Opinion Of The Scientific Committee On Consumer Safety Benzisothiazoli P96 Sccs O 099

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SCCS/1482/12

Scientific Committee on Consumer Safety
SCCS

OPINION ON
Benzisothiazolinone
COLIPA n° P96

The SCCS adopted this opinion at its 15th plenary meeting
of 26-27 June 2012

SCCS/1482/12
Opinion on benzisothiazolinone
___________________________________________________________________________________________

About the Scientific Committees
Three independent non-food Scientific Committees provide the Commission with the
scientific advice it needs when preparing policy and proposals relating to consumer safety,
public health and the environment. The Committees also draw the Commission's attention
to the new or emerging problems which may pose an actual or potential threat.
They are: the Scientific Committee on Consumer Safety (SCCS), the Scientific Committee
on Health and Environmental Risks (SCHER) and the Scientific Committee on Emerging and
Newly Identified Health Risks (SCENIHR) and are made up of external experts.
In addition, the Commission relies upon the work of the European Food Safety Authority
(EFSA), the European Medicines Agency (EMA), the European Centre for Disease prevention
and Control (ECDC) and the European Chemicals Agency (ECHA).
SCCS
The Committee shall provide opinions on questions concerning all types of health and safety
risks (notably chemical, biological, mechanical and other physical risks) of non-food
consumer products (for example: cosmetic products and their ingredients, toys, textiles,
clothing, personal care and household products such as detergents, etc.) and services (for
example: tattooing, artificial sun tanning, etc.).
Scientific Committee members
Jürgen Angerer, Ulrike Bernauer, Claire Chambers, Qasim Chaudhry, Gisela Degen, Elsa
Nielsen, Thomas Platzek, Suresh Chandra Rastogi, Vera Rogiers, Christophe Rousselle, Tore
Sanner, Jan van Benthem, Jacqueline van Engelen, Maria Pilar Vinardell, Rosemary Waring,
Ian R. White
Contact
European Commission
Health & Consumers
Directorate D: Health Systems and Products
Unit D3 - Risk Assessment
Office: B232
B-1049 Brussels
Sanco-SCCS-Secretariat@ec.europa.eu

© European Union, 2012
ISSN 1831-4767

ISBN 978-92-79-30762-1

Doi:10.2772/83092

ND-AQ-12-012-EN-N

The opinions of the Scientific Committees present the views of the independent scientists
who are members of the committees. They do not necessarily reflect the views of the
European Commission. The opinions are published by the European Commission in their
original language only.
http://ec.europa.eu/health/scientific_committees/consumer_safety/index_en.htm

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ACKNOWLEDGMENTS

Prof. J. Angerer
Dr. U. Bernauer
Dr. C. Chambers
Prof. G. Degen
Dr. W. Lilienblum
Dr. E. Nielsen
Dr. S.C. Rastogi
Prof. V. Rogiers
Prof. T. Sanner
Dr. J. van Engelen
Prof. R. Waring
Dr. I.R. White

(rapporteur)
(associate scientific advisor)

(chairman)

Keywords: SCCS, scientific opinion, preservative,
76/768/ECC, CAS 2634-33-5, EC 220-120-9

benzisothiazolinone,

P96,

directive

Opinion to be cited as: SCCS (Scientific Committee on Consumer Safety), Opinion on
benzisothiazolinone, 26-27 June 2012

This opinion has been subject to a commenting period of four weeks after its initial
publication. Comments received during this time have been considered by the SCCS and
discussed in the subsequent plenary meeting. Where appropriate, the text of the relevant
sections of the opinion has been modified or explanations have been added. In the cases
where the SCCS after consideration and discussion of the comments, has decided to
maintain its initial views, the opinion (or the section concerned) has remained unchanged.
Revised opinions carry the date of revision.

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TABLE OF CONTENTS
ACKNOWLEDGMENTS ........................................................................................... 3
1.

BACKGROUND ............................................................................................. 5

2.

TERMS OF REFERENCE.................................................................................. 5

3.

OPINION..................................................................................................... 6
3.1.

Chemical and Physical Specifications....................................................... 6

3.1.1.
3.1.2.
3.1.3.
3.1.4.
3.1.5.
3.1.6.
3.1.7.
3.1.8.
3.1.9.
3.2.
Function
3.3.

Chemical identity ........................................................................ 6
Physical form ............................................................................. 6
Molecular weight ........................................................................ 6
Purity, composition and substance codes........................................ 7
Impurities / accompanying contaminants ....................................... 7
Solubility ................................................................................... 7
Partition coefficient (Log Pow) ...................................................... 8
Additional physical and chemical specifications................................ 8
Homogeneity and Stability ........................................................... 8
and uses ................................................................................ 8

Toxicological Evaluation ........................................................................ 9

4.

3.3.1.
Acute toxicity ............................................................................. 9
3.3.2
Irritation and corrosivity ............................................................ 10
3.3.3.
Skin sensitisation...................................................................... 13
3.3.4.
Dermal / percutaneous absorption............................................... 16
3.3.5.
Repeated dose toxicity .............................................................. 18
3.3.6.
Mutagenicity / Genotoxicity ........................................................ 20
3.3.7.
Carcinogenicity......................................................................... 23
3.3.8.
Reproductive toxicity................................................................. 23
3.3.9.
Toxicokinetics .......................................................................... 25
3.3.10.
Photo-induced toxicity ............................................................... 25
3.3.11.
Human data ............................................................................. 25
3.3.12.
Special investigations ................................................................ 26
3.3.13.
Safety evaluation (including calculation of the MoS)....................... 26
3.3.14.
Discussion ............................................................................... 26
CONCLUSION ............................................................................................ 28

5.

MINORITY OPINION.................................................................................... 28

6.

REFERENCES ............................................................................................. 29

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1. BACKGROUND
1,2-Benzisothiazol-3(2H)-one (CAS No 2634-33-5, EC No 220-120-9) with the INCI name
benzisothiazolinone is currently not listed in Annex VI of the Cosmetics Directive and
therefore cannot be used as preservative.
COLIPA has requested the inclusion of benzisothiazolinone in Annex VI in order to allow the
use of benzisothiazolinone in cosmetic products.
A first scientific opinion (SCCNFP/0811/04) was adopted 1 July 2004 by the Scientific
Committee on Cosmetic Products and Non-Food Products intended for Consumers with the
following opinion:
"The SCCNFP is of the opinion that the information submitted is insufficient to assess the
safe use of benzisothiazolinone.
Before any further consideration, the following information is required:
*
*

percutaneous absorption study in accordance with the SCCNFP Notes of Guidance;
reproduction toxicity data."

The present submission II provides the data requested by this opinion.

2. TERMS OF REFERENCE
1.

Does SCCS consider benzisothiazolinone safe when used as a preservative up to a
maximum authorised concentration of 0.01% in cosmetic products, based on the
provided data?

2.

And/or does the SCCS have any scientific concern with regard to the use of
benzisothiazolinone in cosmetic products?

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3. OPINION
3.1. Chemical and Physical Specifications
Benzisothiazolinone is listed in the EU Cosmetics Inventory, Section 1 with indicated
function "antimicrobial". It is currently not regulated in the annexes of the Cosmetics
Directive 76/768/EEC.
3.1.1.

Chemical identity

3.1.1.1.

Primary name and/or INCI name

Benzisothiazolinone (INCI)
3.1.1.2.

Chemical names

1,2-Benzisothiazol-3(2H)-one (IUPAC)
1,2-Benzisothiazol-3-one
1,2-Benzisothiazolin-3-one
Benzo[a]isothiazol-3-one
3.1.1.3.

Trade names and abbreviations

BIT; Thor BIT; ACTIDE® BIT; Microcare® BIT; Nuosept BIT Technical; Promex BIT
COLIPA P96
3.1.1.4.

CAS / EC number

CAS:
EC:

2634-33-5
220-120-9

3.1.1.5.

Structural formula

3.1.1.6.

Empirical formula

Formula:

C7H5NOS

3.1.2.

Physical form

Off-white to yellowish solid
3.1.3.

Molecular weight

Molecular weight:

151.19 g/mol

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3.1.4.

Purity, composition and substance codes

Substance code:
Batches used:
Purity:
Loss on drying:
Water content:
Ash content:
Sodium chloride:
Lead:
Mercury:
Arsenic:
Iron:

/
batch no 2001 014
74.02-84.02% w/w (84% corresponds to 15% water content)
> 99% w/w on a dry basis
/
15-29% w/w (for batch no 2001 014 spec., 20% max, found 15%)
/
< 0.1% w/w (for batch no 2001 014 spec., 0.2% max, found 0.02%)
/
/
/
/

Impurities
•

5-Chloro-1,2-benzisothiazolin-3(2H)-one:
0.15-0.22% w/w
(for batch no 2001 014, specification 4 ppm max, found 3 ppm)

CAS: 4337-43-3
EC: 224-385-1
emp. Formula: C7H4ClNOS
•

2,2-Dichlorobisbenzamide: < 0.1% w/w
(for batch no 2001 014, specification 0.5% max, found 0.03%)

CAS: 2527-57-3
EC: 219-766-4
emp. Formula: C14H12N2O2S2
Residual solvents:
3.1.5.

