2.6.7.10. がん原性試験 該当する試験なし。
2.6.7.11. 生殖発生毒性試験：重要な試験以外の試験
Test Article: Levocetirizine Species/
Strain
Method of Administration (Vehicle/Formulation)
Dosing Period Doses (mg/kg) No. per Group Noteworthy Findings Report No. Location in CTD Rat, SD Oral, gavage G6 to G15 0, 65, 130, 260 F0: 9 pregnant
female At 260mg/kg, 2 females died or were killed during the study. Clinical signs were restricted to post-dose salivation and noisy respiration and were generally transient. Loss of body tone was seen in 2 females, one of which was killed.
Food consumption was also reduced. There was a dose-related increase in water consumption and a decrease in bodyweight gain at 130 and 260mg/kg. There were no compound-induced fetal effects.
RRLE92G1001 4.2.3.5.2.1/ref
Rabbit,
NZW Oral, gavage Pilot study: 13 days
Prelim study:
G6 to G18
Pilot study: 100 or 300
Prelim study: 0, 23, 45, 90
Pilot study: 4 or 2 non-pregnant females/group.
Prelim study: 6 pregnant females/group
Pilot study: Due to the severity of clinical signs, both animals treated at 300mg/kg were killed after 1 dose. At 100mg/kg, there was anorexia and bodyweight loss causing one death.
Prelim study: Apart from some minor transient reductions in food consumption and
bodyweight gain at 90mg/kg, there were no obvious maternal effects. There were no obvious treatment-related effects on in utero development.
RRLE92G0903 4.2.3.5.2.3/ref
G: Day of gestation
2.6.7.12. 生殖発生毒性試験：受胎能、初期胚発生および胚・胎児発生に関する試験
該当する試験なし。
2.6.7. 毒性試験概要表
2.6.7 - p. 24
2.6.7.13. 生殖発生毒性試験：胚・胎児発生に関する試験
2.6.7.13.1. ラット胚・胎児発生に関する試験
Report Title: A study of the effect of ucb 28556 on the pregnancy of the rat: incorporating toxicokinetics Test Article: Levocetirizine/Cetirizine Design similar to ICH 4.1.3? Yes Duration of Dosing: G6 to G15 Report No. RRLE93F3001
Species/Strain: Rat, SD Day of Mating: Day 0 Location in CTD: 4.2.3.5.2.2 Initial Age: 8-10 weeks Day of C-Section: Day 20 GLP Compliance: Yes Date of First Dose: 19 Method of Administration: Oral, gavage
Special Features: None Vehicle/Formulation: Distilled/deionised water/solution No Observed Adverse Effect Level: F0 Females: 50mg/kg/day
No Observed Adverse Effect Level: F1 Litters: 100mg/kg/day
Levocetirizine Cetirizine
Daily Dose (mg/kg) 0 (Control) 50 100 200 200
Toxicokinetics
C2 on G15 (µg/mL) NA 31.4 60.6 102.7 43.2a; 21.0b
Females with sperm 25 25 25 25 25
Pregnant females 25 24 24 25 25
Evaluated pregnant females 25 24 24 25 23
No. died or sacrificed moribund 0 0 0 0 2
Clinical signs
Post-dose salivation/wet coat - 2 6 25 21
Noisy respiration - - 3 17 15
Hunched posture; pale extremities - - - 1 -
Bodyweight change (g)
At G8 10.6 8.2 7.1* 3.7** 1.3**
At G10 18.0 14.4 13.0* 7.8** 6.0**
At G12 31.9 26.3 27.6 19.7** 21.3**
At G14 43.6 39.2 39.3 32.2** 34.6**
At G16 60.8 57.3 56.5 49.9** 51.6**
At G18 86.8 83.0 78.1* 74.0** 73.2**
At G20 113.0 110.6 108.5 106.0 105.8
Group mean food consumption, G6-G11 (g/rat) 132 124 125 118* 115**
2.6.7. 毒性試験概要表
2.6.7 - p. 25
2.6.7.13.1. ラット胚・胎児発生に関する試験（続き）
Levocetirizine Cetirizine
Daily Dose (mg/kg) 0 (Control) 50 100 200 200
Litter means (arithmetic mean per litter)
Corpora lutea 13.3 13.9 13.4 13.7 13.2
Implantations 12.3 13.1 12.3 12.9 12.1
Live fetuses 11.9 12.3 11.6 12.2 11.4
Dead fetuses 0.1 0 0 0 0.2
Resorptions 0.3 0.8 0.7 0.7 0.5
Weight of fetuses 39.04 39.28 37.65 37.75 36.24
