10, 130.8, 174.4, 232.5, 310.0, 413.4, 551.2, 44 hours 44 hours
734.9, 979.9*, 1307*, 1742*
Present
Test 1 34.45, 49.21, 70.30, 100.4, 143.5, 204.9, 292.8, 418.3, 3 hours 20 hours
597.5, 853.6*, 1219*, 1742*
Test 2 73.57, 98.10, 130.8, 174.4, 232.5, 310.0, 413.4, 551.2, 3 hours 44 hours
734.9, 979.9*, 1307*, 1742*
*Cultures selected for metaphase analysis.
RESULTS
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Test Substance Concentration (礸/mL) Resulting in:
Metabolic
Activation Cytotoxicity in Cytotoxicity in Precipitation Genotoxic Effect
PreliminaryTest Main Test
Absent
Test 1 - None - No
Test 2 - None - No
Present
Test 1 - None - No
Test 2 - None - No
Remarks - Results No mitotic inhibition was apparent in Experiment 1 after treatment in
either the absence or presence of S9. A similar mitotic inhibition result
was seen in experiment 2 with no evidence of an effect on proliferation at
the delayed harvest time.
The notified chemical was not clastogenic to human peripheral blood
CONCLUSION
lymphocytes when tested in vitro under the conditions of the test.
TEST FACILITY Hazelton Microtest (1993)
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ADDITIONAL INVESTIGATIONS
7.10T. 14-day Ocular toxicity - intravenous
TEST SUBSTANCE Notified chemical.
METHOD
Species/Strain Rat (strain not stated)
Vehicle Not stated
Remarks - Method 14 day study period/14 day recovery period
RESULTS
Group Number and Sex DMI Conc. Mortality
of Animals (mg/kg/day)
I 10M 0 0
II 10M 200 0
III 10M 630 0
IV 10M 2000 0
Signs of Toxicity No ocular lesions were observed at any dose either by ophthalmoscopic
examination or gross and microscopic pathology.
General signs of toxicity observed were restricted to the high-dose group
and reversed during the 14-day recovery period. Rats dosed at 2000
mg/kg/day produced a depressant effect on the central nervous system as
well as decreased body tone, heart palpitation, lacrimation, and shaking
of the head. Rats in the high dose group showed significantly retarded
weight gain during the dosing period however no significant effects on
body weight or weight gain were noted for the low and mid-dose groups.
The mid dose of 630 mg/kg/day produced minimal toxic signs in a few
animals only on the first day of dosing and there was no apparent adverse
effect on the health of the animals.
The NOEL was established as 200 mg/kg/day, based on minor effects at
630 mg/kg/day. Based on severe toxicity at the high dose, the NOAEL is
630 mg/kg/day.
Remarks - Results
The notified chemical is of low ocular toxicity via the intravenous route.
CONCLUSION
TEST FACILITY ICI Americas Inc (not stated)
7.11T. Skin sensitisation ?human volunteers
TEST SUBSTANCE Notified chemical
METHOD
Study Design Two hundred human volunteers were tested by application of the
substance to the skin under a closed patch employing cotton felt circles.
Study Group 188 F / 12 M
Ages: 16-65 years
Vehicle None
Induction Procedure Cotton felt circles impregnated with undiluted test substance were
applied for 3 days and then removed.
Rest Period 2 weeks
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Challenge Procedure Cotton felt circles impregnated with undiluted test substance were
applied for 3 days and then removed.
Remarks - Method
RESULTS
Remarks - Results All skin sites were negative except for 2 subjects who showed
questionable reactions. These subjects were immediately retested by
application of the substance to another skin site by a semi-closed patch
(gauze impregnated with the substance and secured only by tape above
and below) and the usual closed patch. Both of these subjects were
negative in each of the retested sites after 48 hours.
A human patch test was conducted using 100% notified chemical under
CONCLUSION
occlusive dressing. The notified chemical was non-irritating and non-
sensitising under the conditions of the test.
TEST FACILITY Atlas Chemical Industries (1968)
7.12T. 1 Developmental toxicity
TEST SUBSTANCE Notified chemical
METHOD
Species/Strain Rabbit ?New Zealand White
Route of Administration Oral ?gavage
Exposure Information Exposure period: 13 days
Vehicle Water
Remarks - Method
RESULTS
Group Number of Animals Dose Mortality
mg/kg bw/day
1 18 0 0
2 18 30 0
3 18 100 0
4 19 300 1(1*)
Mortality and Time to Death
One female rabbit from group 4 was found dead on day 8 following a dosing intubation error and another
rabbit* from group 4 was prematurely killed following abortion of nine foetuses.
Effects on Dams
Reduced faeces production was observed in eight to ten rabbits in each treatment group after commencement
of treatment compared to three in the control group. All other clinical signs such as alopecia were minor in
nature and considered not to be treatment-related.
There was no effect of treatment on either maternal bodyweight or food consumption. There were no
macroscopic abnormalities detected at necropsy that were indicative of an effect of treatment at any dose
level.
Effects on Foetus
Major skeletal abnormalities were observed in the control group including scoliosis, missing ribs, and major
fusion of sternabrea. In the group dosed with 30 mg/kg/day, major external, visceral, and skeletal
abnormalities were observed in one foetus, while another was observed to have major visceral abnormalities,
and two others were observed to have major skeletal abnormalities. In the group dosed with 100 mg/kg/day, a
total of two foetuses from separate litters had major external, visceral and skeletal abnormalities. In the group
dosed at 300 mg/kg/day a total of four foetuses from separate litters had major abnormalities. One foetus had
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major visceral and skeletal abnormalities, two foetuses had major skeletal abnormalities, and one foetus had
major visceral abnormalities.
