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EC number: 246-014-2 | CAS number: 24085-08-3
- Life Cycle description
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Genetic toxicity: in vivo
Administrative data
- 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:
- 23 October 2002 to 09 June 2003
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Performed in accordance to OECD and GLP compliant
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 003
- Report date:
- 2003
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
- Deviations:
- yes
- Remarks:
- Any occasional deviations from these targets were considered not to have affected the purpose or integrity of the study.
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- micronucleus assay
Test material
- Reference substance name:
- 2-[tert-butyl(phenylmethyl)amino]-1-[4-hydroxy-3-(hydroxymethyl)phenyl] hydrochloride
- EC Number:
- 246-014-2
- EC Name:
- 2-[tert-butyl(phenylmethyl)amino]-1-[4-hydroxy-3-(hydroxymethyl)phenyl] hydrochloride
- Cas Number:
- 24085-08-3
- Molecular formula:
- C20H25NO3.HCl
- IUPAC Name:
- 2-[tert-butyl(phenylmethyl)amino]-1-[4-hydroxy-3-(hydroxymethyl)phenyl] hydrochloride
- Test material form:
- solid: particulate/powder
- Remarks:
- migrated information: powder
Constituent 1
Test animals
- Species:
- mouse
- Strain:
- CD-1
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River (UK) Limited, Margate, Kent
- Age at study initiation: five to eight weeks old
- Weight at study initiation: 25 to 30g
- Assigned to test groups randomly: yes, under following basis: selected at random and given a number unique within the study by ear punching and a number written on a colour coded cage card
- Housing: The animals were housed in groups of up to seven in solid-floor polypropylene cages with woodflake bedding.
- Diet (e.g. ad libitum): ad libitum(Certified Rat and Mouse Diet 5LF2, International Product Supplies Limited, Wellingborough, Northants UK)
- Water (e.g. ad libitum): ad libitum (mains drinking water)
- Acclimation period: seven days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25°C
- Humidity (%): 30 to 70%
- Air changes (per hr): fifteen changes per hour
- Photoperiod (hrs dark / hrs light): twelve hours light and twelve hours darkness
IN-LIFE DATES: From: animals were 5 to eight weeks at the beginning of the study, plus minimum of seven days acclimatisation, animals were killed 24 to 48 hrs following dosing.
Administration / exposure
- Route of administration:
- intraperitoneal
- Vehicle:
- - Vehicle(s)/solvent(s) used: arachis oil
- Concentration of test material in vehicle: 0, 7.5, 15 or 30 mg/mL
- Lot/batch no. (if required): lot number: T63 - Details on exposure:
- All animals were dosed once only at the appropriate dose level by gavage (dose range study) using a metal cannula or with a hypodermic needle attached to a graduated syringe. The volume administered to each animal was calculated according to its bodyweight at the time of dosing.
It was initially considered to be unnecessary to investigate the intraperitoneal route of administration. However, after preliminary range-finding work it was then decided to investigate the intraperitoneal route following discussions with the Sponsor. - Duration of treatment / exposure:
- Brief exposure with the test material.
- Frequency of treatment:
- Once
- Post exposure period:
- 24-48 hrs
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
300 mg/kg
Basis:
nominal conc.
- Remarks:
- Doses / Concentrations:
75 mg/kg
Basis:
nominal conc.
- Remarks:
- Doses / Concentrations:
150 mg/kg
Basis:
nominal conc.
- No. of animals per sex per dose:
- 7m/group
- Control animals:
- yes, concurrent vehicle
- Positive control(s):
- Positive Control: cyclophosphamide
- Justification for choice of positive control(s): Cyclophosphamide is a positive control material known to produce micronuclei under the conditions of the test.
- Route of administration: intraperitoneal
- Doses / concentrations: 50 mg/kg
Examinations
- Tissues and cell types examined:
- Bone marrow Erythocytes.