/

Impurities / accompanying contaminants

See 3.1.4.
3.1.6.

Solubility

Solubility in water:

1.1 g/l (0.11%) at 20 °C
6.0 g/l (0.60%) at 30 °C (Directive 92/69/EEC, A6)

Effect of pH and temperature on solubility in water (OECD Guideline 105)
at 10 °C and pH 4.8: 0.736 g/l
at 20 °C and pH 4.8: 0.938 g/l
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at 30 °C and pH 4.8: 1.198 g/l
at 20 °C and pH 6.7: 1.288 g/l
at 20 °C and pH 9.1: 1.651 g/l
3.1.7.

Partition coefficient (Log Pow)

Log Pow:

0.4 at 20 °C (OECD Guideline 117)

Effect of pH and temperature on Log Pow (OECD Guideline 117 (HPLC))
Log
Log
Log
Log
Log

Pow:
Pow:
Pow:
Pow:
Pow:

0.99 at 20 °C and pH 5
0.63 at 10 °C and at pH 7
0.70 at 20 °C and pH 7
0.76 at 30 °C and pH 7
– 0.90 at 20 °C and pH 9

Conclusions
With increasing pH from 5 to 9, the Log Pow decreases very strongly. Only a slight increase
of Log Pow is observed between 10 °C and 30 °C.
3.1.8.

Additional physical and chemical specifications

Melting point:
Boiling point:
Density:
Vapour Pressure:
pKa:
Flash point:
Viscosity:
Refractive index:
UV_Vis spectrum (200-800 nm):
3.1.9.

156.6 °C (Directive 92/69/EEC, A1)
327.6 °C (Directive 84/449/EEC, A2)
1.483 g/cm³ at 20 °C (OECD Guideline 109)
0.0000037 hPa at 25 °C (Directive 92/69/EEC, A4)
7.3 at 25 °C
/
/
/
/

Homogeneity and Stability

No data
General Comments to physico-chemical characterisation
No data on stability are provided
3.2. Function and uses
Benzisothiazolinone is listed in the EU Cosmetics Inventory, Section 1 with indicated
function "antimicrobial". It is currently not regulated in the annexes of the Cosmetics
Directive 76/768/EEC.
The submitted dossier requests a maximum level of 100 ppm as preservative in cosmetic
products. This is greater than the level proposed in the earlier submission, which the
applicant justifies with the availability of more recent studies, demonstration of a greater
margin of safety.
Aside from its use in cosmetic products, there are also other uses:
Under the Biocide review programme for existing substances (Commission Regulation (EC)
No 1451/2007), Benzisothiazolinone is examined for use in the following product types:

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Private area and public health area disinfectants and other biocidal products (2), In-can
preservatives (6), Film preservatives (7), Fibre, leather, rubber and polymerised materials
preservatives (9), Masonry preservatives (10), Preservatives for liquid-cooling and
processing systems (11), Slimicides (12), Metalworking-fluid preservatives (13), Embalming
and taxidermist fluids (22).
Benzisothiazolinone is used as a slimicide in the manufacture of disposable powder-free
polyvinyl chloride gloves.
(Add. ref. 41)
Benzisothiazolinone is widely used in industry as a preservative in water-based solutions
such as pastes, paints and cutting oils.
(Add. ref. 42, 43)

3.3. Toxicological Evaluation
Throughout the studies quoted (unless otherwise specified) the purity of the test material
used was 99.02%, with an active content of 70.02 to 84.02% w/w, water content of 15% to
29% w/w and total impurities of 0.26 to 0.33% w/w.
3.3.1.

Acute toxicity

3.3.1.1.

Acute oral toxicity

Taken from SCCNFP/08441/04
Guideline:
Method:
Species/strain:
Group size:
Test item:
Test substance:
Batch:
Purity:
Dose:
Vehicle:
Route:
GLP:

/
EPA OPP 81-1
Rat, Sprague-Dawley derived, albino
30 (3 groups of 5 males and 5 females each)
Benzisothiazolinone
Nuosept BIT Technical
# 170-138 (PSL Code no E50629-1R (powder)
1,2-Benzisothiazolin-3-one 82.3%; water 17.7%
1000, 2000 and 5000 mg/kg bw/day test substance (823, 1646 and
4115 mg/kg active ingredient)
Water; the test substance was applied as 40% w/w suspension in water
oral intubation/gavage
in compliance

Results
Based on the findings, the Acute Oral Defined LD50 of Nuosept BIT Technical, Lot #170-138
calculated by Probit Analysis was 1450 milligrams of the test substance per kilogram of
bodyweight (when administered as a 40% w/w suspension in distilled water) with 95%
Confidence Limits of 2004 mg/kg bw (upper) and 1.049 mg/kg bw (lower). The LD50 for
males was 2.100 mg/kg bw with 95% Confidence Limits of 5.029 mg/kg bw (upper) and
877 mg/kg bw (lower). The data does not permit calculation of the LD50 for females by
Probit Analysis. Graphically, the LD50 for females was estimated to be 1.050 mg/kg bw.
Ref.: 10

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3.3.1.2.

Acute dermal toxicity

Taken from SCCNFP/08441/04
Guideline:
Method:
Species/strain:
Group size:
Test item:
Test substance:
Batch:
Purity:
Dose:
Vehicle:
Route:
Exposure period:
GLP:

/
EPA OPP 81-2
rat, Sprague-Dawley derived, albino
10 (5 male/5 female)
benzisothiazolinone
nuosept BIT Technical
# 170-138 (PSL Code no E50629-1R (powder)
1,2-Benzisothiazolin-3-one 82.3%; water 17.7%
5000 mg/kg bw/day (Limit test) (4115 mg/kg active ingredient)
water; the test substance was moistened with water for application (1
ml water/1 g test substance)
topical application (24 h)
1 x 24 h. observation period 14 d
in compliance

Results
An Acute Dermal Toxicity test was conducted with rats to determine the potential for
Nuosept Bit Technical, Lot # 170-138 to produce toxicity after topical application. Based on
the results of testing, the single dose Acute Dermal Toxicity LD50 of the test substance is
greater than 5000 mg/kg bw when applied as received, moistened with distilled water.
5000 mg of the test substance per kilogram of bodyweight was moistened with distilled
water and applied to the skin of ten healthy rats (224-232 g) for 24 hours. The animals
were observed for signs of gross toxicity and mortality at least once daily for another 14
days. Bodyweights were recorded just prior to application and again on days 7 and 14
(termination). Necropsies were performed on all animals at terminal sacrifice.
All animals survived, gained weight and appeared active and healthy during the study.
There were no signs of gross toxicity, adverse pharmacologic effects or abnormal behaviour.
Gross necropsy findings at terminal sacrifice were generally unremarkable.
Ref.: 11
3.3.1.3.

Acute inhalation toxicity

No data submitted
3.3.2

Irritation and corrosivity

3.3.2.1.

Skin irritation

Taken from SCCNFP/08441/04 (with some modifications)
Guideline:
Method:
Species/strain:
Group size:
Test substance:
Batch:
Purity:
Dose:
Exposure:
Exposure time:
Readings:
GLP:

/
EPA OPP 81-5
New Zealand albino rabbits
6, 3 males and 3 females
Nuosept BIT Technical
# 170-138
1,2-Benzisothiazolin-3-one, 82.3%; Water, 17.7%
Slurry of 0.5 g in 0.5 ml water
Semi occlusive
4 hour(s)
1, 24, 48, 72 hours and 7 days
in compliance
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Date:

1995

Results
The test substance was moistened with water for application (0.5 ml water/0.5 g test
substance =41.15% a.i.). One hour after patch removal, well-defined moderate erythema
and oedema was noted at all treated sites. This decreased with time. Desquamation
occurred at one site and all animals were free of erythema and oedema by day 7.
Conclusion
Nuosept BIT Technical (Benzisothiazolinone) is a skin irritant.
Ref.: 15
Human study
50 healthy human volunteers (20 males and 30 females aged between 19-60 years) were
recruited for a randomised double blind open epicutaneous application study to compare the
effects of a cream with and without the preservative Microcare® SI. The protocol was
approved by an independent ethics committee and the test was performed in compliance
with the principles of the Declaration of Helsinki. The test substance was Microcare® SI - an
aqueous blend of 2.5% of methylisothiazolinone (MIT) and 2.5% of benzisothiazolinone
(BIT).
The test cream contained Microcare® SI at a level of 0.3% w/w of which 0.15% w/w (75
ppm) was 1,2-benzisothiazolinone. Analysis of the test products showed that the
formulation contained slightly lower concentrations of isothiazolinones than expected,
equivalent to an addition rate of 0.2-0.25%, such as would be used in cosmetic
applications.
Subjects with known sensitivity to isothiazolinones were excluded. 47 subjects completed
the study as planned, and diary cards and product weights were available. Three subjects
withdraw for reasons not related to the study. The test subjects applied twice daily for 4
weeks 1.5 ml of test cream and vehicle to the inner aspects of both forearms in a
randomised and blinded fashion. The test sites were assessed after 2 and 4 weeks and the
skin reactions scored according to a 5 point ranking scale.
Results
7 subjects reported redness or itching, tingling or stinging sensation upon application of the
test cream. The reaction was reported to disappear after the product had been ‘absorbed’
into the skin. Determining causation demonstrated that all 7 subjects experienced
sensations following application of the base cream whereas only 5 experienced sensations
following the test cream.
Conclusion
A skin cream preserved with a mixture of MIT/BIT 1:1 at a concentration of 75 ppm of each
active was tolerated as well as the vehicle cream under the conditions of the test.
Ref.: 22
3.3.2.2.

