Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report date:
1992

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Qualifier:
according to guideline
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Phthalocyanine-N-[3-(diethylamino)propyl]sulfonamide copper complex
EC Number:
413-650-9
EC Name:
Phthalocyanine-N-[3-(diethylamino)propyl]sulfonamide copper complex
Cas Number:
93971-95-0
Molecular formula:
Can not be identified
IUPAC Name:
hexacopper(2+) 5-{[3-(diethylamino)propyl]sulfamoyl}-2,11,20,29,37,38,39,40-octaazanonacyclo[28.6.1.1^{3,10}.1^{12,19}.1^{21,28}.0^{4,9}.0^{13,18}.0^{22,27}.0^{31,36}]tetraconta-1,3(40),4,6,8,10,12,14,16,18,20,22,24,26,28(38),29,31,33,35-nonadecaene-37,39-diide 6,14-bis({[3-(diethylamino)propyl]sulfamoyl})-2,11,20,29,37,38,39,40-octaazanonacyclo[28.6.1.1^{3,10}.1^{12,19}.1^{21,28}.0^{4,9}.0^{13,18}.0^{22,27}.0^{31,36}]tetraconta-1,3(40),4,6,8,10,12,14,16,18,20,22,24,26,28(38),29,31,33,35-nonadecaene-37,39-diide 6,15-bis({[3-(diethylamino)propyl]sulfamoyl})-2,11,20,29,37,38,39,40-octaazanonacyclo[28.6.1.1^{3,10}.1^{12,19}.1^{21,28}.0^{4,9}.0^{13,18}.0^{22,27}.0^{31,36}]tetraconta-1,3(40),4,6,8,10,12,14,16,18,20,22,24,26,28(38),29,31,33,35-nonadecaene-37,39-diide 6-{[3-(diethylamino)propyl]sulfamoyl}-2,11,20,29,37,38,39,40-octaazanonacyclo[28.6.1.1^{3,10}.1^{12,19}.1^{21,28}.0^{4,9}.0^{13,18}.0^{22,27}.0^{31,36}]tetraconta-1,3(40),4,6,8,10,12,14,16,18,20,22,24,26,28(38),29,31,33,35-nonadecaene-37,39-diide 7-{[3-(diethylamino)propyl]sulfamoyl}-2,11,20,29,37,38,39,40-octaazanonacyclo[28.6.1.1^{3,10}.1^{12,19}.1^{21,28}.0^{4,9}.0^{13,18}.0^{22,27}.0^{31,36}]tetraconta-1,3(40),4,6,8,10,12,14,16,18,20,22,24,26,28(38),29,31,33,35-nonadecaene-37,39-diide 8-{[3-(diethylamino)propyl]sulfamoyl}-2,11,20,29,37,38,39,40-octaazanonacyclo[28.6.1.1^{3,10}.1^{12,19}.1^{21,28}.0^{4,9}.0^{13,18}.0^{22,27}.0^{31,36}]tetraconta-1,3(40),4,6,8,10,12,14,16,18,20,22,24,26,28(38),29,31,33,35-nonadecaene-37,39-diide
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
Test Animals
- Source : Charles River (U.K.) Limited, Manston, Kent, U.K.
- Weight at study initiation : male 135 - 171 g, female 127 - 163 g
Environmental Conditions
- Temperature : 16 - 22 ºC
- Humidity : 38 - 73%
- Air exchange : at least 15 changes per hour
- Photoperiod : 12 hours light and 12 hours darkness

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The absorbance was measured at 695 nm in 1 cm cells using chloroform as the reference medium.
The test material formulations were analysed in triplicate within three days of preparation.

Nominal / Mean / Mean concentration / Range / Range /
concentration / concentration / expressed / (mg/ml) / expressed /
(mg/ml) / found (mg/ml)/ as % of nominal / / as % of nominal /
-------------------------------------------------------------------------------
3.75 / 3.89 / 104 / 3.72-4.13 / 99-110 /
37.5 / 37.8 / 101 / 36.1-38.5 / 96-103 /
250 / 258 / 103 / 244-270 / 98-108 /
Duration of treatment / exposure:
28 days
Frequency of treatment:
The test material was administered daily, for twenty-eight consecutive days.
Doses / concentrations
Remarks:
Doses / Concentrations:
Doses level : 0(control), 15, 150 and 1000 mg/kg/day, Treatment volume : 4 ml/kg, Concentration : 0(control), 3.75, 37.5, 250 mg/mL
Basis:
other: nominal in vehicle
No. of animals per sex per dose:
Test groups per dose male:5, female:5
control group mail:5, female:5