- Details of tissue and slide preparation:
- Slide Preparation
Immediately following termination (i.e. 24 or 48 hours following dosing), both femurs were dissected from each animal, aspirated with foetal calf serum and bone marrow smears prepared following centrifugation and re-suspension. The smears were air-dried, fixed in absolute methanol, stained in May-Griinwald/Giemsa, allowed to air-dry and coverslipped using mounting medium. - Evaluation criteria:
- Slide Evaluation
Stained bone marrow smears were coded and examined blind using light microscopy at x1000 magnification. The incidence of micronucleated cells per 2000 polychromatic erythrocytes (PCE• blue stained immature cells) per animal was scored. Micronuclei are normally circular in shape, although occasionally they may be oval or half-moon shaped, and have a sharp contour with even staining. In addition, the number of normochromatic erythrocytes (NCE-pink stained mature cells) associated with 1000 erythrocytes were counted; these cells were also scored for incidence of micronuclei.
The ratio of polychromatic to normochromatic erythrocytes was calculated together with appropriate group mean values and standard deviations. - Statistics:
- A comparison was made between the number of micronucleated polychromatic erythrocytes occurring in each of the test material groups and the number occurring in the corresponding vehicle control group.
A positive mutagenic response was demonstrated when a statistically significant, dose-responsive, toxicologically relevant increase in the number of micronucleated polychromatic erythrocytes was observed for either the 24 or 48-hour kill times when compared to their corresponding control group.
If these criteria were not fulfilled, then the test material was considered to be non-genotoxic under the conditions of the test.
A positive response for bone marrow toxicity was demonstrated when the dose group mean polychromatic to normochromatic ratio was shown to be statistically significantly lower than the concurrent vehicle control group.
All data were statistically analysed using appropriate statistical methods as recommended by the UKEMS Sub-committee on Guidelines for Mutagenicity Testing Report, Part III (1989). The data was analysed following a ~(x + 1) transformation using Student's t-test (two tailed) and any significant results were confirmed using the one way analysis of variance.
Results and discussion
Test results
- Sex:
- male
- Genotoxicity:
- negative
- Toxicity:
- no effects
- Vehicle controls validity:
- valid
- Negative controls validity:
- not examined
- Positive controls validity:
- valid
Any other information on results incl. tables
GLYCYL (GR34000A): MICRONUCLEUS TEST IN THE MOUSE
Table1 Micronucleus Study·Summary of GroupMean Data
Treatment Group |
NumberofPCEwith Micronuclei per2000PCE |
PCE/NCE Ratio |
||
|
|
|||
GroupMean |
SD |
GroupMean |
SD |
|
1. Vehicle Control 48-hour Sampling Time |
2.3 |
1.3 |
0.78 |
0.30 |
2. Vehicle Control 24-hour Sampling Time |
1.6 |
1.1 |
0.80 |
0.31 |
3. Positive Control 24-hour Sampling Time |