Mucous membrane irritation

Taken from SCCNFP/08441/04
Guideline:
Method:
Species/strain:
Group size:
Test substance:
Batch:
Purity:

/
EPA OPP 81-4
New Zealand albino rabbits
9 (4 males and 5 females)
Nuosept BIT Technical
# 170-138
1,2-Benzisothiazolin-3-one, 82.3%; Water, 17.7%
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Dose:
Exposure time:
GLP:
Date:

0.1 g of the undiluted test substance was instilled into the right eye. The
treated eyes of 3 rabbits were rinsed 20-30 seconds after instillation;
the eyes of the remaining 6 animals were not rinsed.
48 hours
in compliance
1995

Results
From 1 to 48 hours, all treated eyes exhibited severe to maximal irritation including corneal
opacity, iritis and conjunctivitis. Overall the severity of irritation increased with time. Due to
the irreversible nature of the irritation the test was terminated after 48 hours.
Conclusion
The test substance was severely irritating to the rabbit eye.

Ref.: 17

An assessment of the eye irritancy potential of 1,2-benzisothiazolin-3-one using
the Bovine Corneal Opacity and Permeability assay in vitro
Guideline:
Method:
Species:
Number corneas:
Test substance:
Batch:
Purity:
Dose:
Exposure time:
GLP:
Date:

/
INVITTOX Protocol 124
Bovine
45
1,2-Benzisothiazolin-3-one
LHW 1355
>99%
75, 750 and 7500 ppm aqueous solution of BIT prepared as its sodium
salt
10 minutes
in compliance
2003

Bovine eyes mounted on holders and incubated with Minimal Essential Medium (MEM) were
exposed to test article or positive or negative control. After 10 minutes exposure the
corneas were rinsed and again incubated with media.
Corneal opacity was measured with an opacimeter and corneal permeability was determined
using sodium fluorescein and measured spectrophotometrically. The corneal opacity and
permeability were combined to give an in-vitro score
Results
The mean in vitro score for BIT at 7500 ppm was 3.012, at 750 ppm 0.666 and at 75 ppm 0.207, compared with 0.490, 0.416 and 0.449 for saline (negative control) and 50.73,
50.23 and 50.25 for ethanol (positive control), respectively.
Conclusion
Benzisothiazolinone was considered to be non-irritant to the eye at all tested concentrations
in the BCOP assay under the conditions of the test.
Ref.: 18
Comment
The method used was not a validated in vitro method in 2003. Meanwhile, it is an OECD test
guideline (number) which can detect strong irritants.

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An assessment of the cytotoxicity of 1,2 benzisothiazolin-3-one by in vitro Neutral
Red Uptake Assay using BalbC 3T3 & SIRC mammalian cell lines
Guideline:
Species:
Test substance:
Batch:
Purity:
Dose:
Exposure time:
GLP:
Date:

/
BALB/c 3T3 Mouse fibroblast cell line
SIRC Rabbit corneal cell line
1,2-Benzisothiazolin-3-one
LHW 1355
> 99%
0-100 ppm range finding; 0-10 ppm testing
24 hours
in compliance
2002

Results
The effects of the test substance on cell viability of the two different cell lines was measured
by the neutral red uptake. A best-fit dose-response curve for each set of experiments was
calculated from the data using non-linear regression and the respective EC50 value was
calculated. The EC50 for 3T3 cells was 3.1414 ppm and that for SIRC cells was 3.6666.
These results may be compared with results previously obtained for other preservative
preparations, as illustrated in the following table demonstrating that BIT is less cytotoxic
than CIT/MIT, yet more cytotoxic than other commonly used preservatives.
Cytotoxicity values for cosmetic preservatives
Cosmetic Preservative
Chloromethylisothiazolinone/methylisothiazolinone (3:1)
Methylisothiazolinone
Methyldibromoglutaronitrile 20% (in phenoxyethanol)
Methyl/ethyl/propyl/butyl/isobutyl parabens in phenoxyethanol

EC50
3T3
1.19
5.76
28.4
439.5

EC50 SIRC
1.89
5.98
29.36
489.0

Ref.: 19
Comment
The SCCS considers the above cytotoxicity data of little value in its overall evaluation of the
safety of benzisothiazolinone.
3.3.3.

Skin sensitisation

Taken from SCCNFP/08441/04
Guinea Pig Maximization Test (Magnusson and Kligman)
Guideline:
Species/ strain:
Size:
Test substance:
Batch:
Purity:
Dosage:
Vehicle:
GLP:
Date:

OECD 406
Albino Dunkin Hartley guinea pigs
38 (20 test, 10 control, 8 range-finding)
1,2-benzisothiazolin-3-one 79.8%, water 19.2%
386-3
79.8% 1,2-benzisothiazolin-3-one (BIT), water, 19.2%
Diamide content 0.28%, PCP < 1 ppm.
1st induction 0.1% w/v intracutaneous
2nd induction 20% w/v occlusive epicutaneous
3rd challenge 10% w/v occlusive epicutaneous
corn seed oil (1st and 2nd concentration), FCA/water (1st
concentration), Ethanol (3rd concentration)
in compliance
1996
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Results
Results from 2 animals in range-finding studies indicated that 0.1% w/v in cottonseed oil
should be used for intradermal induction.
In topical range-finding studies in 4 animals, it was indicated that 20% in cottonseed oil was
minimally irritant and was suitable for topical induction. In further topical range-finding
studies in 2 animals it was found that 10% in ethanol was suitable for challenge.
Following challenge, 9 out of 20 animals in the test group reacted positively to 10% w/v
test article in ethanol at 24 or 48-hour examinations, giving a response incidence of 45%.
Conclusion
BIT is a moderate contact sensitizer.

Ref.: 20

Buehler Method
Guideline:
Method:
Species/strain:
Size:
Test substance:
Batch:
Purity:
Dosage:

Vehicle:
GLP:
Date:

/
EPA OPP 81-6
Hartley albino guinea pigs
8 for range finding, 30 for test protocol
Nuosept Bit technical (82.3% 1,2-Benzisothiazolin-3-one, water 17.7%)
#170-138
1,2-Benzisothiazolin-3-one (BIT) 82.3% a.i.
Induction: Weekly application of 0.3 g of test substance 95% w/w in
corn seed oil for 3 consecutive weeks.
Challenge: 14 days after last induction with same dose as induction to
naive site
Corn seed oil
in compliance
1995

Results
It was found that a 6 hour exposure under 25 mm Hilltop chambers to 95% w/w (78.19%
active) BIT powder in corn oil was suitable for the test group. 0.04% DNCB (dichloronitrobenzene) in acetone was used as the positive control.
No reaction was seen at any test or naive control site following challenge. 7/10 positive
control animals exhibited signs of reaction to challenge at 24 hours. This reaction persisted
in 5 animals at 48 hours.
Conclusion
Nuosept BIT Technical was not a sensitizer in this test.
Ref.: 21
Human study
15 healthy human volunteer patients (2 males and 13 females aged between 25-66 years)
were recruited for a randomised double blind open epicutaneous application study to
compare the effects of a cream with and without the preservative Microcare® SI. The
volunteer subjects were previously diagnosed as being sensitized to chloromethylisothiazolinone.
The test cream Doublebase™ contained Microcare® SI at a level of 0.3% w/w (150ppm) of
which 0.15% w/w (75ppm) was 1,2-benzisothiazolinone.
The test subjects were instructed to apply twice daily for 4 weeks 1-1.5 ml of test cream
and vehicle to the inner aspects of both forearms in a randomised and blinded fashion. They
were asked to complete a diary to record usage of the products, which were weighed at the
end of study.
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___________________________________________________________________________________________

Results
10 subjects completed the study as planned, and diary cards and product weights were
available. Three subjects were withdrawn from the study due to adverse reactions, 2
subjects after less than 7 days and 1 after 21 days. They all noticed flare of eczema on their
forearms. Two subjects were lost to follow up. After four weeks application, the frequency of
each assessment grade is summarised as follows.
Assessment
grading
Code
Withdrawn
No Assessment
No Visible Redness
Slight Redness
Distinct Redness
Total

