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Genetic toxicity in vitro

Description of key information

The genetic toxicity of propan-2-ol (IPA) has been assessed in two in vitro studies. Negative results were reported from mutagenicity studies in bacterial and mammalian cells.

Link to relevant study records

Referenceopen allclose all

Endpoint:
in vitro gene mutation study in bacteria
Remarks:
Type of genotoxicity: gene mutation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1992
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study without detailed documentation. Tn.publication is sufficiently detailed to allow a scientific evaluation of the results
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 471 (Bacterial Reverse Mutation Assay)
Deviations:
yes
Remarks:
- S. typhimurium strain TA102 or E. coli strain WP2 uvrA were not used & 2-aminoanthracene was the only positive control compound used to test the efficacy of the S9 fraction.
GLP compliance:
no
Type of assay:
bacterial reverse mutation assay
Species / strain / cell type:
S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
Additional strain / cell type characteristics:
not applicable
Species / strain / cell type:
S. typhimurium TA 97
Additional strain / cell type characteristics:
not applicable
Metabolic activation:
with and without
Metabolic activation system:
Aroclor 1254-induced rat and hamster liver microsomes (10% and 30% for strains TA 98, TA 100 and TA 1535 and 30% for strain TA 1537)
Test concentrations with justification for top dose:
100, 333, 1000, 3333, or 10000 µg/plate
Vehicle / solvent:
- Vehicle(s)/solvent(s) used: distilled water
Untreated negative controls:
no
Negative solvent / vehicle controls:
yes
True negative controls:
no
Positive controls:
yes
Positive control substance:
other: See Table 1
Details on test system and experimental conditions:
METHOD OF APPLICATION: preincubation

DURATION
- Preincubation period: 20 minutes at 37 ºC
- Exposure duration: 48 hours at 37 ºC