Examinations

Observations and examinations performed and frequency:
a) Clinical signs : observe immediately befor dosing and one hour after dosing at weekends.
b) Bodyweight : start of treatment ( day 0) and days seven, fourteen, twenty-one and twenty-eight.
c) Food consumption : at weekly intervals
d) Water consumption : daily
e) Laboratory investigations i) Haematology and ii) Blood chemistry : end of the study (day 28)
f) Pathology i) Organ weights and ii) Histopathology : end of the study (day 28)

Sacrifice and pathology:
i) Organ Weights
ii) Histopathology

Statistics:
Absolute and relative organ weights, haematological and blood chemical data were analysed by one way analysis of variance incorporating 'F-max' test for homogeneity of variance.
Data showing heterogeneous variances were analysed using Kruskal Wallis non-parametric analysis of variance and Mann Whitney U-Test.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
There were no deaths during the study.
Mortality:
no mortality observed
Description (incidence):
There were no deaths during the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Bodyweight gain in test animals was comparable with that seen in controls.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No adverse effects on food consumption were detected.
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
No overt intergroup differences were detected.
Haematological findings:
no effects observed
Description (incidence and severity):
No treatment-related effects were detected.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No clinically observable signs of toxicity were detected in test or control animals throughout the study period.
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No treatment-related effects were detected.
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No treatment-related microscopic changes were observed.

Effect levels

Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: Mortality data, Clinical observations, Bodyweight, Food consumption, Water consumption, Haematology, Blood chemistry, Necropsy, Organ weight, Histopathology

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Blood chemistry : No treatment-related effects were detected.

Necropsy : No treatment-related macroscopic abnormalities were detected.

  Table 1 : Group mean haematological values and standard deviations (sd) - Males
 Dose Level  Hb  RBC  Hct  MCH  MCV  MCHC  WBC

 mg/kg/day

 (g/dl) (10^12 /l)  (%)  (pg)  (fl) (g/dl)  (10^9 /l)
 1 Control mean 14.9 7.10 42.2 21  59  35  10.5
sd 0.6  0.19  1.7  0 2  0  1.4
 2 15 mean 15.0 7.30 42.7 21 59  35  13.4
 sd  0.8  0.35  2.1  1  1  0  3.7
 3 150 mean  14.8 7.22 41.7 21  58  36** 13.2
sd  0.7  0.29  2.4  1 2  1  4.0
 4 1000 mean  14.7  7.04  41.7  21  59  35  11.1
sd  0.4  0.21  1.4  1  2  0  2.9
                      
 Dose Level  Neut  Lymph  Mono  Eos  Bas CT  PLT
mg/kg/day  (10^9 /l)  (10^9 /l)  (10^9 /l)  (10^9 /l)  (10^9 /l)  (secs)  (10^9 /l)
 1 Control mean  2.52  7.91 0.00 0.11 0.00   31  1128
 sd  1.34  1.06 0.00 0.14  0.00  1  176
 2 15 mean 2.73 10.48  0.08  0.15  0.00 31 1090
 sd  1.03  2.84  0.17  0.18  0.00  2  195
 3 150 mean  3.49   9.48  0.15  0.06  0.00  31  1136
 sd  0.71   3.56  0.15  0.09  0.00  1  81
 4 1000 mean  2.27  8.67  0.05  0.11  0.00  30  1106
 sd  0.60  2.42  0.07  0.11  0.00  2  138
** = significantly different from control group value p =< 0.01                      
  Hb:Haemoglobin, RBC: Erythrocyte count, Hct: Haematocrit, MCH: mean corpuscular haemoglobin, MCV: mean corpuscular volume, MCHC: mean corpuscular haemoglobin concentration, WBC: Total leucocyte count, Neut: Neutrophils, Lymph: Lymphocytes, Mono: Monocytes, Eos: Eosinophils, Bas: Basophils, CT: Clotting time, PLT: Platelet counts

  Table 2 : Group mean haematological values and standard deviations (sd) - Females
 Dose Level  Hb  RBC  Hct  MCH  MCV  MCHC  WBC

 mg/kg/day

 (g/dl) (10^12 /l)  (%)  (pg)  (fl) (g/dl)  (10^9 /l)
 1 Control mean 14.1 6.82 39.5 21  58 36 9.7
sd 0.2 0.19 0.7 0 2 3.4
 2 15 mean 13.9 6.96 39.5 20 57 35  8.3 
  sd 0.4  0.25 1.3  3.3 
 3 150 mean  14.2 6.98 39.7 20 57 36 8.4
 sd  0.5 0.40 1.7 1  1 3.6
 4 1000 mean  14.6*  7.02 40.8 21 58 36  6.9
  sd 0.3 0.28 1.4  2 1 2.4
                      
