Document OEXEaZ3X3jomeJJXMz3zDXb5p
Lab Na L 1538
NOTICE
SBRTC-2016-0335-2
1. It will be invalid for the report without a connective seal. 2. It will be invalid for the report without the signature of study director. 3. It will be invalid for the manual revision of the report. 4. It can't be copied partly on the report without agreement, nor can be as the
recorder of the order receiving and advertisement registration. 5. Please raise the objection to the Center within 15 days after the receipt of the
report, otherwise it will be considered to accept the testing result. 6. It is only responsible for the samples received.
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SHANGHAI BIOMATERIALS RESEARCH & TEST CENTER
Add: 201, Building 2, Ns 427 Jumen Road, Shanghai, China
Zip Code: 200023
TEL: 0086-21-63034903 Web site: www.sbrtc.com
EMI FAX: 00
E-mail:
)163
com
Lab 1\T2 L 1538
TABLE OF CONTENTS
SUMMARY INTRODUCTION MA l'ERIALS METHODS DEVIATIONS RESULTS CONCLUSION RECORD STORAGE PHOTOGRAPH OF THE TEST ARTICLE APPENDIX
SBRTC-2016-0335-2
4 5 5 5 7 7 .8 8 8 9
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SHANGHAI BIOMATERIALS RESEARCH & TEST CENTER
Add: 201, Building 2, Ng 427 Jumen Road, Shanghai, China
Zip Code: 200023
TEL: 0086-21-63034903
FAX: 001111111111
Web site: www.sbrtc.com
E-mail:
163.com
Lab NQ L 1538
SBRTC-2016-0335-2
INTRODUCTION
The purpose of the study was to evaluate the potential of the test article to cause subchronic systemic toxicity by subcutaneous Implantation Route in the rat. This test was conducted based on the requirements of ISO 10993-11:2006 Part 11: Tests for systemic toxicity. The test article was received on Jun. 16, 2015. The animals were treated on Nov. 17, 2015, and the terminal procedures were performed on Mar. 31, 2016.
This study, initiated by protocol signature on Oct. 8, 2015, was completed in the Lab of Shanghai Biomaterials Research & Test Center (SBRTC) and was conducted in accordance with the provisions of the ISO/IEC 17025-2005.
MATERIALS
The test article provided by the sponsor was identified and handled as follows:
Test Article:
Non-absorbable Surgical Suture (model: PTFE)
<Specification: Z21302-60 (USP2-0/EP2.5)>
Identification No:
150643
Temperature Tolerance: STERILE
Storage Conditions:
Room temperature
Test Article Preparation:
According the requirement of the sponsor, 450cm (0.72g)/ 70kg [sample amount/human weight] of clinical maximum dosage, 30 times of animal experiment amplification, 237cm of the test sample was implanted into the subcutaneous tissue per 200g of a rat, respectively.
Blank Control:
According the requirement of the sponsor, the blank control group received surgical insult only.
METHODS
Test System: Species: Strain: Source: Sex: Body Weight Range: Number of Animals:
Rat SD Shanghai Jiesijie Experimental Animal CO., LTD 20 male, 20 female 184.2g to 218.6g before injection 40
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SHANGHAI BIOMATERIALS RESEARCH & TEST CENTER
Add: 201, Building 2, NQ 427 Jumen Road, Shanghai, China
Zip Code: 200023
TEL: 0086-21-63034903
FAX: 00/Mill
Web site: www.sbrtc.com
E-mail:
163.com
Lab Na L 1538
SBRTC-2016-0335-2
Animal Management: Husbandry:
Food: Water: Housing:
Environmental:
Personnel: Selection:
Conditions conformed to "Laboratory animal-Requirements of environment and housing facilities"; "ISO 10993-2:2006: Biological evaluation of medical devices Part 2: Animal welfare requirements".
Diet was provided from Shanghai Pu Lu Teng Biological Technology Co. Ltd.
Pure water
Healthy animals were acclimatized to the laboratory conditions for 5 days before the treatment, and then they were randomized and assigned to groups in stainless steel suspended cages identified by a card indicating the Identification Na of the test article and first treatment date.