NUMBER OF REPLICATIONS: At least five doses of each chemical were tested in triplicate, and repeat experiments were performed at least one week following the initial trial.
Evaluation criteria:
Revertant colonies were counted
Statistics:
None performed (revertant colonies were counted)
Species / strain:
S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity
Remarks:
no cytotoxicity when tested at levels ≤ 10,000 µg/plate which is higher than the limit concentration of 5,000 µg/plate
Vehicle controls validity:
valid
Untreated negative controls validity:
not applicable
Positive controls validity:
valid
Species / strain:
S. typhimurium TA 97
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity
Remarks:
no cytotoxicity when tested at levels ≤ 10,000 µg/plate which is higher than the limit concentration of 5,000 µg/plate
Vehicle controls validity:
valid
Untreated negative controls validity:
not applicable
Positive controls validity:
other: Revertant colony count did not double in the presence of 30% hamster liver microsomes. An adequate positive control response was observed for all other tested conditions.
Species / strain:
S. typhimurium TA 1535
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity
Remarks:
no cytotoxicity when tested at levels ≤ 10,000 µg/plate which is higher than the limit concentration of 5,000 µg/plate
Vehicle controls validity:
valid
Untreated negative controls validity:
not applicable
Positive controls validity:
valid
Species / strain:
S. typhimurium TA 1537
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity
Remarks:
no cytotoxicity when tested at levels ≤ 10,000 µg/plate which is higher than the limit concentration of 5,000 µg/plate
Vehicle controls validity:
valid
Untreated negative controls validity:
not applicable
Positive controls validity:
valid
Species / strain:
S. typhimurium TA 98
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity
Remarks:
no cytotoxicity when tested at levels ≤ 10,000 µg/plate which is higher than the limit concentration of 5,000 µg/plate
Vehicle controls validity:
valid
Untreated negative controls validity:
not applicable
Positive controls validity:
valid
Species / strain:
S. typhimurium TA 100
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity
Remarks:
no cytotoxicity when tested at levels ≤ 10,000 µg/plate which is higher than the limit concentration of 5,000 µg/plate
Vehicle controls validity:
valid
Untreated negative controls validity:
not applicable
Positive controls validity:
valid
Conclusions:
Interpretation of results:
negative with metabolic activation
negative without metabolic activation
Endpoint:
in vitro gene mutation study in bacteria
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 471 (Bacterial Reverse Mutation Assay)
Deviations:
yes
Remarks:
Duplicate plates, no historical control data
Principles of method if other than guideline:
Modified Ames test
GLP compliance:
not specified
Type of assay:
bacterial reverse mutation assay
Target gene:
Histidine (Salmonella typhimurium)
Tryptophan (Escherichia coli)
Species / strain / cell type:
S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and E. coli WP2
Species / strain / cell type:
S. typhimurium TA 1538
Metabolic activation:
with and without
Metabolic activation system:
S9 from polychlorinated biphenyl KC500-treated male rat livers
Test concentrations with justification for top dose:
5, 10, 50, 100, 500, 1000, 5000 μg/plate
Vehicle / solvent:
Water
Untreated negative controls:
no
Negative solvent / vehicle controls:
yes
True negative controls:
no
Positive controls:
yes
Positive control substance:
4-nitroquinoline-N-oxide
9-aminoacridine
N-ethyl-N-nitro-N-nitrosoguanidine
benzo(a)pyrene
other: 2-(2-Furyl)-3-(5-nitro-2-furyl)acrylamide (FFA); 2-aminoanthracene (2AA)
Details on test system and experimental conditions:
Details on test system and experimental conditions
- Number of replicates: Duplicates
- Application: Preincubation method
- Pre-incubation time: 20 minutes at 37 deg C
- Incubation time: 48 hours at 37 deg C
Evaluation criteria:
Not reported
Key result
Species / strain:
S. typhimurium TA 1535
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity nor precipitates, but tested up to recommended limit concentrations
Vehicle controls validity:
valid
Positive controls validity:
valid
Key result
Species / strain:
S. typhimurium TA 1537
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity nor precipitates, but tested up to recommended limit concentrations
Vehicle controls validity:
valid
Positive controls validity:
valid
Key result
Species / strain:
S. typhimurium TA 98
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity nor precipitates, but tested up to recommended limit concentrations
Vehicle controls validity:
valid
Positive controls validity:
valid
Key result
Species / strain:
S. typhimurium TA 100
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity nor precipitates, but tested up to recommended limit concentrations
Vehicle controls validity:
valid
Positive controls validity:
valid
Key result
Species / strain:
S. typhimurium TA 1538
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity nor precipitates, but tested up to recommended limit concentrations
Vehicle controls validity:
valid
Positive controls validity:
valid
Key result
Species / strain:
E. coli WP2 uvr A
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity nor precipitates, but tested up to recommended limit concentrations
Vehicle controls validity:
valid
Positive controls validity:
valid

Number of revertants per plate, pre-incubation (mean of two plates)

Dose

µg/plate

TA

100

TA

1535

WP2

uvr A

TA

98

TA

1537

TA

1538

MA

-

+

-

+

-

+

-

+

-

+

-

+

0 (solvent control)