61.6*** |
32.2 |
1.11 |
0.39 |
4. GLYCYL (GR34000A)300mg/kg 48-hour Sampling Time |
2.1 |
0.9 |
0.58 |
0.13 |
5. GLYCYL (GR34000A)300mg/kg 24-hour Sampling Time |
1.9 |
2.3 |
0.64 |
0.21 |
6. GLYCYL (GR34000A)150mg/kg 24-hour Sampling Time |
1.6 |
1.1 |
0.71 |
0.28 |
7. GLYCYL (GR34000A)75mg/kg 24-hour Sampling Time |
1.0 |
0.8 |
0.74 |
0.24 |
PCE =Polychromatic erythrocytes
NCE =Normochromatic erythrocytes
SD =Standarddeviation
*** =P<0.001
Table 2 Micronucleus Study -Individual and Group Means and Standard Deviations: Vehicle Control (10ml/kg) 48-Hour
Sampling Time
Treatment Group |
Animal Number |
Bodyweight (g) When Dosed |
Polychromatic Erthyrocytes (PCE) |
Normochromatic Erythrocytes (NCE) |
PCE/NCE Ratio |
|||
Number scored |
PCE+MN |
%PCE+MN |
Number scored |
NCE+MN |
PCE/NCE Ratio |
|||
1.VECHICLE CONTROL 10 ml/kg 48 -hour sampling time |
1 |
29 |
2000 |
3 |
0.15 |
613 |
2 |
0.63 |
2 |
29 |
2000 |
3 |
0.15 |
689 |
0 |
0.45 |
|
3 |
26 |
2000 |
2 |
0.10 |
564 |
0 |
0.77 |
|
4 |
27 |
2000 |
2 |
0.10 |
429 |
0 |
1.33 |
|
5 |
27 |
2000 |
0 |
0.00 |
496 |
0 |
1.02 |
|
6 |
27 |
2000 |
4 |
0.20 |
607 |
0 |
0.65 |
|
7 |
28 |
2000 |
2 |
0.10 |
616 |
1 |
0.62 |
|
Group Mean |
27.6 |
2000 |
2.3 |
0.11 |
573 |
0.4 |
0.78 |
|
SD |
1.1 |
0 |
1.3 |
0.06 |
86 |
0.8 |
0.30 |
Table 3 Micronucleus Study -Individual and Group Means and Standard Deviations: Vehicle Control (10ml/kg) 24-Hour
Sampling Time
Treatment Group |
Animal Number |
Bodyweight (g) When Dosed |
Polychromatic Erthyrocytes (PCE) |
Normochromatic Erythrocytes (NCE) |
PCE/NCE Ratio |
|||
Number scored |
PCE+MN |
%PCE+MN |
Number scored |
NCE+MN |
PCE/NCE Ratio |
|||
2. VEHICLE CONTROL 10 ml/kg 24 -hour sampling time |
8 |
26 |
2000 |
2 |
0.10 |
597 |
1 |
0.68 |
9 |
28 |
2000 |
0 |
0.00 |
567 |
0 |
0.76 |
|
10 |
28 |
2000 |
3 |
0.15 |
608 |
1 |
0.64 |
|
11 |
28 |
2000 |
1 |
0.05 |
624 |
0 |
0.60 |
|
12 |
27 |
2000 |
3 |
0.15 |
607 |
0 |
0.65 |
|
13 |
29 |
2000 |
1 |
0.05 |
403 |
0 |
1.48 |
|
14 |
27 |
2000 |
1 |
0.05 |
557 |
0 |
0.80 |
|
Group Mean |
27.6 |
2000 |
1.6 |
0.08 |
566 |
0.3 |
0.80 |
|
SD |
1.0 |
0 |
1.1 |
0.06 |
76 |
0.5 |
0.31 |
Table 4 Micronucleus Study - Individual and Group Means and Standard Deviations: Cyclophosphamide (50 mg/kg) 24-Hour Sampling Time
Treatment Group |
Animal Number |
Bodyweight (g) When Dosed |
Polychromatic Erthyrocytes (PCE) |
Normochromatic Erythrocytes (NCE) |
PCE/NCE Ratio |
|||
Number scored |
PCE+MN |
%PCE+MN |
Number scored |
NCE+MN |
PCE/NCE Ratio |
|||
3 CYCLOPHOSPHAMIDE 50 mg/kg 24-hour sampling time |
15 |
30 |
2000 |
31 |
1.55 |
407 |
1 |
1.46 |
16 |
27 |
2000 |
30 |
1.50 |
641 |
0 |
0.56 |
|
17 |
27 |
2000 |
71 |
3.55 |
473 |
0 |
1.11 |
|
18 |
25 |
2000 |
107 |
5.35 |
518 |
0 |
0.93 |
|
19 |
28 |
2000 |
69 |
3.45 |
403 |
0 |
1.48 |
|
Group Mean |
27.4 |
2000 |
61.6 |
3.08 |
488 |
0.2 |
1.11 |
|
SD |
1.8 |
0 |
32.2 |
1.61 |
98 |
0.4 |
0.39 |
Table 5 Micronucleus Study -Individual and Group Means and Standard Deviations: Test Material (300 mg/kg) 48-Hour
Sampling Time
Treatment Group |
Animal Number |
Bodyweight (g) When Dosed |