 Dose Level  Neut  Lymph  Mono  Eos  Bas CT  PLT
mg/kg/day  (10^9 /l)  (10^9 /l)  (10^9 /l)  (10^9 /l)  (10^9 /l)  (secs)  (10^9 /l)
 1 Control mean 2.08  7.51 0.00 0.12 0.00 30  972
 sd 1.34   2.19 0.00 0.09 0.00 1 302
 2 15 mean 1.20  6.94 0.05  0.07 0.00  30  1134
sd  0.75 3.19  0.07  0.04 0.00 39 
 3 150 mean 1.52 6.83 0.01 0.09 0.00 31  1124 
sd  0.97 2.83 0.02 0.08  0.00 2 170
 4 1000 mean  1.35 5.38 0.01 0.14 0.00 29 1050 
sd 0.16 2.22 0.03 0.11 0.00 1 33 

* = significantly different from control group value p =< 0.05 
Hb:Haemoglobin, RBC: Erythrocyte count, Hct: Haematocrit, MCH: mean corpuscular haemoglobin, MCV: mean corpuscular volume, MCHC: mean corpuscular haemoglobin concentration, WBC: Total leucocyte count, Neut: Neutrophils, Lymph: Lymphocytes, Mono: Monocytes, Eos: Eosinophils, Bas: Basophils, CT: Clotting time, PLT: Platelet counts
 
Table 3 : Group mean blood chemistry values and standard deviations (sd) -Males
 Dose Level  UREA  GLUCOSE  TOT.PROT  ALBUMIN  A/G  Na+  K+  Cl-
 mg/kg/day  (mg/dl)  (mg/dl)  (g/dl)  (g/dl)  ratio  (mmol/l)  (mmol/l)  (mmol/l)
 1 Control mean  26  142  6.82  3.99  1.42  144  4.77  96
 sd  4  16  0.26  0.07  0.13  8  0.18  3
 2 15 mean  29 149  7.09 4.16* 1.42  142  4.74  98
 sd  4  22  0.10  0.11  0.07  4  0.28  3
 3 150 mean  33**  142  6.96  4.09  1.43  138  4.82  96
 sd  3  13  0.27  0.11  0.13  9  0.30  2
 4 1000 mean  32*  144  7.01  4.01  1.35  139  4.83  95
 sd  3  17  0.36  0.14  0.16  6  0.35  1
                         
 Dose Level  Ca++  P  ASAT  ALAT  AP  CREAT  BILI  
 mg/kg/day  (mmol/l)  (mmol/l)  (IU/l)  (IU/l)  (IU/l)  (mg/dl)  (mg/dl)  
 1 Control mean  3.00  2.18  87  48  701  0.60  1.24  
 sd  0.12  0.22  8  4  108  0.01  0.56  
 2 15 mean  3.00  2.20  98  52  602  0.59  1.04  
 sd  0.05  0.15  12  5  131  0.03  0.28  
 3 150 mean  3.00  2.28  92  51  717  0.62  1.15  
 sd  0.10  0.28  28  11  93  0.05  0.44  
 4 1000 mean  2.92  2.20  97  46  602  0.63  0.88  
 sd  0.07  0.19  8  3  118  0.03  0.40  
* = significantly different from control group value p =< 0.05               
** = significantly different from control group value p =< 0.01                    
 TOT.PROT : Total protein, A/G: Albumin/globulin ratio, P: Inorganic phoshorus, ASAT: Aspartate aminotransferase, ALAT: Alanine aminotransferase, AP:Alkaline phosphatase, CREAT: Creatinine, BILI: Total bilirubin
Table 4 : Group mean blood chemistry values and standard deviations (sd) - Famales

 Dose Level  UREA  GLUCOSE  TOT.PROT  ALBUMIN  A/G  Na+  K+  Cl-
 mg/kg/day  (mg/dl)  (mg/dl)  (g/dl)  (g/dl)  ratio  (mmol/l)  (mmol/l)  (mmol/l)
 1 Control mean  31  130  6.91  4.11  1.47  135  4.39  98
sd   7  12  0.29  0.18  0.02  4  0.28  4
 2 15 mean  32  145*  6.82  4.22  1.63*  128  4.10  98
 sd  5  12  0.46  0.24 0.10  7  0.33  1
 3 150 mean  31  134  6.79  4.30  1.73***  132  4.04  99
 sd  3  10  0.41  0.28  0.14  8  0.22  3
 4 1000 mean  28  150**  6.98  4.17  1.49  137  4.09  97
 sd  2  8  0.29  0.17  0.04  3  0.32  3
                         