Product

Product Code
1
3
2
9
0
1
15

2
3
2
10
0
0
15

There were three cases of flare of eczema related to the study preparations.
Two were associated with the application of product 1, and one with product 2.
Ref.: 23
Comments
The study included a low number of test subjects; there was no detailed description of their
existing chloromethylisothiazolinone (CMI) allergy, lack of assessment of skin reactions
under the 4 week study period, and a significant variation in product usage, from around 35
grams to 110 grams per test period. Limited conclusions can be drawn. The test products
seem to elicit dermatitis in some test subjects.
Local Lymph Node Assay and Human Repeat Insult Patch Test
The relative sensitising potencies and potential for cross sensitisation/reaction of
chloromethylisothiazolinone (CMI or CIT/MIT), methyl trimethylene isothiazolinone (MTI)
and benzisothiazolinone (BIT) were considered from newly generated and historical data.
However, although CMI was specifically mentioned, it was not stated whether the mixture of
chloromethylisothiazolinone with methylisothiazolinone was actually used. Original
experimental data were not provided in this review.
Using the LLNA, the EC3 for Benzisothiazolinone was established at 10.4%, that for MTI at
2% and CIT/MIT at 0.01%.
Using the HRIPT resulted in no reactions to BIT at 360 ppm and 9% of volunteers reacting
at 725 ppm. There were also no reactions to CMIT/MIT at 10 ppm and 4.4% reacted at 20
ppm. For MTI there were no reactions at 100 ppm but 16% reacted at 300 ppm.
Data are summarized:
Preservative
BIT
BIT
MTI
MTI
CIT/MIT
CIT/MIT

Test concentration
(ppm)
725
360
300
100
20
10

Proportion of human
panel sensitised (%)
5/58 (9%)
0/54 (0%)
3/19 (16%)
0/211(0%)
2/45 (4.4%)
0/175(0%)

LLNA EC3
10.4%
2.0%
0.007-0.01%

Ref.: 24
Comment
The HRIPT is not considered ethical.
15

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___________________________________________________________________________________________

Local Lymph Node Assay
An EC3 of 2.3% for 1,2-benzisothiazolin-3-one (CAS 2634-33-5) and 1.9% for 2-methyl2H-isothiazol-3-one (CAS 2682-20-4) is tabulated in a review but no experimental details
are provided.
(Add. ref.: 49)
Overall Comment Sensitisation
Benzisothiazolinone is a contact allergen with the guinea pig maximization (Magnusson
Kligman) test indicating BIT as a moderate sensitiser, as does the LLNA with an EC3 of
2.3% for BIT.
Since the human in-use study provided by the applicant included a low number of subjects,
only limited conclusions could be drawn. Therefore, the SCCS conducted a literature search
on the sensitising potential of benzisothiazolinone in humans. From the dermatological
literature case reports describe allergic contact dermatitis to benzisothiazolinone. It is a
well-documented contact allergen. However, its potency is lower than other marketed
cosmetic preservatives, and the irritancy profile makes it a difficult contact allergen to test
with.
(Add. ref.: 37, 38, 39, 40)
Benzisothiazolinone is widely used in industry as a preservative in water-based solutions
such as pastes, paints and cutting oils. Occupational dermatitis has been reported mainly
due to cutting fluids, paint manufacture, pottery mould-makers, acrylic emulsions
manufacture, printers, paper makers etc. which contain benzisothiazolinone.
(Add. ref. 42, 44, 45, 46, 47, 48)
Moreover, benzisothiazolinone is used as a slimicide in the manufacture of disposable
powder-free polyvinyl chloride (PVC) gloves. Of 31 glove brands studied 9 (30%) contained
3–26 ppm benzisothiazolinone. Individuals wearing such gloves developed allergic contact
dermatitis. A concentration of 20 ppm benzisothiazolinone in a glove seems to be enough
for sensitization.
(Add. ref. 41)
3.3.4.

Dermal / percutaneous absorption

New study
Guideline:
Species/strain:
Group size:
Method
Membrane integrity
Test substance:
Batch:
Purity:
Radiochemical
Vehicle:
Test item:
Dose volume:
Receptor
Solubility
Method of Analysis:
GLP:
Study period:

OECD 428
human skin (5 abdominal, 1 breast); 400 μm dermatomed skin
10 membranes
flow through diffusion cell
Tritiated water
benzisothiazolinone
12409EE
97%
14
C benzisothiazolinone; 99.9%
water
0.01% w/v benzisothiazolinone aqueous
20 μl/cm2
Tissue culture medium containing 6% PEG, 0.01% sodium azide,
1% glucose and streptomycin
(in water) 1 mg/ml
liquid scintillation
in compliance
2008
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___________________________________________________________________________________________

The absorption of radiolabelled 0.01% w/v benzisothiazolinone in aqueous solution was
determined from the use of 10 chambers with human dermatomed skin.

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___________________________________________________________________________________________

Conclusion
Following topical application of [14C]-Benzisothiazolinone in water (0.01%, w/v) to human
skin, the absorbed dose of [14C]-Benzisothiazolinone was 25.63% (0.54 μg equiv./cm2). The
dermal delivery of [14C]-Benzisothiazolinone was 49.83% (1.04 μg equiv./cm2). The total
dislodgeable dose was 42.05% of the applied dose.
Ref.: 36
Comment
This was a properly performed study. Therefore, the mean + 1SD may be used for
calculating the MOS. This is 61.9% of the applied dose (1.29 μg/cm2) when 0.01%
benzisothiazolinone aqueous was applied. The dermal absorption studies had not been
performed with representative cosmetic formulations.
3.3.5.

Repeated dose toxicity

3.3.5.1.

Repeated Dose (28 days) oral toxicity

Taken from SCCNFP/08441/04 (with modifications)
Guideline:
Species/strain:
Group size:
Test item:
Test substance:
Purity:
Batch:
Dose levels:
Route:
Exposure period:
GLP:
Date:

OECD 407
Rat, Wistar Hsd Cpb:WU
12 (6 male/6 female)
Benzisothiazolinone, Code 072/1-PBP
Promex BIT (paste)
1,2-Benzisothiazolin-3-one, 84.29%; water, 15%, purity of active
ingredient on dry weight basis, 99.02%
2001 014//sample no. KP 070601//cb 181100
0, 15, 45 and 135 mg/kg bw/day (12.63, 37.89 and 113.67 mg/kg a.i.),
suspended in 0.5% CMC
daily oral intubation/gavage
28 days
in compliance
2001

Results

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Oral administration of 1,2-Benzisothiazolin-3-one, by gavage in Wistar rats at the dose of
15 mg/kg bw/day (12.63 mg a.i./kg bw/day) had no adverse effect on general health,
neurological effects, growth, food consumption, haematological and clinical chemistry
parameters, organ weights and its ratios, gross and histopathological changes.
Treatment related signs of slight salivation were observed in all the males in the main group
at 135 mg/kg bw/day and its recovery group from treatment day 17 and in two females
from the test group and two in the recovery group from treatment day 20 till the end of the
treatment period. During the recovery period, treatment related signs of salivation were not
observed in the 135 mg/kg bw/day group indicating the reversibility of the effect.
Body weight was unaffected in the 15 and 45 mg/kg bw/day groups. At 135 mg/kg bw/day
there was a significant decrease in body weight and cumulative net weight gain in the male
group throughout the treatment period with the exception of the first week where it was not
statistically significant.
Weekly body weights were significantly lower throughout the treatment and recovery period
in the high dose (135 mg/kg bw/day) for males and on weeks 4, 5, and 6 for females.
Cumulative net weight gains were also significantly lower throughout the treatment and
recovery period in males and females with the exception of the first week where it was not
statistically significant.
Increased incidences of histopathological lesions in the non-glandular stomach
(hyperkeratosis, epithelial hyperplasia, ulceration) were observed in mid- (45 mg/kg
bw/day) and high-dose (135 mg/kg bw/day) males and females. The severity of the lesions
was reduced in the high-dose recovery group.
The NOAEL in this study was 15 mg/kg bw/day (12.63 mg a.i./kg bw/day).
Ref.: 12
Comment
The SCCS noted that the NOAEL of 15 mg/kg bw/day (12.63 mg a.i./kg bw/day) was based
on the histopathological lesions observed in the non-glandular stomach, which are most
likely due to the irritant property of the test substance.
3.3.5.2.

Sub-chronic (90 days) toxicity (oral, dermal)

Taken from SCCNFP/08441/04
Guideline:
Species/strain:
Group size:
Test item:
Batch:
Purity:
Dose levels:
Vehicle:
Route:
Exposure period:
GLP:
Study period:

OECD 408
Rat, Wistar
Total 20; 10 male/10 female
Benzisothiazolinone (Promex-BIT)
G00Z-0600-1907-13//072/1.PBP//2001 014//KP 070601
1,2-Benzisothiazolin-3-one, 84.29%; water 15%; purity of active
ingredient on dry weight base 99.1%
10, 30 and 75 mg/kg bw/day (8.42, 25.26 and 63.15 mg/kg bw/day
a.i.)
0.5% carboxymethylcellulose (CMC)
daily oral intubation/gavage
90 days
in compliance
2001-2002

Results
The oral administration of 1,2-Benzisothiazolin-3-one by gavage in Wistar rats at the dose
of 10 mg/kg bw/day (8.42 mg a.i./kg bw/day) had no adverse effect on general health,
neurological effects, growth, food consumption, haematological and clinical chemistry
parameters, sperm evaluation, organ weights and its ratios and gross and histopathological
changes.