Sex ratio of fetuses (%M) 49.2 50.1 53.9 49.2 52.0 Skeletal and visceral malformations - - - - -
Visceral anomalies - - -
Skeletal anomalies
Variants Foetuses examined 147 143 138 149 130
Unossified sternebrae No. 86 94 86 105 100
% 58.5 64.2 61.1 70.2 75.0
Toxicokinetic evaluation report RRLE94C0902, -: No noteworthy findings, NA: Not applicable, G= Gestation day
*: p<0.05; **: p<0.01. (Statistical significance determined by analysis of variance followed by Student’s ‘t’ test or Williams’ test or non-parametric tests Kruskal-Wallis followed by Shirley’s test)
2.6.7. 毒性試験概要表
2.6.7 - p. 26
a: Concentration of levocetirizine, b: Concentration of gsk002#
# 新薬承認情報提供時に置き換え
2.6.7.13.2. ウサギ胚・胎児発生に関する試験
Report Title: A study of the effect of ucb 28556 on pregnancy of the rabbit incorporating toxicokinetics Test Article: Levocetirizine/Cetirizine Design similar to ICH 4.1.3? Yes Duration of Dosing: G6 to G18 Report No. RRLE93C3005
Species/Strain: Rabbit, NZW Day of Mating: Day 0 Location in CTD: 4.2.3.5.2.4 Initial Age: 16 to 25 weeks Day of C-Section: Day 29 GLP Compliance: Yes Date of First Dose: 19 Method of Administration: Oral, gavage
Special Features: None Vehicle/Formulation: Distilled/deionised water, solution No Observed Adverse Effect Level: F0 Females: 30mg/kg/day
No Observed Adverse Effect Level: F1 Litters: 60mg/kg/day
Levocetirizine Cetirizine
Daily Dose (mg/kg) 0 (Control) 30 60 120 120
Toxicokinetics
C1.5 on Day 18 (µg/mL) NA 23.6 38.7 95.7 51.3a; 42.9b
Females per group 16 16 16 16 16
Pregnant females 14 16 16 16 15
Evaluated pregnant females 13 15 16 13 13
No. died or sacrificed moribund 1 c 0 0 3 1 d Clinical signs - - - a slightly increased
incidence of reduced faecal output in 4/13 vs 2/13 control females with live young.
post-dose increased respiration rate, dilated pupils and salivation in 5/13, 2/13 and 1/13 females with live young respectively
Bodyweight change (g)
At G8 32 42 83 25 -46*
At G10 61 90 117 80 -11*
At G14 166 257 240 187 129
At G19 229 303 314 262 177
At G23 274 362 304 301 217
At G29 443 488 428 470 344
Food consumption cumulative value (g/rabbit)
Prior to treatment G0 to G5 688 694 862* 853* 726 During treatment G6 to G18 1899 2267* 2372** 2195** 1841 Post-treatment G19 to G22 596 517 438* 480* 442**
2.6.7. 毒性試験概要表
2.6.7 - p. 27
2.6.7.13.2. ウサギ胚・胎児発生に関する試験（続き）
Levocetirizine Cetirizine
Daily Dose (mg/kg) 0 (Control) 30 60 120 120
Litter means (arithmetic mean per litter)
Corpora lutea 9.5 10.5 11.5* 11.3* 10.1
Implantations 7.8 8.5 10.0 9.7 8.9
Live fetuses 7.5 7.7 8.5 8.5 7.8
Dead fetuses 0.2 0.5 0.8 0.4 0.5
Resorptions 0.2 0.3 0.7 0.8 0.7
Weight of fetuses 324.8 339.1 369.8 362.3 340.7 Sex ratio of fetuses (%M) 41.5 54.3 42.9 52.7 51.2
Skeletal and visceral malformations - - - - -
Visceral anomalies - - - - -
Skeletal anomalies
Skeletal variants Foetuses examined 96 113 131 109 97 Fetuses with 12 ribs No. 45 47 72 35 22
% 48.5 42.8 52.5 25.3 22.8*
Fetuses with 13 ribs No. 51 66 59 74 75
% 51.5 57.2 47.5 74.7 77.2*
Toxicokinetic evaluation report RRLE94A1102, G = Gestation day, -: No noteworthy findings, NA: Not applicable
c: One control animal was found dead on Day 25 of pregnancy but the cause of death was not established. Clinical signs observed prior to death included reduced or no faecal output, cold ears, dark eyes, unsteady gait and blood on tray paper.