Abnormalities were therefore observed in 2, 4, 2 and 4 foetuses with major abnormalities in the control group
and the groups dosed with 30, 100 and 300 mg/kg/day respectively. As some of the observations were present
in the control group and there was little consistency of findings in treatment groups, the observations were
considered not to be treatment related.
There were two statistically significant differences in the incidence of minor abnormalities between treatment
groups and control group. At 100 mg/kg/day, the incidence of abnormal parietals was significantly higher
than in the control group. At 30 and 300 mg/kg/day, the incidence of non-ossified metacarpals was greater
than control group. In both cases however, not all dosage groups were affected, and neither observation was
therefore considered treatment related.
Remarks ?Results
CONCLUSION
Based on the lack of evidence of maternal toxicity or developmental toxicity at any of the dosage levels
investigated., the NOAEL was 300 mg/kg/day.
TEST FACILITY Toxicol Laboratories Ltd. (1993b)
7.12T. 2 Developmental toxicity
TEST SUBSTANCE Notified chemical
METHOD
Species/Strain Rat ?Sprague Dawley
Route of Administration Oral ?gavage
Exposure Information Exposure period: 10 days
Vehicle Water
Remarks - Method
RESULTS
Group Number of Animals Dose Mortality
mg/kg bw/day
1 24 0 0
2 24 30 0
3 24 100 0
4 24 300 0
Mortality and Time to Death
No rats died during the observation period or were prematurely killed.
Effects on Dams
There were no treatment related changes in clinical condition observed. No effect on either maternal body
weights or food consumption were observed. Macroscopic examination revealed no treatment related
abnormalities at necropsy. Pregnancy incidence, corpora lutea numbers and pre-implantation losses were
similar in all groups. Litter size, post-implantation losses, foetal sex ratio and foetal weights were also
unaffected at all treatment levels.
Effects on Foetus
No major abnormalities were observed in the foetuses of the 30 mg/kg/day treatment group. An unusually
high incidence of major abnormalities occurred in the group dosed at 100 mg/kg/day, however only 2 of 23
litters were affected, one of which contained five affected foetuses from a total of seven. Abnormalities
observed were external/visceral and skeletal including micrognathia, cleft palate, protruding tongue,
hypoplastic lung lobes, short body (and associated movement restriction), short mandible, and retarded
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ossification of the long bones and misshapen long bones in both fore- and hind limbs. At 300 mg/kg/day one
foetus was observed with major external/visceral abnormalities which were domed head, umbilical hernia, and
short body (and associated movement restriction).
As there were no dose related trends and since all abnormalities were of a type and incidence that can occur
spontaneously in this strain of rat, none of the observed effects were considered to be treatment related.
The incidence of abnormal parietals was significantly higher than in the control group, and at 30 and 300
mg/kg/day the incidence of non-ossified metacarpals was greater than in the control group. However, as in
both cases, not all doage groups were affected, neither observation is considered to be treatment related.
There were no treatment related differences in the incidences of specific types of foetal external and visceral
abnormalities or skeletal variants at any of the dose levels investigated.
Remarks ?Results
CONCLUSION
Based on the lack of evidence of maternal toxicity or developmental toxicity at any of the dosage levels
investigated, the NOAEL was 300 mg/kg/day.
TEST FACILITY Toxicol Laboratories Ltd. (1993c)
7.13T. Oral tolerance of teeth cleaning gels containing Notified Chemical ?Human
TEST SUBSTANCE Notified Chemical
15 male volunteers took part in the study which involved brushing with
METHOD
toothpaste formulations containing varying concentrations of the test
chemical. Initial and weekly examination of participants was undertaken
in order to determine the extent, if any, of toxic effects.
STUDY DESIGN AND OBJECTIVE
The study design was designed to have four two week brushing sessions each separated by a one week hiatus
to avoid any possible carry over effect. The distibution of teeth cleaning gels was as follows:
Session I Placebo dental gel
Session II Dental gel with 5% notified chemical
Session IV Dental gel with 10% notified chemical
Session V Dental gel with 25% notified chemical
Initial and weekly clinical evaluations included thorough observations of the soft tissues of the mouth
including:
1. Oral mucosa
2. Gingiva
3. Tongue
4. Tonsillar area
5. Lips
RESULTS
No adverse tissue reactions were observed or reported except for one subject who developed a chapped lower
lip during the second week use of the 10% gel. This condition persisted to the end of the study. This subject
had, however a prior history of frequent episodes of chapped lips which were unrelated to the use of the
notified chemical. At the outset of the study, one subject presented with geographic tongue, which remained
unchanged throughout the test periods with all concentrations of the notified chemical. The oral mucosa of two
subjects showed evidence of cheek biting which was present at the outset of the study and unrelated to the use
of the notified chemical.
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CONCLUSION
No treatment related effects were observed following the use of the notified chemical in concentrations up to
25% in the gels with the possible exception of one case of chapped lips which may have been aggravated by
notified chemical.
TEST FACILITY Forsyth Dental Centre (1985)
7.14T. Absorption after percutaneous admninistration.