149

161

28

15

32

33

29

39

16

21

21

28

5

174

181

26

10

29

32

36

40

14

22

20

29

10

182

145

25

11

29

30

40

38

17

24

25

29

50

165

151

26

10

23

36

39

37

14

21

33

34

100

185

168

24

9

27

25

41

35

10

27

25

28

500

166

176

21

15

27

29

36

36

12

14

20

34

1000

176

158

25

16

33

31

26

35

14

26

17

25

5000

173

171

27

10

30

30

38

47

18

22

27

28

AF2 0.01

501

-

-

-

-

-

-

-

-

-

-

-

AF2 0.05

-

-

-

-

1082

-

278

-

-

-

-

-

ENNG 5.0

-

-

1101

-

-

-

-

-

-

-

-

-

9AC 80.0

-

-

-

-

-

-

-

-

889

-

-

-

4NQO 0.25

-

-

-

-

-

-

-

-

-

-

270

-

B(a)P 5.0

-

1084

-

-

-

-

-

809

-

313

-

354

2AA

-

-

-

440

-

359

-

-

-

-

-

-
Conclusions:
s
Endpoint:
in vitro gene mutation study in mammalian cells
Remarks:
Type of genotoxicity: gene mutation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1990
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well documented, according to accepted guidelines
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 476 (In Vitro Mammalian Cell Gene Mutation Test)
Deviations:
no
GLP compliance:
yes
Type of assay:
mammalian cell gene mutation assay
Species / strain / cell type:
Chinese hamster Ovary (CHO)
Additional strain / cell type characteristics:
not applicable
Metabolic activation:
with and without
Metabolic activation system:
Aroclor 1254-induced rat liver microsomes (S9)
Test concentrations with justification for top dose:
Range-finding (cytotoxicity) assay: 0.0098, 0.0195, 0.0391, 0.0781, 0.156, 0.313, 0.625, 1.25, 2.5, or 5.0 mg/mL
Mutation assay (- & + S9): 0.5, 1.0, 2.0, 3.0, 4.0, or 5.0 mg/mL (Trial 1)
Mutation assay (- S9): 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, or 5.0 mg/mL (Trial 2)
Mutation assay (+ S9): 0.5, 1.0, 2.0, 3.0, 3.5, 4.0, 4.5, or 5.0 mg/mL (Trial 2)
Mutation assay (- S9): 1.0, 2.0, 3.0, 4.0, 4.5, or 5.0 mg/mL (Trial 3)
Vehicle / solvent:
- Vehicle(s)/solvent(s) used: sterile, deionized water
Untreated negative controls:
yes
Negative solvent / vehicle controls:
yes
Remarks:
sterile, deionized water
True negative controls:
no
Positive controls:
yes
Positive control substance:
other: 5-bromo-2-deoxyuridine (-S9) and 3-methylcholanthrene (+S9)
Details on test system and experimental conditions:
METHOD OF APPLICATION: in medium

DURATION
- Exposure duration: 4 hours at 37 ºC
- Expression time (cells in growth medium): 7 days
- Selection time (if incubation with a selection agent): 7 to 10 days at 37 ºC

NUMBER OF REPLICATIONS: 3 (-S9) or 2 (+S9) independent experiments.
Evaluation criteria:
(a) A dose- or toxicity-related increase in mutant frequency must be observed for at least 3 doses.
(b) A mutagenic dose-response in one assay should be confirmed in a second mutation assay.
(c) If an increase in mutant frequency is observed in one trial for a treated culture near the highest testable toxicity and the number of mutant colonies is more than twice the value needed to indicate a significant response, the test article generally will be considered to be mutagenic.
(d) Applied concentration or toxicity (% survival) can be used to establish whether the mutagenic activity is related to an increase in effective treatment.
(e) Treatments that reduce relative clonal survival to less than 5% may be included in the assay but will not be used as sufficient evidence of mutagenicity as it relates to risk assessment.
Statistics:
Not performed (colonies are counted)
Species / strain:
Chinese hamster Ovary (CHO)
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity nor precipitates, but tested up to recommended limit concentrations
Vehicle controls validity:
valid
Untreated negative controls validity:
not applicable
Positive controls validity:
valid
Conclusions:
Interpretation of results:
negative with metabolic activation
negative without metabolic activation
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Genetic toxicity in vivo

Description of key information

The genetic toxicity of propan-2-ol (IPA) has been assessed in 2 in an in vivo micronucleus assay.  The result of this study was negative.