19

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___________________________________________________________________________________________

At 30 mg/kg bw/day (25.26 mg a.i./kg bw/day) there were no treatment related clinical
signs or neurological effects and no adverse effects on growth, haematological and clinical
chemistry parameters, sperm evaluation, organ weights and its ratios. Food consumption
was lower in females in weeks 2 and 4. There were some changes primarily in the nonglandular stomach region both macroscopically and histologically which were considered
treatment related and were reversible. These effects may have been due to the irritant
nature to the test substance. Increased incidences of histopathological lesions in the nonglandular stomach (hyperkeratosis, epithelial hyperplasia, ulceration) were observed in
males and females.
At 75 mg/kg bw/day (63.15 mg a.i./kg bw/day) there were no treatment related
neurological effects and no adverse effects on haematological and clinical chemistry
parameters, sperm evaluation, organ weights and its ratios. Treatment related signs of
slight salivation were observed in four males and three females in the main group and in
three males and five females in the recovery group during the treatment period. During the
recovery period, treatment related signs of salivation were not observed indicating the
reversibility of the effect. Weekly body weights and cumulative net weight gains were
significantly lower in males throughout the treatment and recovery period except for the
body weight at week 3 which were lower but not statistically significant. The body weight
gains were significantly higher in males and in females (weeks 15, 16 and 17) during the
recovery period. There was a significant reduction in food consumption in males (weeks 1,
2, 7, 8, 12 and 13) and in females (weeks 1, 2 and 4), which returned to control levels in
the recovery period.
Increased incidences of histopathological lesions in the non-glandular stomach (hyperkeratosis, epithelial hyperplasia, ulceration, keratin cysts) were observed in males and females.
The severity of the lesions was reduced in the recovery group.
The NOAEL in this study was 10 mg/kg bw/day (8.42 mg a.i./kg bw/day).

Ref.: 13

Comment
The SCCS noted that the NOAEL of 10 mg/kg bw/day (8.42 mg a.i./kg bw/day) was based
on the histopathological lesions observed in the non-glandular stomach, which are most
likely due to the irritant property of the test substance.
Therefore, the NOAEL is 25.26 mg a.i./kg bw/day based on systemic effects.
3.3.5.3.

Chronic (> 12 months) toxicity

No data submitted
3.3.6.

Mutagenicity / Genotoxicity

3.3.6.1

Mutagenicity / Genotoxicity in vitro

Taken from SCCNFP/08441/04
Bacterial Reverse Mutation Assay
Guideline:
Species/strain:
Test substance:
Batch:
Lot number:
Purity:
Concentrations:

OECD 471 (1997)
Salmonella typhimurium TA98, TA1537, TA100, TA1535
Escherichia coli WP2uvrA pkM 101
Promex BIT 1,2–Benzisothiazolin-3-one
2001 014
KP 070601
99.02%
0, 20, 35, 60, 100 and 175 μg/plate (1st experiment)
0, 30, 50, 75, 120 and 180 μg/plate (2nd experiment)
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Replicate:
Positive controls:
Metabolic activation:
GLP:
Date:

3 plates/concentration
according to guideline
Aroclor induced rat liver homogenate
in compliance
2001

Results
Toxicity: in a preliminary study with a series of concentrations up to 5000 μg/plate, there
was a decrease in the mean number of revertants from the concentrations up to 160
μg/plate.
Mutagenicity: only the lowest doses could be evaluated in comparison with the untreated
plates (10-20 μg/plate).
The study cannot be used for the evaluation due to the high toxicity of the test item
towards the bacterial cells.
Ref.: 25
In vitro Mammalian Cell Gene Mutation Test
Guideline:
Species/strain:
Test substance:
Batch:
Lot number:
Purity:
Concentrations:
Treatment time:
Replicate:
Positive controls:
Metabolic activation:
GLP:
Date:

OECD 476 (1997)
CHO-K1 (Chinese hamster ovary cells) HPRT locus
Promex BIT; 1,2-Benzisothiazolin-3-one
2001 014
KP 070601
99.02%
0, 0.65, 1.30, 2.60, 5.20 μg/ml
5 hours, with and without metabolic activation
2 experiments in the same conditions.
B(a)P; EMS
Aroclor 1254 induced rat liver homogenate.
in compliance
2002

Results
Toxicity: in the presence of metabolic activation a toxic effect produced by the test item
between 4 and 6 μg/ml was observed; in the absence of metabolic activation a toxic effect
produced by the test item was observed between 2 and 4 μg/ml. The toxic doses reduced
the survival to less than 50% of the untreated cells.
Mutagenicity: there was no increase of mutants in the treatment with the test substance, in
the presence and in the absence of metabolic activation after 5 hours of treatment.
In the absence of metabolic activation, a treatment of 20 hours was not performed as
suggested by the guideline.
The study indicates that the test item is not mutagenic in the condition of the test.
Ref. 26
In vitro Mammalian Chromosome Aberration test
Guideline:
Species/strain:
Test substance:
Batch:
Lot number:
Purity:
Concentrations:
Replicate:

OECD 473 (1997)
CHO-K1 cell line (Chinese hamster ovary cells)
Promex BIT; 1,2–Benzisothiazolin-3-one
2001 014
KP 070601
99.02%
0, 1.6, 3.2, 6.4 μg/ml in the presence of S9-mix
0, 1.25, 2.50, 5.0 μg/ml in the absence of S9-mix
2 experiments (200 metaphases analysed)
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Treatment time:
Positive controls:
Metabolic activation:
GLP:
Date:

1st experiment: 3 hours
2nd experiment: 3 hours, in the presence of S9-mix; 19 hours, in
the absence of S9-mix
CPA (55 μg/ml); EMS (600 μg/ml)
Aroclor 1254 induced rat live homogenate
in compliance
2001

Results
Toxicity: 2 preliminary experiments showed that the test item was toxic at concentrations
between 75 and 5000 μg/ml and between 14 and 58.94 μg/ml.
Clastogenicity: the test item induced chromosome aberrations at the maximum tested dose
in the presence of a metabolic activation, and at all concentrations, in the absence of a
metabolic activation system.
The test item is clastogenic in CHO mammalian cells.
Ref.: 27
3.3.6.2

Mutagenicity / Genotoxicity in vivo

Taken from SCCNFP/08441/04
Mammalian Erythrocyte Micronucleus Test
Guideline:
Species/strain:
Test substance:
Batch:
Lot number:
Purity:
Doses:
Treatment:
Positive control:
GLP:
Date:

OECD 474 (1997)
Swiss albino mice-HsdOla: MF1 strain
Promex BIT; 1,2–Benzisothiazolin-3-one
2001 014
KP 070601
99.02%
63.15; 126.3; 210.5 mg/kg a.i.
oral (gavage) twice, at 24 hours of interval. The animals were sacrificed
24 hours after the second treatment.
CPA, 40 mg/kg bw, oral treatment
in compliance
2001

Results
Toxicity: in a preliminary test, a dose of 250 mg/kg bw was found not toxic (no clinical
signs), whereas 450 and 900 mg/kg bw were toxic.
Clastogenicity: in all treated mice, there was a reduction of the ratio PCE/NCE, thus
indicating that the test item has reached the target cells.
The positive control, CPA, induced a number of MN significantly higher than the untreated
animals. The test item did not induce a number of MN higher than the untreated animals.
The test item is not clastogenic in mice, treated in vivo.
Ref.: 28
Unscheduled DNA Synthesis (UDS) Test with Mammalian Liver Cells In Vivo
Guideline:
Species/strain:
Test substance:
Batch:
Purity:
Doses:
Treatment times:

OECD 486 (1997)
Wistar Hanlbm: WIST (SPF) rats
Promex BIT
2001014
99.02%
0 (corn oil), 375, 750 mg a.i./kg bw
2 hours, 16 hours, orally, once

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Positive controls:
GLP:
Date:

N,N’-dimethylhydrazine dihidrochloride (DMH): 40 mg/kg bw; 2 hours 2acetylaminofluorene (2-AAF): 100 mg/kg bw; 16 hours.
in compliance
2002

Results
Toxicity: in preliminary experiments, doses of 1200 and 1000 mg a.i./kg bw were found
toxic to the animals.
DNA repair: autoradiography was done on at least three cultures of hepatocytes per
animals.
There was no indication of induction of UDS by the test item. The two positive controls
induced a significant increase of UDS.
The test item does not induce UDS in rat hepatocytes in in vivo treatment.
Ref.: 29
3.3.7.

Carcinogenicity

No data submitted
3.3.8.

Reproductive toxicity

3.3.8.1.

Two generation reproduction toxicity study

Guideline:
Species/strain:
Group size:
Test substance:
Batch:
Purity:
Dose levels:
Route:
Administration:
Control:
GLP statement:
Study period:

EPA Health Effects Test Guidelines OPPTS 870.3800, of aug 1998
Crl:W1 (Glx/BRL/Han)BR
24 males and 24 females (P generation)
Proxel Press Paste (1,2-Benzisothiazolin-3-one)
No. 103 and No. 344
Purity of active ingredient: 92.7% +/- 1.1%
P generation: 250, 500 and 1000 ppm
F1 generation: 250, 500 1000 ppm
oral
dietary
control diet only
Yes
2000-2001

Study design
Groups of 24 male and 24 female rats were given Proxel Press Paste by admixture with the
diet, at dose levels of 250, 500 and 1000 ppm. A similar group received the control diet
only. The animals received the test diet for 10 weeks before being paired for up to 2 weeks.
Dosing continued during this pairing period, and throughout the resulting pregnancies. The
P generation females were allowed to litter and rear their offspring (F1a) until weaning.
Administration of the test article continued throughout the weaning of the F1 offspring up
until necropsy.
24 animals of each sex were randomly selected from each group to form the filial (F1)
generation. Direct treatment of the F1 generation continued during their maturation period
(10 weeks), the mating period (up to two weeks) and throughout the resulting pregnancies
and weaning of the F2 offspring until necropsy. All F1 females were allowed to litter and
rear their F2a offspring to weaning.
Result
Analysis of samples from the diets prepared for administration in weeks 1, 17 and 19 of the
study showed that the achieved concentrations were within the target range (all values
within 89 to 110% of nominal). Analysis of samples from the diets prepared for

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___________________________________________________________________________________________

administration in weeks 34, 36, 37 and 38 of the study showed that the achieved
concentrations were below the target range.