TEST SUBSTANCE Notified chemical
A 100 mg/kg dose of 14C-DMI was applied dorsally to a 4 ?3 cm
METHOD
shaved skin area of eight male rats. The skin of four of the rats was
further prepared by stripping stratum corneum cells from the epidermal
layer of the skin with Scotch Tape prior to dosing. Small beads of the
test material were applied to the skin and spread evenly using a small
glass rod. The glass rod was rinsed with acetonitrile and the dose
corrected by the 14C measured in the rinse. Urine was collected over dry
ice for 12 hours, and stored frozen prior to analysis. Faeces were
collected for 12 hours. The animals were killed 12 hours after dosing.
The tongue and oesophagus were excised and later assayed to determine
if the animal had licked the treated area. The treated skin and
surrounding perimeter were removed and the body stored prior to assay.
Samples collected were analysed for total 14C by liquid scintillation
counting. The body except for the tongue and oesophagus, was ground
and homogenised. Aliquots were prepared for LSC by combustion. The
tongue and oesophagus were combusted separately.
STUDY DESIGN AND OBJECTIVE
The objective of the study was to determine the percutaneous absorption of 14C-DMI in male rats.
RESULTS
The percentage of dose measure in the excretion products and in the body as 14C after the percutaneous
administration of 14C-DMI was determined to be an average of 31.8% ?7.6% absorbed dose in 12 hours. The
kidney was the major excretory path for total 14C. Tongue and oesophagus tissue to body ratios obtained in the
percutaneous study were not significantly different to ratios obtained in a pilot study using intraperitoneal-
dosed rats
CONCLUSION
The notified chemical is absorbed through the skin.
TEST FACILITY Stuart Pharmaceuticals (1984)
7.15T. Skin penetration enhancement.
TEST SUBSTANCE Notified chemical
14
C radiolabeled glycerol was applied to the skin of hairless mice in the
METHOD
presence of water alone and in water plus the notified chemical. Depth of
penetration was measured by serially stripping back stratum corneum and
analysing for radiolabelled 14C glycerol, with and without the notified
chemical. The notified chemical enhancement was evaluated by
comparing absolute and relative depth profiles of radiolabeled 14C
glycerol, with and without the notified chemical in aqueous solution.
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STUDY DESIGN AND OBJECTIVE
The objective of the study was to determine effect of the notified chemical on enhancing the penetration of
glycerin in hairless mice.
RESULTS
The radiolabelled 14C glycerol was applied and tracked through the stratum corneum of hairless mice with the
concentration profiles analysed by tape stripping of the stratum corneum at 1, 5, 10, and 15 layers. The
notified chemical raised absolute concentration and relative concentrations at 1 and 12 hours post application.
Absolute concentration at 12 hours was about 1/10 that measured at 1 hour. Depletion of surface activity from
about 400 000 to 20 000 units of activity occurred within 1 hour.
The glycerol with notified chemical in aqueous solution was found to penetrate the stratum corneum at a
greater rate than that of glycerol without notified chemical.
CONCLUSION
The notified chemical enhances the penetration of glycerol through the stratum corneum.
TEST FACILITY Xienta Institute for Skin Research (1989)
7.16T. In Vitro Blood Compatability
TEST SUBSTANCE Notified chemical
The notified chemical was prediluted with saline to achieve
METHOD
concentrations of 2, 10, 20, 40, 60, and 100% (v/v). 0.5 mL of test
solution was mixed with 0.5 mL of blood from rats, dogs, and drug free
humans. The final concentrations in blood were 0, 1, 5, 10, 20, 30 and
50%. The tubes were vortexed and read macroscopically and
microscopically for agglutination. Following centrifugation, supernatants
were graded for haemolysis compared with negative controls.
Phytohaemaglutinin served as a positive control for Phytohaemaglutinin.
STUDY DESIGN AND OBJECTIVE
The objective of the study was to determine the maximum concentration of notified chemical compatible with
blood from rats, dogs, and humans, when used as a solvent in parenteral formulations of pharmaceuticals.
RESULTS
Rat
Agglutination was absent and hemolysis was graded as equal to the negative control in all rat specimens at
20% notified chemical. At 30% notified chemical, no changes in pH were observed. Five of 10 and 9 of 10
samples showed agglutination and hemolysis, respectively, at 30% notified chemical. Significant changes in
pH were observed at concentrations of 50% notified chemical.
Dog
One of 10 and two of ten dog samples showed agglutination at 10% and 20% respectively, however the sample
which showed minimal agglutination at 10% was negative at 20%. Two of 10 dog samples had haemolysis
gradings greater than the negative control at 20% concentration. A difference from control of greater than 0.10
pH units was noted for female means at 5%. However at 10%, the pH change was within 0.10 pH units,
therefore the 5% change in pH was dismissed.
Humans
Eight of 10 human bloods were agglutinated at 30% and three of 10 human specimens were haemolysed at this
concentration. Cloudy supernatants were observed during hemolysis evaluation at 20% concentration and 30%
concentration of all human samples. No significant change in pH means was noted in any human specimen at
30% concentration.
CONCLUSION
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In vitro data indicates the compatibility with blood of a notified chemical concentration of 10% or less in dogs
and humans and 20% or less in rats. There was no apparent sex difference in any of the species when tested
with the notified chemical.
TEST FACILITY ICI Americas (1981)
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8. ENVIRONMENT
8.1. Environmental fate
8.1.1. Ready biodegradability
TEST SUBSTANCE Dimethyl Isosorbide
OECD TG 301 F Ready Biodegradability: Manometric Respirometry
METHOD
Test.