 Dose Level  Ca++  P  ASAT  ALAT  AP  CREAT  BI LI  
 mg/kg/day  (mmol/l)  (mmol/l)  (IU/l)  (IU/l)  (IU/l)  (mg/dl)  (mg/dl)  
 1 Control mean  2.91  1.96  104  50  566  0.67  0.78  
 sd  0.05  0.36  12  10  163  0.03  0.18  
2 15 mean   2.88  1.99  101  48  521  0.67  0.52  
 sd  0.09  0.51  20  13  152  0.09  0.22  
 3 150 mean  2.89  1.78  94  47  626  0.67  0.77  
 sd  0.05  0.32  15  7  167  0.03  0.25  
 4 1000 mean  2.86  1.60  100  46  477  0.68  0.64  
 sd  0.07  0.24  13  7  136  0.04  0.12  
* = significantly different from control group value p =< 0.05                  
** = significantly different from control group value p =< 0.01
*** = significant different from control group value p =< 0.001
  TOT.PROT : Total protein, A/G: Albumin/globulin ratio, P: Inorganic phoshorus, ASAT: Aspartate aminotransferase, ALAT: Alanine aminotransferase, AP:Alkaline phosphatase, CREAT: Creatinine, BILI: Total bilirubin

Table 5 : Group mean relative organ weights (% of bodyweight) and standard deviations (sd) - Males

 Dose Level Relative Organ weight (%)
 mg/kg day adrenals  brain gonads heart  kidneys liver pituitary spleen
1 Control mean 0.0151  0.5801  1.2194  0.3388  0.7031  3.9632  0.0014  0.2183
 sd  0.0043  0.0375  0.1342  0.0085  0.0419  0.2375  0.0009  0.0328

2 15 mean

 0.0107*  0.5337  1.2920  0.3561  0.6983  4.3429*  0.0023  0.2374
sd  0.0023  0.0511 0.1008  0.0350  0.0609  0.3787  0.0003  0.0125

3 150 mean

 0.0107*  0.5466  1.2337  0.3501  0.6720  3.8972  0.0027** 0.2219 
sd  0.0016  0.0473  0.1066  0.0229  0.0525  0.1673  0.0007  0.0224
 4 1000 mean  0.0130  0.5440 1.1743  0.3452  0.6750  3.9266  0.0022  0.2183
 sd  0.0021  0.0419  0.1394  0.0379  0.0487  0.2772  0.0007  0.0212

* = significantly different from control group value p =< 0.05

** = significantly different from control group value p =< 0.01

 

Table 6 : Group mean relative organ weights (% of bodyweight) and standard deviations (sd) - Females

 Dose Level Relative Organ weight (%)
 mg/kg day adrenals  brain gonads heart  kidneys liver pituitary spleen
1 Control mean  0.0214  0.7636  0.0500  0.4104  0.7312  3.7100 0.0049   0.2340
 sd  0.0030  0.0816  0.0050  0.0151  0.0413  0.2159  0.0008  0.0162

2 15 mean

0.0199  0.7988  0.0545  0.4041  0.7551  3.8450  0.0048  0.2428
sd  0.0036  0.0476  0.0062  0.0170  0.0673 0.2569  0.0010  0.0411

3 150 mean

 0.0222  0.7753  0.0523  0.4038  0.7606  3.7874  0.0041  0.2349
sd  0.0033  0.0628  0.0087  0.0302  0.0357  0.1688  0.0008  0.0323
 4 1000 mean  0.0214  0.7709  0.0456  0.3952  0.7123  4.0536*  0.0044  0.2378
 sd  0.0056  0.0550  0.0057  0.0117  0.0469  0.2503  0.0011  0.0186
* = significant different from control group value p =< 0.05             
 

Table 7 : Summary incidence table - Male

   Group 1 Control  Group 4 1000 mg/kg/day
 number of animals  5  5

Heart

Focal myocarditis 1 1
absent  4  4
(minimal)       
Kindneys
 Groups of basophilic / dilated tubules    
absent  2  2
(minimal)  4  3
 Mononuclear cell foci    
 absent  4  5
 (minimal)  1  0
 Hydronephrosis    
 absent  4  4
 (minimal)  0  1
 (slight)  1  0
  Liver
 Mononuclear cell foci    
 (Minimal)  4  3
 (slight)  1  2
  Statistical information
 Mode of death    
 Terminal kill  5
 

Table 8 : Summary incidence table - Female

   Group 1 Control  Group 4 1000 mg/kg/day
 number of animals  5  5
Heart
Focal myocarditis
absent  2  0
(minimal)  3  5
Kindneys
 Groups of basophilic / dilated tubules    
absent  2  4
 (minimal)  3  1
  Liver
 Mononuclear cell foci    
 (Minimal)  4  3
 (slight)  1  2
  Statistical information
 Mode of death    
 Terminal kill 5  5

Applicant's summary and conclusion

Conclusions:
Oral administration of the test material for twenty-eight consecutive days in the rat at dose levels of up to 1000 mg/kg/day, produced no toxicologically significant changes in the parameters measured.
Executive summary:

NOEL (No Observed Effect Level) : 1000 mg/kg/day