P Generation: Clinical observations, body weights and food intakes were unaffected by
treatment. Mating data, duration of gestation, number of implantations, numbers of pups
born and pup survival were similar in all groups.
Mean pup weight of the high dose pups was slightly lower than the control over the first
week post-partum. But, over the whole lactation period, mean pup weight was similar in all
groups.
There were no adverse effects of treatment on seminology data.
In the high dose group, mean liver weight of the males was slightly higher, and mean testes
weight slightly lower than control.
Minor limiting ridge hyperplasia in the stomach was noted in some intermediate and many
high dose animals. Squamous cell hyperplasia and forestomach gastritis was also seen in a
few animals.
F1 Generation: Males in the high dose group gained slightly less weight than the controls
during the study and the high dose females gained slightly less weight during the prepairing period only. Clinical observations and food intakes were unaffected by treatment.
Physical development of the F1 generation, mating data, duration of gestation and F2a pup
sex ratio were unaffected by treatment. Pup survival to day 4 post-partum and mean pup
weight gain were slightly lower in the high dose group compared to controls. Seminology
investigations, organ weights and ovarian follicle counts were unaffected by treatment.
In the intermediate and high dose groups, limiting ridge hyperplasia in the stomach was
noted. This was most prominent in the high dose females where there was also squamous
cell hyperplasia, fore stomach gastritis, hyperkeratosis and erosion/ulcer.
Conclusion
Dietary administration of 1000 ppm PROXEL Press Paste to rats for two generations
produced slight adult toxicity, in the F1 generation in terms of lower body weight gain, and
in both generations limiting ridge hyperplasia of the stomach together with incidences of
squamous cell hyperplasia, forestomach gastritis, hyperkeratosis and erosion/ulcer. At this
concentration, the growth of the offspring was slightly impaired and in the F2a offspring,
there was a slight reduction in pup survival.
At 500 ppm, there were incidences of limiting ridge hyperplasia in the stomach only.
There were no adverse effects of treatment at 250 ppm, equivalent to an approximate
overall mean intake of 24 mg/kg bw/day.
Note: The dose levels refer to the concentration of the active ingredient (BIT) and a
correction factor of 1.074 was made for the stated purity of the PROXEL.
Ref.: 14
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Comments
No significant effects were reported for the reproductive parameters at any dose level and
only slight effects were noted in the offspring at the highest dose level (slightly lower pup
survival to day 4 post-partum and slightly lower mean pup weight gain).
Based on this study, a NOAEL of approximately 50 mg a.i./kg bw/day is used as a
conservative estimate for the MOS calculation. This NOAEL is lower than the lowest LOAEL
for systemic effects (63 mg a.i./kg bw/day) in the 90-day study.
3.3.8.2.

Teratogenicity

No evidence for teratogenicity in the two-generation oral reprotoxicity study

3.3.9.

Ref.: 14

Toxicokinetics

No data provided.
3.3.10.

Photo-induced toxicity

3.3.10.1.

Phototoxicity / photoirritation and photosensitisation

Guideline:
Test:
Test substance:
Batch:
Purity:
UV-A Irradiation:
Concentrations:
Replicate:
Positive control:
GLP:
Date:

OECD Test guideline 432
Neutral Red uptake phototoxicity test with Balb/c 3T3 cells
1,2–Benzisothiazolin-3-one
LMS 414, CH-0405-ST-7
> 99%
SOL-500 lamp fitted with a H1-filter mounted at a distance of 60 cm
to achieve an UV-irradiance of 5 J/cm2
0, eight concentrations between 0.2 to 50 µg/mL in the presence and
absence of UV-A exposure
3 main experiments
Chlorpromazine
in compliance
2004

Results
The 3T3 NRU phototoxicity assay was performed on four occasions for BIT, once as a range
finding experiment and three times as main experiment. The PIF values calculated from the
results for BIT range between 1.197 and 2.166 with a mean value of 1.54. The positive
control chlorpromazine yielded PIF values of about 100.
Conclusion
1,2 Benzisothiazol-3(2H)-one is predicted to be non-phototoxic by the 3T3 NRU PT assay
OECD Test Guideline 432
Ref.: 16
3.3.10.2.

Phototoxicity / photomutagenicity / photoclastogenicity

No data submitted
3.3.11.

Human data

See section 3.3.3. Sensitisation

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3.3.12.

Special investigations

No data submitted
3.3.13.

Safety evaluation (including calculation of the MoS)
CALCULATION OF THE MARGIN OF SAFETY
Benzisothiazolinone

Daily exposure to all cosmetic products (excl. sunscreens) =
Concentration Benzisothiazolinone (BIT)
=
Daily exposure BIT
=
Dermal absorption
=
Typical body weight of human
=
Systemic exposure dose
=
No Observed Adverse Effect Level
=
(2-generation-study, oral, rat)
NOAEL corrected for 50% oral bioavailability
=

17.4 g/d
0.01%
1.74 mg
61.9%
60 kg
0.018 mg/kg bw/d
50 mg/kg bw/d

Margin of Safety

1392

3.3.14.

NOAEL/SED

=

25 mg/kg bw/d

Discussion

Physico-chemical properties
Benzisothiazolinone is an off-white to yellowish solid that is soluble in water (1.1 g/L at
20°C); its log Pow shows a significant dependence on the pH. No data on stability are
provided.
Irritation, sensitisation
According to a study conducted in rabbits benzisothiazolinone (BIT) can be classified as a
moderate irritant to skin. A study in rabbits classified the compound as a severe eye irritant.
A guinea pig maximization test classified BIT as a moderate contact sensitizer whilst the
Buehler test classifies BIT as non-sensitising. Literature data for the local lymph node assay
support a classification of BIT as a moderate dermal sensitizer (EC3 2.3%).
From a four week in-use study with humans only limited conclusions can be drawn due to
the low number of subjects, no detailed description of pre-existing chloromethylisothiazolinone allergy and a significant variation in product use.
Several case reports in the dermatological literature describe allergic contact dermatitis to
benzisothiazolinone, and some individuals wearing disposable powder-free polyvinyl chloride
gloves containing 3 - 36 ppm benzisothiazolinone have developed allergic contact dermatitis
(Aalto-Korte et al. 2007). According to the latter study, a concentration of 20 ppm
benzisothiazolinone in a glove seems to be enough for sensitization. Moreover, in the
context of occupational uses, benzisothiazolinone (BIT) is a well-documented contact
allergen.
As has been seen with MCI/MI and now with MI itself, these isothiazolinones are important
contact allergens for the consumer in Europe. Within the mixture, MCI is known to be the
more potent allergen (EC3 0.009%). MI is less potent (EC3 1.9%) and is now permitted at
up to 100 ppm in leave on and rinse off cosmetic products; contact allergy to MI itself is
26

SCCS/1482/12
Opinion on benzisothiazolinone
___________________________________________________________________________________________

now a considerable problem in Europe and this is of concern (Add. ref: 50-61). If BIT is to
be used as a preservative in cosmetic products, it is essential that the level be sufficiently
low to prevent a repeat of history.
It is recommended that the incidence of contact allergy to BIT and other isothiazolinones be
monitored at regular intervals (e.g. annually), by reference to dermatology clinic data in
Europe. Necessary early interventions can then be introduced to reduce exposures and
hence contact allergy and allergic contact dermatitis as required.
Dermal absorption
An in vitro study with human skin has been provided. The mean value + 1SD can be used
for calculating the MOS. This was 61.9% of the applied dose (1.29 μg/cm2) when 0.01%
benzisothiazolinone aqueous was applied.
The dermal absorption studies had not been performed with representative cosmetic
formulations.
General toxicity
The acute toxicity of benzisothiazolinone upon oral or dermal administration to rats is low
(LD50 of 1193 and 4115 mg/kg bw, respectively). The NOAEL derived from a subacute 28
day oral (gavage) toxicity study in rats was 12.63 mg a.i./kg bw/day. Subchronic toxicity
was evaluated in a 90 day oral (gavage) study (according to OECD guideline 408) and
provided a NOAEL of 8.42 mg/kg bw/day for the active ingredient. The NOAELs in the 28day and 90-day studies were based on histopathological lesions observed in the nonglandular stomach, which are most likely due to the irritant property of the test substance
and are therefore, not relevant for the safety assessment of benzisothiazolinone as a
cosmetic ingredient.
Reproductive Toxicity
In a two generation study in rats with dietary administration benzisothiazolinone produced
at 1000 ppm slight adult toxicity in the F1 generation in terms of lower body weight gain,
and in both generations limiting ridge hyperplasia of the stomach together with incidences
of squamous cell hyperplasia, forestomach gastritis, keratosis and erosion/ulcer. At this
concentration, the growth of the offspring was slightly impaired and in the F2a offspring,
there was a slight reduction in pup survival. At 500 ppm, there were incidences of limiting
ridge hyperplasia in the stomach only. There were no adverse effects of treatment at 250
ppm, equivalent to an approximate overall mean intake of 24 mg/kg bw/day (active
ingredient). The NOAEL was based on histopathological lesions observed in the nonglandular stomach, which are most likely due to the irritant property of the test substance
and therefore, not relevant for the safety assessment of benzisothiazolinone as a cosmetic
ingredient. Therefore, the NOAEL of 50 mg a.i./kg bw/day for the systemic effects of
benzisothiazolinone will be used for the safety assessment.
Mutagenicity
Benzisothiazolinone has been tested for the induction of gene mutation in bacterial and
mammalian cells treated in vitro, for clastogenicity on mammalian cells treated in vitro, for
the induction of micronuclei in mice and for the induction of UDS in rats treated in vivo. The
study on the induction of gene mutations on bacterial cells is inadequate due to the toxicity
of the test item. The compound has been found to be clastogenic in mammalian cells
treated in vitro. The compound has been found non mutagenic in vitro, non clastogenic and
DNA damaging in vivo.
Carcinogenicity
No data provided
27