Inoculum Activated sludge from Buckland Sewage Treatment Works which mainly
treats domestic effluent.
Exposure Period 28 days
Auxiliary Solvent None
Analytical Monitoring None
Remarks - Method Reference substance ?sodium acetate
Temperature 20?oC
Treatments:
- bottles 1-3 control blanks
- bottles 4-6 reference substance, 200 mg/L
- bottles 7-9 test material, 100 mg/L
Oxygen uptake was measured daily.
RESULTS
Control Sodium Acetate Dimethyl Isosorbide
Day % degradation Day % degradation Day % degradation
5 0 5 67 5 0
10 0 10 76 10 0
15 0 15 78 15 0
20 0 20 78 20 0
25 0 25 78 25 0
28 0 28 78 28 0
Remarks - Results The reference substance degradation exceeded 60% thus indicating that
the study was valid.
The test material, dimethyl isosorbide, is not readily biodegradable under
CONCLUSION
the study conditions.
TEST FACILITY Brixham Environmental Laboratory, 1993b.
8.1.2. Bioaccumulation
Estimation method
METHOD
Remarks The estimation method, BCF program in the EPIWIN package, uses the composition and
structure of the chemical to estimate its bioaccumulation.
Estimations Log BCF = 0.5 (BCF = 3.162)
The estimation indicates that the notified chemical is slightly concentrating (Mensink,
1995).
TEST FACILITY Not stated.
8.1.3 Fugacity model
Estimation method
METHOD
Remarks The estimation method, BIOWIN in the EPIWIN package, uses the composition and
structure of the chemical to estimate its fate in the environment.
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Estimations Compartment Distribution in environment (%) Half Life (hr)
Air 0.003 5.33
Water 45.4 360
Soil 54.6 360
Sediment 0.08 1440
TEST FACILITY Not stated.
8.2. Ecotoxicological investigations
8.2.1. Acute toxicity to fish
TEST SUBSTANCE Dimethyl Isosorbide
Estimation Method.
METHOD
Remarks ?Method The estimation method, ECOSAR in the EPIWIN package, uses the
composition and structure of the chemical to estimate its potential
toxicity to various trophic levels and based on a log Pow of ?.62.
Fish: 96 hr LC50 3.26X105 mg/L
Results
Fish Saltwater: 96 hr LC50 1.2991 X104 mg/L
The estimation indicates that the notified chemical may be slightly more
COMMENT/CONCLUSION
toxic to saltwater fish, but in both cases appears to be practically non-
toxic to fish.
8.2.2. Acute toxicity to aquatic invertebrates
TEST SUBSTANCE Dimethyl Isosorbide
OECD TG 202 Daphnia sp. Acute Immobilisation Test and Reproduction
METHOD
Test ?static conditions.
EC Directive 92/69/EEC C.2 Acute Toxicity for Daphnia - static
conditions.
Species Daphnia magna
Exposure Period 48 hours
Auxiliary Solvent None
173 mg CaCO3/L
Water Hardness
Analytical Monitoring None
Remarks - Method
RESULTS
Concentration mg/L Number of D. magna Number Immobilised
Nominal 24 h 48 h
0 20 0 0
1000 20 0 0
> 1000 mg/L at 48 hours
LC50
NOEC (or LOEC) > 1000 mg/L at 48 hours
Remarks - Results
Under the conditions of the limit test, the test material was practically
CONCLUSION
non-toxic to daphnia.
TEST FACILITY Brixham Environmental Laboratory, 1993c.
Acute toxicity to aquatic invertebrates
TEST SUBSTANCE Dimethyl Isosorbide
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METHOD Estimation Method.
Daphnid
SPECIES
Remarks ?Method The estimation method, ECOSAR in the EPIWIN package, uses the
composition and structure of the chemical to estimate its potential
toxicity to various trophic levels and based on a log Pow of ?.62.
48 hr LC50 2.72X105 mg/L
Results
The estimation indicates that the chemical may be practically non-toxic to
COMMENT/CONCLUSION
Daphnid.
This estimation is in agreement with the above study.
Acute toxicity to aquatic invertebrates
TEST SUBSTANCE Dimethyl Isosorbide
Estimation Method.
METHOD
Mysid shrimp
SPECIES
Remarks ?Method The estimation method, ECOSAR in the EPIWIN package, uses the
composition and structure of the chemical to estimate its potential
toxicity to various trophic levels and based on a log Pow of ?.62.
96 hr LC50 1.25X106 mg/L
Results
The estimation indicates that the chemical may be practically non-toxic to
COMMENT/CONCLUSION
Mysid shrimp.
8.2.3. Algal growth inhibition test
TEST SUBSTANCE Dimethyl Isosorbide
Estimation Method.
METHOD
Remarks - Method The estimation method, ECOSAR in the EPIWIN package, uses the
composition and structure of the chemical to estimate its potential
toxicity to various trophic levels.
Green Algae: 96 hr EC50 1.38X105 mg/L
Results
The estimation indicates that the chemical may be practically non-toxic to
COMMENT/CONCLUSION
algae.
8.2.4. Inhibition of microbial activity
TEST SUBSTANCE Dimethyl Isosorbide
Based on method described by Bringman and Kuehn and modified by
METHOD
Slabbert. This method measures the degree of inhibition of a pure culture
of Pseudomonas putida during a 6 hour period when the cells are in the
logarithmic growth phase.
Inoculum Pseudomonas putida/growth medium solution with an optical density
with an absorbance of 0.8 at 600 nm.