Polychromatic Erthyrocytes (PCE) |
Normochromatic Erythrocytes (NCE) |
PCE/NCE Ratio |
|||
Number scored |
PCE+MN |
%PCE+MN |
Number scored |
NCE+MN |
PCE/NCE Ratio |
|||
4 Glycyl (GR34000A) 300 mg/kg 48-hour sampling time |
20 |
27 |
2000 |
3 |
0.15 |
606 |
0 |
0.65 |
21 |
27 |
2000 |
1 |
0.05 |
562 |
0 |
0.78 |
|
22 |
27 |
2000 |
3 |
0.15 |
667 |
1 |
0.50 |
|
23 |
29 |
2000 |
2 |
0.10 |
636 |
0 |
0.57 |
|
24 |
27 |
2000 |
1 |
0.05 |
591 |
0 |
0.69 |
|
25 |
26 |
2000 |
2 |
0.10 |
723 |
1 |
0.38 |
|
26 |
27 |
2000 |
3 |
0.15 |
661 |
1 |
0.51 |
|
Group Mean |
27.1 |
2000 |
2.1 |
0.11 |
635 |
0.4 |
0.58 |
|
SD |
0.9 |
0 |
0.9 |
0.04 |
54 |
0.5 |
0.13 |
Table 6 Micronucleus Study - Individual and Group Means and Standard Deviations: Test Material (300 mg/kg) 24-Hour Sampling Time
Treatment Group |
Animal Number |
Bodyweight (g) When Dosed |
Polychromatic Erthyrocytes (PCE) |
Normochromatic Erythrocytes (NCE) |
PCE/NCE Ratio |
|||
Number scored |
PCE+MN |
%PCE+MN |
Number scored |
NCE+MN |
PCE/NCE Ratio |
|||
5 Glycyl (GR34000A) 300 mg/kg 24-hour sampling time |
27 |
29 |
2000 |
1 |
0.05 |
596 |
0 |
0.68 |
28 |
27 |
2000 |
3 |
0.15 |
505 |
1 |
0.98 |
|
29 |
28 |
2000 |
0 |
0.00 |
612 |
0 |
0.63 |
|
30 |
27 |
2000 |
0 |
0.00 |
696 |
2 |
0.44 |
|
31 |
30 |
2000 |
6 |
0.30 |
717 |
0 |
0.39 |
|
32 |
25 |
2000 |
0 |
0.00 |
557 |
0 |
0.80 |
|
33 |
27 |
2000 |
3 |
0.15 |
653 |
0 |
0.53 |
|
Group Mean |
27.6 |
2000 |
1.9 |
0.09 |
619 |
0.4 |
0.64 |
|
SD |
1.6 |
0 |
2.3 |
0.11 |
75 |
0.8 |
0.21 |
Table 7 Micronucleus Study-Individual and Group Means and Standard Deviations: Test Material (150mg/kg) 24-Hour
Sampling Time
Treatment Group |
Animal Number |
Bodyweight (g) When Dosed |
Polychromatic Erthyrocytes (PCE) |
Normochromatic Erythrocytes (NCE) |
PCE/NCE Ratio |
|||
Number scored |
PCE+MN |
%PCE+MN |
Number scored |
NCE+MN |
PCE/NCE Ratio |
|||
6 Glycyl (GR34000A) 150 mg/kg 24-hour sampling time |
34 |
28 |
2000 |
1 |
0.05 |
689 |
0 |
0.45 |
35 |
28 |
2000 |
3 |
0.15 |
468 |
1 |
1.14 |
|
36 |
27 |
2000 |
3 |
0.15 |
609 |
1 |
0.64 |
|
37 |
26 |
2000 |
1 |
0.05 |
610 |
1 |
0.64 |
|
38 |
27 |
2000 |
0 |
0.00 |
499 |
0 |
1.00 |
|
39 |
28 |
2000 |
1 |
0.05 |
572 |
0 |
0.75 |
|
40 |
26 |
2000 |
2 |
0.10 |
745 |
1 |
0.34 |
|
Group Mean |
27.1 |
2000 |
1.6 |
0.08 |
599 |
0.6 |
0.71 |
|
SD |
0.9 |
0 |
1.1 |
0.06 |
98 |
0.5 |
0.28 |
Table 8 Micronucleus Study -Individual and Group Means and Standard Deviations: Test Material (75 mg/kg) 24-Hour
Sampling Time
Treatment Group |
Animal Number |
Bodyweight (g) When Dosed |
Polychromatic Erthyrocytes (PCE) |
Normochromatic Erythrocytes (NCE) |
PCE/NCE Ratio |
|||
Number scored |
PCE+MN |
%PCE+MN |
Number scored |
NCE+MN |
PCE/NCE Ratio |
|||
7 Glycyl (GR34000A) 75 mg/kg 24-hour sampling time |
41 |
29 |
2000 |
0 |
0.00 |
543 |
0 |
0.84 |
42 |
27 |
2000 |
1 |
0.05 |
628 |
0 |
0.59 |
|
43 |
29 |
2000 |
0 |
0.00 |
447 |
1 |
1.24 |
|
44 |
30 |
2000 |
1 |
0.05 |
576 |
0 |
0.74 |
|
45 |
27 |
2000 |
1 |
0.05 |
601 |
0 |
0.66 |
|
46 |
25 |
2000 |
2 |
0.10 |
676 |
0 |
0.48 |
|
47 |
29 |
2000 |
2 |
0.10 |