Link to relevant study records
Reference
Endpoint:
in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
Remarks:
Type of genotoxicity: chromosome aberration
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1991
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study without detailed documentation. The publication is sufficiently detailed to allow a scientific evaluation of the results
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
Deviations:
yes
Remarks:
- 1000 polychromatic erythrocytes were evaluated per animal, rather than 2000
GLP compliance:
yes
Type of assay:
micronucleus assay
Species:
mouse
Strain:
ICR
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: from Harlan Sprague-Dawley, Inc., Frederick, MD
- Age at study initiation: 8 to 11 weeks old
- Assigned to test groups randomly: yes, under following basis: by a computer generated randomization program
- Housing: 5 mice/cage
- Diet (e.g. ad libitum): Purina Certified Laboratory Chow #5002 ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: Quarantined for seven days before being placed on study

ENVIRONMENTAL CONDITIONS
- Temperature: Reported in the study to be 72 ± 6 ºF (approximately 22.2 ºC)
- Humidity (%): 50 ± 20%
- Photoperiod (hrs dark / hrs light): 12 hours: 12 hours
Route of administration:
intraperitoneal
Vehicle:
- Vehicle(s)/solvent(s) used: 0.9% sodium chloride
Details on exposure:
Thirty randomly assigned mice/group (15 males/15 females) were treated with isopropanol dissolved in 0.9% sodium chloride at dose levels of 0 (vehicle control), 350, 1173 and 3500 mg isopropanol/kg bw by intraperitoneal injection. Mice were observed for toxic symptoms and/or mortalities immediately after dosing and twice daily for the duration of the assay.
Duration of treatment / exposure:
Single exposure
Frequency of treatment:
Single exposure
Post exposure period:
None
Remarks:
Doses / Concentrations:
350 mg/kg bw
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
1173 mg/kg bw
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
2500 mg/kg bw
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
3500 mg/kg bw
Basis:
nominal conc.
No. of animals per sex per dose:
15/sex/dose
Control animals:
yes, concurrent vehicle
Positive control(s):
cyclophosphamide
- Route of administration: oral (gavage)
- Doses / concentrations: 80 mg/kg bw
Tissues and cell types examined:
Bone marrow was extracted from 10 mice/group (5 males/5 females) at 24, 48, and 72 hours after dosing. An additional group of 10 mice (5 males/5 females) was treated with 3500 mg/kg bw and held to ensure that 10 mice were available for bone marrow extraction at each interval. These mice were scheduled for use only if mortalities occurred in the primary dose group. As needed, mice were randomly selected from this secondary group for bone marrow extraction and unused mice were euthanized at the completion of the trial. Bone marrow for the positive control group was harvested at 24 hours. Terminal body weights were collected on all animals prior to euthanization for bone marrow harvest.
Details of tissue and slide preparation:
At the appropriate harvest time, the animals were euthanized with CO2 and the adhering soft tissue and epiphyses of both tibias were removed. The marrow was flushed into a centrifuge tube (one tube for each animal) with 3 mL fetal calf serum. Following centrifugation to pellet the tissue, most of the supernatant was drawn off, the cells were resuspended, and the suspension spread on slides and air-dried. The slides were then fixed in methanol and stained in May-Gruenwald solution followed by Giemsa. After being air-dried, the slides were coverslipped using Depex mounting medium. The coded slides were then scored blind for micronuclei and the polychromatic (PCE) to normochromatic (NCE) cell ratio. Standard forms were used to record these data. One thousand PCEs per animal were scored. The frequency of micronucleated cells was expressed as percent micronucleated cells based on the total PCEs present in the scored optic field. The normal frequency of micronuclei in this mouse strain is about 0.0-0.4%. The frequency of PCEs versus NCEs was determined by scoring the number of NCEs observed in the optic fields while scoring the 1000 PCEs for micronuclei.
Evaluation criteria:
The criteria for the identification of micronuclei were those of Schmid (1976). Micronuclei were darkly stained and generally round, although almond and ring-shaped micronuclei occasionally occur. Micronuclei had sharp borders and were generally between 1/20 and 1/5 the size of the PCE. The unit of scoring was the micronucleated cell, not the micronucleus; thus the occasional cell with more than one micronucleus was counted as one micronucleated PCE, not two (or more) micronuclei. The staining procedure permitted the differentiation by color of PCEs and NCEs (bluish-grey and red, respectively).
Statistics:
ANOVA followed by Tukey's
Sex:
male/female
Genotoxicity:
negative
Toxicity:
yes
Remarks:
See remarks section.
Vehicle controls validity:
valid
Negative controls validity:
not applicable
Positive controls validity:
valid