Exposure Period 6 hours
Concentration Range 100 mg/L
Nominal
Remarks ?Method Reference substance ?3,5-dichlorophenol, 18 mg/L.
Treatments:
- 3 flasks with 100 mg/L Dimethyl Isosorbide
- 3 flasks with 18 mg/L 3,5-dichlorophenol
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- 3 flasks as control blanks
Each flask had 4 mL of growth medium concentrate and 1 mL of
inoculum (except to the blank and chemical controls) added and were
made up to 50 mL with deionised water. The flasks were shaken at 150
rpm for 6 hours at 25oC, after which the optical density at 600 nm of each
flask was measured. An 8% v/v growth medium solution was used as the
reference cell.
RESULTS
>100 mg/L
EC50
NOEC >100 mg/L
Remarks ?Results The reference substance, 3,5-dichlorophenol, produced a 96% inhibition
of growth.
The test material is practically non-toxic to Pseudomonas putida
CONCLUSION
bacterium.
TEST FACILITY Brixham Environmental Laboratory, 1993d.
9. RISK ASSESSMENT
9.1. Environment
9.1.1. Environment ?exposure assessment
The majority of the notified chemical (up to 9700 kg annually) will eventually be released into
the environment via discharge into sewerage systems during personal washing. It is expected
that up to 100 kg per annum will remain in the consumer product containers and be disposed of
to landfill, along with 200 kg from end-user product formulation.
The notified chemical is expected to be highly soluble in water and have a low Pow. Therefore
it will be mobile in both the aquatic and terrestrial compartments. It will not readily hydrolyse in
natural waters at environmental pH values and is not readily biodegradable. However, the
notified chemical will degrade through biological and abiotic processes to water and oxides of
carbon. Residual chemical disposed of to landfill with empty containers is also expected to
slowly degrade by similar mechanisms.
As the majority of the notified chemical in the skin care products will eventually be released into
the aquatic environment via the sewerage systems, the predicted environmental concentration
(PEC) in the aquatic environment is estimated using a worst-case scenario assuming all the
notified chemical is released to sewer, where there is no removal and it is used across Australia:
Amount released to sewer 10000 kg
Population 20 million
Water use per person 200 L
Number of days used 365
10 000 000 000
PECsewer
365X200X20 000 000
= 0.0068 mg/L
= 6.8 礸/L
6.8 礸/L
PECinland (dilution factor 1)
0.68 礸/L
PECocean (dilution factor 10)
The ready biodegradability test results showed that the notified chemical was not readily
biodegradable. The SIMPLETREAT model (European Commission, 1996) for modelling
partitioning and losses in sewage treatment plants (STP) was used to estimate the proportions of
the chemical partition into the different environmental compartments. The results indicate that
when the chemical is released into the aqueous phase of a STP, all of it will partition into the
water compartment with no removal or degradation. Thus, there will be no change to the above
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estimated PECs.
STP effluent re-use for agricultural irrigation occurs throughout Australia The following
calculation is undertaken assuming an application rate of 1000 L/m2/year (10 ML/ha/year) and
that any notified chemical in the water is assumed to infiltrate and accumulate in the top 0.1 m
of soil (density 1000 kg/m3).
Concentration in effluent 6.8 礸/L
Soil concentration, PECsoil (mg/kg) (assumes no degradation)
1 year 0.068
5 years 0.34
10 years 0.68
Bioaccumulation is not expected due to the high water solubility and low log Pow of the notified
chemical, which indicates a poor affinity to lipids.
9.1.2. Environment ?effects assessment
The results of the aquatic toxicity tests are listed below.
Organism Duration End Point mg/L
3.26?05 est.
Fish 96 h LC50
1.29?04 est.
Daphnia 48 h EC50 >1000 actual
2.72?05 est.
1.38?05 est.
Algae 96 h EC50
> 100 actual
Microbial activity 6h EC50
ECETOC (2003) states that non-ionic chemicals with a narcotic mode of action can be
predicted reliably with relatively simple QSARs (based on log Pow) for fish, invertebrates and
algae. The actual daphnia study results support the estimated results, thus in this situation the
use of QSAR is acceptable.
Using the lowest EC50 actual datum (ie. > 100 mg/L) and a safety factor of 1000 (OECD) since
there is actual data for only one trophic level, a predicted no effect concentration (PNEC) for
aquatic ecosystems of <0.1 mg/L has been determined (EC50/1000).
9.1.3. Environment ?risk characterisation
The risk of the release of all the imported notified chemical can be estimated by determining the
aquatic risk quotient (RQ = PEC/PNEC).
Location PEC PNEC Risk Quotient (RQ)
Australia-wide STPs
Aquatic
0.00068 mg/L <0.1 mg/L <0.0068
Ocean outfall
0.0068 mg/L <0.1 mg/L <0.068
Inland River
Since the RQ values are less than 1, the proposed use of the notified chemical is
unlikely to pose an unacceptable risk to the aquatic life.
9.2. Human health
9.2.1. Occupational health and safety ?exposure assessment
Reformulation
Skin contact will be the main route of exposure, although eye contact is also possible. Given the
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STD/1027
molecular weight distribution of the polymer, absorption through intact skin cannot be excluded.
Exposure to the notified polymer may occur during transfer of neat chemical from the 20 L pails
and 200 L drums into the mixing vessel via residual or leaking chemical from hoses, fittings
and/or pumps.