d: One animal treated with cetirizine was found dead on Day 18 of pregnancy immediately after dosing. Prior to death clinical signs of increased respiration rate, poor food intake and reduced faecal output.
However, autopsy revealed brown fluid in the thoracic cavity and perforated oesophagus, findings consistent with an incubation error and unrelated to treatment with cetirizine.
*: p<0.05; **: p<0.01. Statistical significance of bodyweight and food consumption determined by analysis of variance followed by Student’s ‘t’ test or Williams’ test or non-parametric tests Kruskal-Wallis followed by Shirley’s test. Analysis of malformation and anomalies was performed using a trend test on the number of litters affected followed by a 2 sample permutation test (Eddington, 1980; Franck, 1986).
2.6.7. 毒性試験概要表
2.6.7 - p. 28
# 新薬承認情報提供時に置き換え
a: Concentration of levocetirizine, b: Concentration of gsk002#
2.6.7.14. 生殖発生毒性試験：出生前および出生後の発生ならびに母体の機能に関する試験 該当する試験なし。
2.6.7.15. 新生児を用いた試験
該当する試験なし。
2.6.7.16. 局所刺激性試験
該当する試験なし。
2.6.7.17. その他毒性試験
2.6.7.17.1. 免疫毒性試験
Test Article: Levocetirizine/Cetirizine Species/Strain Method of
Administration (Vehicle/Formulation)
Duration of Dosing
Doses (mg/kg/day)
Gender and No.
per Group Noteworthy Findings Report No. Location in CTD Immunotoxicity
Rat, SD Oral, gavage (Distilled water/solution)
13 weeks Levocetirizine;
0, 18.7, 37.5, 75 Cetirizine; 37.5, 75
15M/15F;
control and high dose groups;
10M/10F other groups
Treatment of rats with levocetirizine and cetirizine up to 75mg/kg did not produce any effect on the immune system as assessed by lymphocyte subset counts.
RRLE98H2403 4.2.3.7.2.1
2.6.7. 毒性試験概要表
2.6.7 - p. 29
2.6.7.17.2. 不純物の毒性試験（細菌を用いる復帰突然変異試験）
Report Title: Bacterial mutation assay. Test Article: Levocetirizine No. of Independent Assays: 2 Report No. RRLE92B1303 Strains: Salmonella typhimurium TA98, TA100, TA1535, TA1537, TA1538
No. of Replicate Cultures: 3 Location in CTD: 4.2.3.7.6.1 Metabolizing System: Aroclor 1254 induced rat liver S9-fraction. No. of Cells Analyzed/Culture: Not applicable GLP Compliance: Yes
Vehicles: For test article - water. For positive controls - DMSO. Date of Treatment: to 19 . Treatment: 3 days (+S9 or -S9)
Cytotoxic No toxicity observed up to 5000µg/plate (-S9 or +S9).
Genotoxic Effects: No genotoxicity observed up to 5000µg/plate (-S9 or +S9).
Mean revertant colony counts
TA98 TA100 TA1535 TA1537 TA1538 Metabolic
Activation Test Article Conc.
(µg/plate)
1 2 1 2 1 2 1 2 1 2
Solvent 22 27 101 118 14 12 15 13 15 12
0 23 21 110 107 9 13 13 11 14 12
50 23 21 97 111 14 12 15 12 12 12
150 23 28 107 123 14 15 15 10 13 13 500 22 22 102 112 14 13 9 9 11 14
1500 26 22 98 114 12 11 10 10 10 9
Levocetirizine
5000 24 22 96 94 11 13 12 11 7 10
3.0 307 337
N-ethyl-N’-nitro-N-nitrosoguanidine
5.0 176 197
1.0 134 130
2-nitrofluorene
2.0 69 100
Without activation
9-aminoacridine 80.0 X X
2.6.7. 毒性試験概要表