SCCS/1482/12
Opinion on benzisothiazolinone
___________________________________________________________________________________________

4. CONCLUSION
1.

Does SCCS consider benzisothiazolinone safe when used as a preservative up to a
maximum authorised concentration of 0.01% in cosmetic products, based on the
provided data?

The SCCS considers benzisothiazolinone safe for use as a preservative in cosmetics products
up to 0.01% with respect to systemic toxicity.
However, its sensitising potential is of concern.
2.

And/or does the SCCS have any scientific concern with regard to the use of
benzisothiazolinone in cosmetic products?

Sensitisation from related isothiazolinones is an important problem in consumers. This has
occurred because there has been consumer exposure before safe levels of exposure
relevant to sensitisation have been established. Benzisothiazolinone is a skin sensitiser in
animal models with potency similar to methylisothiazolinone. Methylisothiazolinone, at 100
ppm (0.01%) in cosmetic products is causing contact allergy and allergic contact dermatitis
in the consumer. Benzisothiazolinone is known to be a sensitiser in man and has induced
sensitisation at circa 20 ppm in gloves.
There is no information on what may be safe levels of exposure to benzisothiazolinone in
cosmetic products from the point of view of sensitisation.
Until safe levels of exposure have been established, the use of benzisothiazolinone in
cosmetic products as a preservative or for other functions cannot be considered safe in
relation to sensitisation.

5. MINORITY OPINION
Not applicable

28

SCCS/1482/12
Opinion on benzisothiazolinone
___________________________________________________________________________________________

6. REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.

20.

Material Safety Data Sheet, Acticide BIT, Thor GmbH 22-11-2001
RCC Ltd, Environmental Chemistry & Pharmanalytics Div., Project No. 702731
"Determination of the Melting Point/Melting Range of ACTICIDE BIT" (Sponsor: THOR
Chemie GmbH), 22-10-1998
RCC Ltd, Environmental Chemistry & Pharmanalytics Div., Project No. 840980
"Determination of the Boiling Point/Boiling Range of 1,2-Benzisothiazol-3(2H)-one"
(Sponsor: Thor GmbH), 2002
Thor Specialities (UK) Limited, Study No: RS/01/025 "Determination of the Density of
1,2-benzisothiazol-3(2H)-one (BIT)" (Sponsor: Thor GmbH), 18-01-2002
RCC Ltd, Environmental Chemistry & Pharmanalytics Div., Project No. 702696
"Determination of the Vapour Pressure of ACTICIDE BIT" (Sponsor: THOR Chemie
GmbH), 19-11-1998
RCC Ltd, Environmental Chemistry & Pharmanalytics Div., Project No. 702718
"Determination of the Partition Coefficient (n-Octanol/Water) of ACTICIDE BIT"
(Sponsor: THOR Chemie GmbH), 22-10-1998
Thor Specialities (UK) Limited, Study No: RS/01/025 "Determination of the Partition
Coefficient (noctanol/water) of 1,2-benzisothiazol-3(2H)-one (BIT) at a range of
temperatures and pHs" (Sponsor: Thor GmbH), March 2002
RCC Ltd, Environmental Chemistry & Pharmanalytics Div., Project No. 702431
"Determination of the Water Solubility of ACTICIDE BIT" (Sponsor: THOR Chemie
GmbH), 19-11-1998
Thor Specialities (UK) Limited, Study No: RS/01/029 "Determination of the water
solubility of 1,2-benzisothiazol-3(2H)-one (BIT) at a range of temperatures and pHs"
(Sponsor: Thor GmbH), 2002
psl - product safety labs, Study No. 3859 "Acute Oral Toxicity Defined LD50" (Sponsor:
Hüls America Inc., joint ownership: Prom Chem Ltd and Thor GmbH), 24-01-1996
psl - product safety labs, Study No. 3862 "Acute Dermal Toxicity Limit Test" (Sponsor:
Hüls America Inc., joint ownership: Prom Chem Ltd and Thor GmbH), 24-01-1996
Toxicology Department Rallis Research Centre, Study No. 3286/01 "Repeated Dose
(28-Day) Oral Toxicity Study by Gavage with Promex BIT in Wistar Rats" (Sponsors:
Prom Chem Ltd. and Thor GmbH), 27-02-02
Toxicology Department Rallis Research Centre, Study No. 3287/01 "Repeated Dose
(90-Day) Oral Toxicity Study by Gavage with Promex BIT in Wistar Rats" (Sponsors:
Prom Chem Ltd and Thor GmbH), 2002
Covance Report Number 18D3114-D6154. PROXEL Press Paste (BIT): Two Generation
Oral (Dietary Administration) Reproduction Toxicity Study in the Rat. (Sponsor Avecia
Limited) September 2003
psl - product safety labs, Study No. 3861 "Primary Skin Irritation" (Sponsor: Hüls
America Inc.), joint ownership: Prom Chem Ltd and Thor GmbH), 24-01-1996
Thor Specialities (UK) Limited, Study RS/02/036. “3T3 Neutral Red Uptake
Phototoxicity assay “. (Sponsor: Thor Group Management Limited) March 2005.
psl - product safety labs, Study No. 3860 "Primary Eye Irritation" (Sponsor: Hüls
America Inc., joint ownership: Prom Chem Ltd and Thor GmbH), 24-01-1996
Thor Specialities (UK) Limited, Study RS/02/036. “An assessment of the eye irritancy
potential of 1,2-benzisothiazolin-3-one using the In-vitro BCOP assay“. (Sponsor: Thor
Group Management Limited) March 2003.
Thor Specialities (UK) Limited, Study RS/02/039. “An assessment of the cytotoxicity of
1,2-benzisothiazolin-3-one by the In-vitro Neutral Red Uptake Assay, using BalbC 3T3
and SIRC mammalian cell lines.“ (Sponsor: Thor Group Management Limited) January
2003
Quintiles England limited, Project Code A/K/42557 "Skin Sensitisation Study In The
Guinea Pig Magnusson and Kligman Maximisation Test" (Sponsor: H&C Prom Kemi
ApS, joint ownership: Prom Chem Ltd and Thor GmbH), 02-1997

29

SCCS/1482/12
Opinion on benzisothiazolinone
___________________________________________________________________________________________

21.
22.
23.

24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.

36.