Mixing occurs mechanically in a closed or open system and thus exposure may occur when open
systems are used. Exposure to the chemical during manufacturing is controlled through the use
of semi-automatic equipment, engineering control measures, such as sealed vessels and the use
of PPE such as safety glasses, gloves, protective clothing and respirator if required. Inhalation
exposure is expected to be low, given the chemical's low vapour pressure.
Exposure to the notified chemical in the reformulated product is not expected to occur during
automated filling and packaging activities, however incidental exposure to small amounts of
product containing up to 25% notified chemical may occur as a result of faulty plant and
equipment, or damaged packaging. Maintenance personnel may also be exposed to small
amounts of these products in the event of any unscheduled repairs. The use of personal
protective equipment such as safety glasses, gloves, and protective clothing is sufficient to
mitigate any such exposure.
Retail
Sales representatives demonstrating the products in shopping centres and other points-of sale
will be dermally exposed to the notified chemical several times per day, several days per week
through application of the products to potential consumers or themselves. Inadvertant ocular
exposure may also occur. The notified chemical is non-volatile, however, if it is present in
product applied as a mist or aerosol, inadvertent inhalation of the notified chemical may also
occur.
End-Use
Intermittent, wide-dispersive use with direct handling is expected to occur among hairdressers,
cosmeticians, and beauticians. According to EASE (1997) modelling of this work environment,
exposure in the range of 1-5 mg/cm2/day of products containing up to 0.5-1.2% of the notified
chemical could result. Dermal exposure is expected during application of certain products and
accidental ocular exposure may also occur. The notified chemical is non-volatile, however, if it
is present in product applied as a mist or aerosol, inadvertent inhalation of the notified polymer
may also occur.
9.2.2. Public health ?exposure assessment
Personal care products containing the notified chemical at concentrations of up to 25% are for
sale to the general public. Members of the public will make dermal contact and possibly
accidental ocular contact with products containing the notified chemical. In most cases
exposure is expected to be limited to 1-10 grams of product, 1-2 times per day. Inhalation
exposure may also occur during application of a spray product containing the notified chemical.
Potentially all the notified chemical will be released to the environment however no significant
indirect exposure to the general population is expected.
9.2.3. Human health - effects assessment
The notified chemical has a molecular weight of 174, a high degree of water solubility, and is
expected to cross biological membranes readily. A study conducted using a radio-labelled dose
of the notified chemical demonstrated a high degree (31.8 % ?7.6%) of percutaneous
absorption in 12 hours. Additionally, the notified chemical was shown to increase the
penetration of the stratum corneum by glycerol.
A study designed to determine the maximum concentration of the notified chemical compatible
with blood from rats, dogs, and humans indicated that the notified chemical is compatible with
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STD/1027
blood at concentrations up to 10% or less in dogs and humans and up to 20% in rats.
The acute oral toxicity of the notified chemical was determined to be low in rats, with an LD50
of 6531 mg/kg bw. In an acute intravenous toxicity study using mice and rats, the 14-day
LD50s for the notified chemical using both 20% and 40% aqueous solutions were greater than
5000 mg/kg (for combined sexes), with no marked difference between LD50s for the two
concentrations. Females were slightly more affected, with the difference more apparent in rats.
In a separate 14-day intravenous study in rats, no ocular toxicity was observed, however, severe
effects on the central nervous system were observed at the highest dose, 2000 mg/kg/day. The
NOAEL was 630 mg/kg/day.
Acute dermal toxicity studies were not conducted, however on the basis of the data supplied for
acute oral toxicity and acute intravenous toxicity, the notified chemical is not expected to be
acutely toxic by the dermal route.
Several skin and eye irritation studies in the rabbit were provided. The studies were conducted
several decades ago, however, the results indicated that the notified chemical was slightly
irritant to both skin and eye of the rabbit. An additional rabbit study indicated that the notified
chemical was not irritating to the skin of the external auditory canal. The notified chemical was
also found to be non-irritating and non-sensitising in a human patch test.
In a 13-week repeated dose oral toxicity study in rats, the NOAEL was 375 mg/kg/day, the top
dose. Only adaptive changes in the liver and kidney were observed at this dose. In a similar
study in beagle dogs, the NOAEL was 100 mg/kg/day, based on signs of general toxicity,
including reduced body weight gain and food consumption, liver effects and clinical chemistry
changes (increased alkaline phosphatase levels and reduced red blood cell parameters) at the top
dose (700 mg/kg/day).
Two developmental toxicity studies failed to produce evidence of maternal or developmental
toxicity at concentrations up to 300 mg/kg bw/day in the rabbit or rat.
The notified chemical was not mutagenic in an Ames test nor clastogenic in an in vitro human
lymphocyte chromosomal aberration test.
No treatment related effects were observed or reported in a study which tested the human oral
tolerance to teeth-cleaning gels containing up to 25% of the notified chemical.
Based on the above toxicological information, the notified chemical is not determined to be
hazardous in accordance with the Approved Criteria for Classifying Hazardous Substances
(NOHSC, 2002).
9.2.4. Occupational health and safety ?risk characterisation
The notified chemical is a slight skin and eye irritant and may be absorbed through the skin.
Intermittent dermal exposure to the notified chemical may occur during the reformulation of the
notified chemical into personal care products and during unscheduled maintenance of automated
filling lines. However as the notified chemical is of overall low toxicity, the OHS risk presented
by the notified polymer during reformulation is expected to be low. However, due to the
chemical's irritant properties, PPE consisting of eye protection, gloves, and protective clothing
should be worn. Workers involved in the transport and storage of the notified chemical are not
expected to be exposed to the notified chemical except in the event of accidental spillage.