604 |
0 |
0.66 |
|
Group Mean |
28.0 |
2000 |
1.0 |
0.05 |
582 |
0.1 |
0.74 |
|
SD |
1.7 |
0 |
0.8 |
0.04 |
73 |
0.4 |
0.24 |
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information): negative
The test material was considered to be non-genotoxic under the conditions of the test. - Executive summary:
Introduction
The study was performed to assess the potential of the test material to produce damage to chromosomes or aneuploidy when administered to mice. The method was designed to comply with the UKEMS Sub-committee on Guidelines for Mutagenicity Testing, Report, Part 1 revised (Basic Mutagenicity Tests: UKEMS recommended procedures, 1990). The study design also complies with the 1997 OECD Guidelines for Testing of Chemicals No.474 "Micronucleus Test", Method B12 of the EC Commission Directive 2000/32/EC, the USA EPA, TSCA and FIFRA guidelines and the Japanese METI/MHLW guidelines for testing of new chemical substances.
Methods
A range-finding test was performed to find suitable dose levels of the test material, route of administration and investigate to see if there was a marked difference in toxic response between the sexes. There was no marked difference in test material toxicity between the sexes; therefore the main study was performed using only male mice. The micronucleus test was conducted using the intraperitoneal route in groups of seven mice at the dose maximum tolerated dose (MTD) of 300mg/kg with 150 and 75 mg/kg as the two lower dose levels. Animals were killed 24 or 48 hours later, the bone marrow was extracted, smear preparations made and stained. Polychromatic (PCE) and normochromatic (NCE) erythrocytes were scored for the presence of micronuclei.
Further groups of mice were given a single intraperitoneal dose of arachis oil (7 mice) or dosed orally with cyclophosphamide (5 mice), to serve as vehicle and positive controls respectively. Vehicle control animals were killed 24 or 48 hours later, and positive control animals were killed after 24 hours.
Results
No statistically significant decreases in the PCE/NCE ratio were observed in the 24 or 48-hour test material dose groups when compared to their concurrent control groups. Though it should be noted that at both exposure times marked reductions in the PCE/NCE were observed with the test material at 300 mg/kg. This accompanied with the presence of clinical signs was taken to indicate that systemic absorption had occurred and exposure of the bone marrow achieved.
There was no evidence of a significant increase in the incidence of micronucleated polychromatic erythrocytes in animals dosed with the test material when compared to the concurrent vehicle control groups.
The positive control group showed a marked increase in the incidence of micronucleated polychromatic erythrocytes hence confirming the sensitivity of the system to the known mutagenic activity of cyclophosphamide under the conditions of the test.
Conclusion
The test material was considered to be non-genotoxic under the conditions of the test.
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