psl - product safety labs, Study No. 3863 "Dermal sensitization test – Buehler Method"
(Sponsor: Hüls America Inc., joint ownership: Prom Chem Ltd and Thor GmbH), 2401-1996
Sequani Consumer Limited. Study No TWP0001. “A four week home-use study to
evaluate the tolerance to a topical cream containing a new preservative“. (Sponsor
Thor Group Mangement Limited). June 2002.
Sequani Consumer Limited. Study No TWP0002 June 2002. “ A four week home-use
study to evaluate the tolerance to a topical cream containing a new preservative in
subjects sensitized to a mixture of isothiazolinones“. Start of experimental work
December 2002
D.A.Basketter, R.Rodford, I.Kimber, I.Smith, J.Wahlberg. Skin sensitisation risk
assessment: a comparative evaluation of 3 Isothiazolinone biocides. Contact
Dermatitis 1999; 40:150-4.
Toxicology Department Rallis Research Centre, Study No. 3288/01 "Bacterial Reverse
Mutation Test with Promex BIT" (Sponsors: Prom Chem Ltd and Thor GmbH), 01-0302
Toxicology Department Rallis Research Centre, Study No. 3291/01 "In vitro
Mammalian Cell Gene Mutation test with Promex BIT" (Sponsors: Prom Chem Ltd and
Thor GmbH), 03-02
Toxicology Department Rallis Research Centre, Study No. 3289/01 "In vitro
Mammalian Chromosome Aberration test with Promex BIT" (Sponsors: Prom Chem Ltd
and Thor GmbH), 03-02
Toxicology Department Rallis Research Centre, Study No. 3290/01 "Mutagenicity
Study - Micronucleus Test in Swiss Albino Mice with Promex BIT" (Sponsors: Prom
Chem Ltd and Thor GmbH), 2002
RCC Cytotest Cell Research. Study Number: 736501. "Unscheduled DNA synthesis with
1,2-Benzisothiazolin-3-one“ Study Commissioned June 2002
B.R Alexander (2002) An assessment of the comparative sensitisation potential of
some common isothiazolinones. Contact Dermatitis 46, 191-196
Steinberg, D.C. (2000) Measuring synergy. Cosmetics & Toiletries 115(11), 59-62.
Küll, F.C., Eisman, P.C., Sylwestrowicz, J.D. & Mayer, R.L. (1961) Mixtures of
quaternary ammonium compounds and long chain fatty acids as antifungal agents.
Applied Microbiology 9, 538-541.
Seal K.J., Alexander B.R., (2001) Special Agents. Global Cosmetic Industry, 169 (6),
24-30
Chapman, J.S., Diehl, M.A., Fearnside, K.B. (1998) Preservative tolerance &
resistance. International Journal of Cosmetic Science 20, 31-39.
Kroes R, Galli C, Munro I, Schilter B, Tran L-A, Walker R, Wurtzen G. (2000) Threshold
of Toxicological Concern for Chemicals Substances Present in the Diet: A Practical Tool
for Assessing the Need for Toxicity Testing. Food and Chemical Toxicology 38, 2-3,
255-312
Charles River Laboratories Study No. 782039, Report No. 28709, 2008. The In Vitro
Percutaneous Absorption of Radiolabelled Benzisothiazolinone Through Human Skin
(Sponsor: Thor Group, Ramsgate Road, Margate, Kent, CT9 4JY, UK)

Additional References
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Ayadi M, Martin P. Pulpitis of the fingers from a shoe glue containing 1,2benzisothiazolin-3-one. Contact Dermatitis 1999; 40: 115-116
Fischer T, Bohlin S, Edling C, Rystedt I, Wieslander G. Skin disease and contact
sensitivity in house painters using water-based paints, glues and putties. Contact
Dermatitis 1995; 32: 39-45
Taran JM, Delaney TA. Allergic contact dermatitis to 1,2-benzisothiazolin-3-one in the
carpet industry. Australas J Dermatol 1997; 38: 42-43
Chew AL, Maibach HI. 1,2-Benzisothiazolin-3-one (Proxel): irritant or allergen? A
clinical study and literature review. Contact Dermatitis 1997; 36: 131-136
30

SCCS/1482/12
Opinion on benzisothiazolinone
___________________________________________________________________________________________

41.
42.
43.
44.
45.
46.
47.
48.

49.

50.
51.
52.
53.
54.

55.
56.

57.
58.
59.

Aalto-Korte K, Ackermann L, Henriks-Eckerman ML, Vlimaa J, Reinikka-Railo H,
Leppnen E, Jolanki R (2007). 1,2-Benzisothiazolin-3-one in disposable polyvinyl
chloride gloves for medical use. Contact Dermatitis 57; 365–370.
Burden AD, O’Driscoll JB, Page FC, Beck MH (1994) Contact hypersensitivity to a new
isothiazolinone. Contact Dermatitis 30; 179-180
Chew AL, Maibach H (1997) 1,2-Benzisothiazolin-3-one (Proxel®): irritant or allergen?
A clinical study and literature review. Contact Dermatitis 23; 131-136
Dias M, Lamarao P, Vale T (1992) Occupational contact allergy to 1,2-benzisothiazol-3one in the manufacture of air fresheners. Contact Dermatitis 36; 205-206
Greig DE (1991) Another isothiazolinone source. Contact Dermatitis 25; 201-202
Sanz-Gallen P, Planas J, Martinez P, Gimenez-Arnau JM (1992) Allergic contact
dermatitis due to 1,2-benzisothiazolin-3-one in paint manufacture. Contact Dermatitis
27; 271-272.
Geier J, Lessmann H, Dickel H, Frosch PJ, Koch P, Becker D, Jappe U, Aberer W,
Schnuch A, Uter W (2004). Patch test results with the metalworking fluid series of the
German Contact Dermatitis Research Group (DKG). Contact Dermatitis 51; 118–130.
Walker SL, Yell JA, Beck MH (2004). Occupational allergic contact dermatitis caused by
1,2-benzisothiazolin-3-one in a varnish maker, followed by sensitization to
benzalkonium chloride in Oilatum® Plus bath additive. Contact Dermatitis 50; 104–
105.
Roberts DW, Patlewicz G, Kern PS, Gerberick F, Kimber I, Dearman RJ, Ryan CA,
Basketter DA, Aptula AO (2007) Mechanistic applicability domain classification of a
local lymph node assay dataset for skin sensitisation. Chem. Res. Toxicol; 20; 10191030.
Cuesta L, Silvestre JF, Toledo F, Ballester I, Betlloch I (2010). Delayed hypersensitivity
to methylchloroisothiazolinone/methylisothiazolinone not detected the baseline series
of the Spanish group. Contact Dermatitis; 62; 250-251
García-Gavín J, Goossens A (2010). Moist toilet paper: allergy to the nonhalogenated
derivative methylisothiazolinone preservative alone. Archives of Dermatology; 146;
1186
Amaro C, Santos R, Cardoso J (2011). Contact allergy to methylisothiazolinone in a
deodorant. Contact Dermatitis; 64; 298-299
Lundov MD, Thyssen JP, Zachariae C, Johansen JD (2010). Prevalence and cause of
methylisothiazolinone contact allergy. Contact Dermatitis; 63; 164-167
Gardner KH, Davis MD, Richardson DM, Pittelkow MR (2010). The hazards of moist
toilet
paper:
allergy
to
the
preservative
methylchloroisothiazolinone/methylisothiazolinone. Archives of Dermatology;
146;
886-890
Schnuch A, Lessmann H, Geier J, Uter W (2011). Contact allergy to preservatives.
Analysis of IVDK data 1996-2009. The British Journal of Dermatology; 164; 13161325
Ackermann L, Aalto-Korte K, Alanko K, Hasan T, Jolanki R, Lammintausta K, Lauerma
A, Laukkanen A, Liippo J, Riekki R, Vuorela AM, Rantanen T (2011). Contact
sensitization to methylisothiazolinone in Finland--a multicentre study.
Contact
Dermatitis; 64; 49-53
Lundov MD, Zachariae C, Johansen JD (2011). Methylisothiazolinone contact allergy
and dose-response relationships. Contact Dermatitis; 64; 330-336
Lundov MD, Krongaard T, Menné TL, Johansen JD (2011). Methylisothiazolinone
contact allergy: a review. The British Journal of Dermatology; 165; 1178-1182
Uter W, Werner A, Armario-Hita JC, Fernandez-Vozmediano JM, Ayala F, Balato A,
Bauer A, Ballmer-Weber B, Beliauskiene A, Fortina AB, Bircher A, Brasch J, Chowdhury
MM, Coenraads PJ, Schuttelaar ML, Cooper S, Czarnecka-Operacz M, Zmudzinska M,
Elsner P, English JS, Frosch PJ, Fuchs T, García-Gavín J, Fernández-Redondo V,
Gawkrodger DJ, Giménez-Arnau A, Green CM, Horne HL, Johansen JD, Jolanki R,
Pesonen M, King CM, Krêcisz B, Chomiczewska D, Kiec-Swierczynska M, Larese F,
Mahler V, Ormerod AD, Peserico A, Rantanen T, Rustemeyer T, Sánchez-Pérez J,
Sansom JE, Silvestre JF, Simon D, Spiewak R, Statham BN, Stone N, Wilkinson M,
31

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60.

61.

Schnuch A (2012). Current patch test results with the European baseline series and
extensions to it from the 'European Surveillance System on Contact Allergy' network,
2007-2008. Contact Dermatitis; 67; 9-19
Uter
W,
Gefeller
O,
Geier
J,
Schnuch
A.
(2012).
Methylchloroisothiazolinone/methylisothiazolinone contact sensitization: diverging
trends in subgroups of IVDK patients in a period of 19 years. Contact Dermatitis; Epub
ahead of print 5 May 2012; doi: 10.1111/j.1600-0536.2012.02075.x.
Maio P, Carvalho R, Amaro C, Santos R, Cardoso (2012). Contact allergy to
methylchoroisothiazolinone/methylisothiazolinone (MCI/MI): findings from a Contact
Dermatitis Unit. J Cutaneous and Ocular Toxicology; 31; 151-153

32



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Title                           : Opinion of the Scientific Committee on Consumer Safety on benzisothiazolinone
Title (x-repair)                : Opinion of the Scientific Committee on Consumer Safety on benzisothiazolinone
Description                     : Scientific Committee on Consumer Safety
Description (x-repair)          : Scientific Committee on Consumer Safety
Creator                         : Office 2004 Test Drive-Benutzer
Subject                         : Scientific Committee on Consumer Safety
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Keywords                        : SCCS, scientific opinion, preservative, benzisothiazolinone, P96, directive 76/768/ECC, CAS 2634-33-5, EC 220-120-9
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