Potential for occupational exposure occurs in professions such as hairdressing and beauty
therapy, where workers may apply cosmetic products containing the notified chemical several
times each working day. Dermal exposure is the main route of exposure although inadvertent
ocular and inhalation exposure may also occur. However, the notified chemical is of low
toxicity, and only used in small amounts, therefore the risk to these workers is considered low.
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9.2.5. Public health ?risk characterisation
The products containing the notified chemical will be used by the general public applying the
products themselves, and also by those having products applied during professional hairdressing
or cosmetic applications. The notified chemical is readily absorbed by the skin but will be used
infrequently in small amounts. Despite the potential widespread use, the risk to public health is
considered low due to the low toxicity nature of the notified chemical and the small amounts of
product applied.
10. CONCLUSIONS ?ASSESSMENT LEVEL OF CONCERN FOR THE ENVIRONMENT AND
HUMANS
10.1. Hazard classification
Based on the available data the notified chemical is not classified as hazardous under the
NOHSC Approved Criteria for Classifying Hazardous Substances.
As a comparison only, the classification of notified chemical using the Globally Harmonised
System for the Classification and Labelling of Chemicals (GHS) (United Nations, 2003) is
presented below. This system is not mandated in Australia and carries no legal status but is
presented for information purposes. Under the Globally Harmonised System for the
Classification and Labelling of Chemicals, the notified chemical would not need to be classified.
10.2. Environmental risk assessment
The chemical is not considered to pose a risk to the environment.
10.3. Human health risk assessment
10.3.1. Occupational health and safety
There is low concern to occupational health and safety under the conditions of the occupational
settings described.
10.3.2. Public health
There is low concern to public health when used in the intended manner.
11. MATERIAL SAFETY DATA SHEET
11.1. Material Safety Data Sheet
The MSDS of the notified chemical provided by the notifier was in accordance with the NOHSC
National Code of Practice for the Preparation of Material Safety Data Sheets (NOHSC, 1994a).
It is published here as a matter of public record. The accuracy of the information on the MSDS
remains the responsibility of the applicant.
11.2. Label
The label for the notified chemical provided by the notifier was in accordance with the NOHSC
National Code of Practice for the Labelling of Workplace Substances (NOHSC, 1994b). The
accuracy of the information on the label remains the responsibility of the applicant.
12. RECOMMENDATIONS
CONTROL MEASURES
Occupational Health and Safety
?Employers should implement the following safe work practices to minimise
occupational exposure during handling of the notified chemical.
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- Avoid skin and eye contact
? Employers should ensure that the following personal protective equipment is used by
workers to minimise occupational exposure to the notified chemical as introduced:
- Protective clothing
- Chemically resistant gloves or gauntlets
- Chemical goggles or safety glasses
Guidance in selection of personal protective equipment can be obtained from
Australian, Australian/New Zealand or other approved standards.
? A copy of the MSDS should be easily accessible to employees.
? If products and mixtures containing the notified chemical are classified as hazardous to
health in accordance with the NOHSC Approved Criteria for Classifying Hazardous
Substances, workplace practices and control procedures consistent with provisions of
State and Territory hazardous substances legislation must be in operation.
Environment
? The following control measures should be implemented by reformulator to minimise
environmental exposure during (reformulation and use) of the notified chemical:
- Ensure all process areas and storage areas are properly bunded;
- Storm drains should not be within processor storage areas, to avoid any of the
notified chemical entering the storm drains.
Disposal
? The notified chemical should be disposed of to an approved landfill or incineration.
Emergency procedures
? Spills/release of the notified chemical should be handled by containment with
absorbent material, collection and storage in sealable labelled container.
12.1. Secondary notification
The Director of Chemicals Notification and Assessment must be notified in writing within 28
days by the notifier, other importer or manufacturer:
(1) Under Section 64(2) of the Act:
- if any of the circumstances listed in the subsection arise.
The Director will then decide whether secondary notification is required.
No additional secondary notification conditions are stipulated.
13. BIBLIOGRAPHY
Atlas Chemical Industries (1963). Dimethyl ether of isosorbide (DMI) ?Primary irritation to the skin of
albino rabbits and primary irritation to the external auditory canal of Albino rabbits. Atlas Chemical
Industries.
Atlas Chemical Industries (1964a). Irritation to the mucosa of the rabbit eye using the dimethyl ether of
isosorbide (DMI). Atlas Chemical Industries.
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STD/1027
Atlas Chemical Industries (1964b). Irritation to the mucosa of the rabbit eye using the dimethyl ether of
isosorbide (DMI) (80% and 60% w/v). Atlas Chemical Industries.
Atlas Chemical Industries (1968a). Dimethyl ether of isosorbide (DMI) ?Primary irritation to rabbit skin.
Atlas Chemical Industries. Atlas Chemical Industries.
Atlas Chemical Industries (1968b). Report of human patch tests on human subjects. Atlas Chemical
Industries.
Atlas Chemical Industries (1968c). Dimethyl isosorbide: Irritation to the eye mucosa of the albino rabbit.
Atlas Chemical Industries.
Bio-Research Laboratories Ltd. (1987a). A 13-week oral toxicity study of dimethyl isosorbide (DMI) in the
albino rat ?Bio-Research Project No. 82404. Bio-Research Laboratories Ltd. Boston, Massachusetts.