All animals in the 3500 mg/kg bw dose group became prostrate after dosing. Within 22 hours after dosing, 35 of the 40 animals dosed at 3500 mg/kg had expired. Due to this toxicity, the 3500 mg/kg bw dose level was eliminated from the study.

Immediately after dosing, the animals receiving 2500 mg/kg became prostrate. Approximately four hours after dosing, the animals were languid with squinted eyes. The following morning, approximately 23 hours after dosing, one male (#8371) was languid with squinted eyes. This animal also exhibited dyspnea approximately 30 hours after dosing. All other animals appeared normal; however, within 46 hours of dosing three animals (male #8371; female #’s 8319 and 8354) were found dead. Another female (#8369) expired approximately 53 hours after dosing and several other animals were languid. On the third morning, approximately 70 hours after dosing, two males (#’s 8326 and 8405) were found dead. All remaining test article dosed animals had rough haircoats and this condition remained at the 72 hour harvest time. A gross necropsy was performed on all animals which expired during the observation period. Male #8371 had a moderate amount of clear yellow fluid in the trachea and thoracic cavity and an irregular black stomach mucosa. Female #8369 also had a moderate amount of a clear orange fluid in the thoracic cavity. The other necropsied animals had moderate to significant distension of the stomachs or colons, two with an abnormally thin fluid content. No other abnormalities were noted in the animals examined. The terminal body weight range of the animals harvested in this trial of the micronucleus assay was 28.1 - 37.4 grams for males and 19.0 - 26.9 grams for females. Terminal body weight gains were significantly lower at the 48 and 72 hour sacrifice intervals in mice treated with 2,500 mg/kg bw compared to corresponding vehicle control body weight gains indicating that there was a test article related reduction in body weights.

The test article, isopropanol, induced no significant increases in micronucleated polychromatic erythrocytes over the levels observed in the vehicle controls in either sex or at any of the harvest times. The positive control, CP, induced significant increases in micronucleated PCEs in both sexes, with means and standard errors of 3.24% ± 0.84% and 1.22% ± 0.19% for the males and females, respectively. The vehicle and positive control rates of micronucleated PCEs were within the historical control values in this laboratory (TRIAL 1).

The test article, isopropanol, induced no significant increases in micronucleated polychromatic erythrocytes over the levels observed in the vehicle controls in either sex or at any of the harvest times. The positive control, CP, induced significant increases in micronucleated PCEs in both sexes, with means and standard errors of 1.56% ± 0.42% and 1.66% ± 0.39% for the males and females, respectively. The vehicle and positive control rates of micronucleated PCEs were within the historical control values in this laboratory (TRIAL 2).

Conclusions:
Interpretation of results: negative
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Additional information

In a mammalian gene mutation assay, conducted according to a method equivalent to OECD Test Guideline 476 and in compliance with GLP, the ability of IPA to increase mutation frequencies was investigated in Chinese Hamster Ovary (CHO) cells in the absence and presence of exogenous metabolic activation (Aroclor 1254-induced rat liver S9) (Young, 1990).  Twelve plates were used per dose and 3 or 2 independent experiments were conducted in the absence or presence of metabolic activation, respectively. The doses used in each experiment were as follows:

1.      0, 0.5, 1.0, 2.0, 3.0, 4.0, or 5.0 mg/mL in the absence and presence of metabolic activation (Trial 1);

2.      0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, or 5.0 mg/mL and 0, 0.5, 1.0, 2.0, 3.0, 3.5, 4.0, 4.5, or 5.0 mg/mL in the absence and presence of metabolic activation, respectively (Trial 2);

3.      0, 1.0, 2.0, 3.0, 4.0, 4.5, or 5.0 mg/mL in the absence of metabolic activation (Trial 3).