(Unpublished report provided by the notifier)
Bio-Research Laboratories Ltd. (1987b). A 13-week oral toxicity study of dimethyl isosorbide (DMI) in
beagle dogs ?Bio-Research Project No. 82405. Bio-Research Laboratories Ltd. Boston, Massachusetts.
(Unpublished report provided by the notifier)
Brixham Environmental Laboratory (1993a). Dimethyl isosorbide, Calculation of octanol water-partition
coefficient. Zeneca Limited. Brixham, Devon. (Unpublished report provided by the notifier)
Brixham Environmental Laboratory (1993b). Dimethyl isosorbide: Determination of acute toxicity to Daphnia
Magna. Zeneca Limited. Brixham, Devon. (Unpublished report provided by the notifier)
Brixham Environmental Laboratory (1993c). Dimethyl isosorbide: Determination of acute toxicity to
Pseudomonas putida. Zeneca Limited. Brixham, Devon. (Unpublished report provided by the notifier)
Brixham Environmental Laboratory (1993d). Dimethyl isosorbide (Arlasolve DMI): Determination of
biodegradability by Manometric Respiration Test. Zeneca Limited. Brixham, Devon. (Unpublished report
provided by the notifier)
ECETOC (2003). (Q)SARs: Evaluation of the commercially available software for human health and
environmental endpoints with respect to chemical management applications. ECETOC Technical Report 89.
European Centre for Ecotoxicology and Toxicology of Chemicals, Brussels, Belgium.
Forsyth Dental Centre (1985). A clinical trial to determine human oral tolerance of teeth cleaning gels
containing dimethyl isosorbide. Forsyth Dental Centre. Boston, Massachusetts. (Unpublished report provided
by the notifier)
Hazleton Laboratories (1957). Dimethyl isosorbide ?acute oral toxicity test report. (Unpublished report
provided by the notifier)
Hazleton Microtest. (1993). Study to evaluate the chromosome damaging potential of dimethyl isosorbide by
its effects on cultured human lymphocytes using an in vitro cytogenics assay. Hazleton Microtest. Harrogate,
North Yorkshire. (Unpublished report provided by the notifier)
ICI (1995). Arlasolve DMI, Dimethyl Isosorbide ?Drug Master File. (Unpublished report provided by the
notifier)
ICI Americas Inc. (1980). Mutagenic assay of dimethyl isosorbide. (Unpublished report provided by the
notifier).
ICI Americas Inc. (1981a). Dimethyl isosorbide: A developmental acute intravenous toxicity study in male
and female rats and mice. ICI Americas Inc. Biomedical Research Dept. Wilmington, Delaware.
(Unpublished report provided by the notifier)
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STD/1027
ICI Americas Inc. (1981b). Dimethyl isosorbide: A developmental acute intravenous toxicity study to assess
systemic ocular toxicity in male rats. ICI Americas Inc. Wilmington, Delaware. (Unpublished report provided
by the notifier)
ICI Americas Inc. (1981b). An exploratory in vitro compatabilty study of dimethyl isosorbide in blood from
rats, dogs and humans. ICI Americas Inc. Wilmington, Delaware. (Unpublished report provided by the
notifier)
Imperial Chemical Industries P.L.C. (1986). Atlas G-100 dimethyl isosorbide ?an evaluation in the
Salmonella mutagenicity assay. Report number CTL/P/1583. Imperial Chemical Industries. Macclesfield,
Cheshire. (Unpublished report provided by the notifier)
NOHSC (1994) National Code of Practice for the Labelling of Workplace Substances [NOHSC:2012(1994)].
National Occupational Health and Safety Commission, Canberra, Australian Government Publishing Service.
NOHSC. (2002). Approved Criteria for Classifying Hazardous Substances [NOHSC:1008(1999)]. Australian
Government Publishing Service: Canberra.
NOHSC. (2003). National Code of Practice for the Preparation of Material Safety Data Sheets
[NOHSC:2011(2003)]. Australian Government Publishing Service: Canberra.
Stuart Pharmaceuticals (1984). Absorption of 14C-dimethyl isosorbide in male rats after percutaneous
administration. Stuart Pharmaceuticals. Wilmington, Delaware. (Unpublished report provided by the notifier)
Toxicol Laboratories Limited (1993a). Dimethyl isosorbide (DMI) ?Oral gavage rabbit repeat dose tolerance
study. Toxicol Laboratories Limited. Ledbury, Herefordshire. (Unpublished report provided by the notifier)
Toxicol Laboratories Limited (1993b). Dimethyl isosorbide (DMI) ?Oral gavage rat developmental toxicity
study. Toxicol Laboratories Limited. Ledbury, Herefordshire. (Unpublished report provided by the notifier)
Toxicol Laboratories Limited (1993c). Dimethyl isosorbide (DMI) ?Oral gavage rabbit developmental
toxicity study. Toxicol Laboratories Limited. Ledbury, Herefordshire. (Unpublished report provided by the
notifier)
Unidentified Report. Effect of Arlasolve DMI on stratum corneum. (Unidentified report provided by the
notifier.)
United Nations (2003) Globally Harmonised System of Classification and Labelling of Chemicals (GHS).
United Nations Economic Commission for Europe (UN/ECE), New York and Geneva.
Xienta Institute for Skin Research. (1989). Penetration enhancement ?DMI study for ICI Americas, Inc.
Xienta Institute for Skin Research. Bernville, Philadelphia. (Unpublished report provided by the notifier)
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