Sterile, deionized water was used as the vehicle and 5-bromo-2-deoxyuridine and 3-methylcholanthrene were used as the positive control compounds in the absence and presence of metabolic activation, respectively. No cytotoxicity and no increase in the mutant frequency were observed at any IPA concentration either in the absence or presence of metabolic activation. Additionally, incubation with the positive control substances in the absence or presence of metabolic activation resulted in anticipated increases in the mutation frequencies.

In a bacterial reverse mutation assay, conducted according to a method equivalent to OECD Test Guideline 471, but not in compliance with GLP, IPA was tested at doses of 0; 100; 333; 1,000; 3,333 or 10,000 µg/plate in Salmonella typhimurium strains TA 97, TA 98, TA 100, TA 1535, and TA 1537 both in the presence and absence of exogenous metabolic activation (Aroclor 1254-induced rat and hamster liver S9) (Zeiger et al., 1992).  The incubations were conducted in triplicate and an independent repeated experiment was performed. Distilled water was used as the vehicle and positive controls were included in all incubations. No cytotoxicity was observed and no increase in the reverse mutation rate was observed at at any IPA concentration either in the presence or absence of metabolic activation. Incubation with positive control substances in the presence or absence of metabolic activation did not always result in anticipated increases in reverse mutation rates. As a result this study is considered reliable with restrictions. This study did not test IPA for mutagenicity to a strain capable of detecting oxidising mutagens, cross-linking agents and hydrazines (E.coli WP2 or S. typhimurium TA102), however, an older study which included E. coli WP2 uvr A as a test organism is available.

IPA has been tested in a bacterial reverse mutation assay conducted according to a protocol similar to OECD 471, no information on GLP compliance (Shimizu, 1985). The substance was tested to limit concentrations in the presence and absence of metabolic activation (polychlorinated biphenyl KC500-treated male rat liver S9) in histidine-dependent Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 11538, and in tryptophan-dependent Escherichia coli WP2 uvr A. The strains were tested in duplicate with a pre-incubation time of 20 minutes. No cytotoxicity was observed and no increase in revertants was observed at any concentration or in any of the bacterial strains tested. Solvent and positive controls gave expected results. It is concluded that the substance is negative for mutagenicity to bacteria under the conditions of the test.

In an in vivo micronucleus assay, conducted according to a method equivalent to OECD Test Guideline 474 and in compliance with GLP, IPA was administered via intraperitoneal (IP) injection to male and female ICR mice at doses of 350; 1,173; 2,500, or 3,500 mg/kg body weight (Ivett, 1991).  Sodium chloride was used as the vehicle and oral (gavage) cyclophosphamide was administered as the positive control compound. Mice were sacrificed at 24, 48, or 72 hours after dosing (5 mice/sex/time point). Twenty-two hours following dosing, most of the mice receiving 3,500 mg IPA/kg body weight died. Due to this toxicity, the 3,500 mg/kg body weight dose level was eliminated from the study. Deaths and clinical signs also were noted in mice receiving 2,500 mg/kg body weight; however, findings in the groups receiving 350 or 1,173 mg IPA/kg body weight were not reported. No statistically significant increases in the number of micronucleated polychromatic erythrocytes were noted at any dose level at any time point. The evaluation of 1,000 polychromatic erythrocytes per animal instead of 2,000 rendered this study reliable with restrictions.

Justification for classification or non-classification

The substance does not meet the criteria for classification and labelling for mutagenicity according to Regulation (EC) No. 1272/2008.