The room temperature and humidity were monitored daily. The room temperature range was from 20 C to 24 C. The room humidity range was from 50 % to 60%. The light cycle was controlled using an automatic timer (12 hours light, 12 hours dark).
Associates involved were appropriately qualified and trained.
Only healthy, unused animals were selected.
Experimental Procedure: Prior to dosing, each rat was weighed and identified. Forty rats (20 male, 20 female) divided into two groups. Each group (10 male, 10 female) was treated with the test sample and the blank control by the subcutaneous implantation route respectively. Rats were observed daily for general health.
Laboratory Observation: 1.Body weights were recorded for each rat prior to injection, weekly, the day prior to termination
(pre-fasted weights) and the day of termination (fasted weights). 2.Animals were observed daily for general health. 3.Detailed examinations for clinical signs of disease or abnormality were conducted daily for the
90 days.
Terminal Procedures: At the end of the workday on day 90, the animals were weighed and food was withheld for a maximum of 20 hours. On day 91, the animals were weighed. The blood specimen was collected from femoral artery and then performed a complete blood cell count with differential and clinical chemistry analyses. Then the rats were euthanatized by an intravenous bolus of a pentobarbital sodium.
Page 6 of 15
SHANGHAI BIOMATERIALS RESEARCH & TEST CENTER
Add: 201, Building 2, NQ 427 Jumen Road, Shanghai, China
Zip Code: 200023
TEL: 0086-21-63034903
FAX: 001.1.1.
Web site: www.sbrtc.com
E-mail:
163.com
Lab Na L 1538
SBRTC-2016-0335-2
Every attempt was made to account for each test sample and control. A macroscopic observation of the viscera was also conducted. The following organs were removed: Heart, Lung, Thymus, Liver, Spleen, Mesenteric Lymph Node, Kidneys, Adrenals, Thyroid gland, Esophagus, Trachea, Stomach, Duodenum, Jejunum, Ileum, Colon, Pancreas, Rectum, Bladder, Abdominal aorta, Peripheral nerve, Gonads, Bone marrow, Cecum, Eyes, Muscle, Parathyroid gland, Pituitary, Prostate, Salivary glands, Salivary gland, Spinal cord, Sternum, vagina and Tissue with visible gross lesion. The heart, lungs, liver, spleen, kidneys and adrenal glands were weighed. Paired organs were weighed together. The tissues were preserved in 10% neutral buffered formalin (NBF), until further processing. These sections were histologically processed (embedded, sectioned and stained in hematoxyl in and eosin) for microscope evaluation. Evaluations and Statistics: The test and control groups were considered the variable for comparison. The body weight, organ weight data, organ/body weight ratio, hematology data, clinical chemistry values were analyzed statistically. Pre-fasted body weights were used to determine weight gain and the fasted body weight were used to determine anesthetic dosages at termination and organ/body weight ratio. Descriptive statistic and group comparisons of data were accomplished using a validated statistical software package. Calculations resulting in probability (P) values less than 0.05 were considered statistically signification.
DEVIATIONS
There were no deviations from the ISO 10993-11: 2006 and SBRTC-PROTOCOL-10-24.
RESULTS
A summary of body weight, organ weight, organ/body weight ratio, hematology and clinical chemistry data were presented in Table 1-5.
Clinical Observation: No behavioral changes or signs of toxicity were observed in any rat. None of the test and control animals exhibited any signs of toxicity noted at gross necropsy for either the test or control animal. Body weight: Individual weight gain and group mean body weights for test and control rats were considered to be clinically acceptable treatment. Necropsy: All organs appeared macroscopically normal, and there were no macroscopic changes in the viscera at necropsy that could be attributed to the test sample. Organ Weight: Absolute organ weights and organ/body weight ratios were similar between test and control groups. There was no difference between the two groups that was considered to be related to treatment. Hematology: Compared to the male control group, the LYM of the male test group decreased (p<0.05), while the GRA increased (p<0.05). Compared to the female control group, the MCV and PLT of the female test group increased (p<0.05), while the MCHC decreased (p<0.05).
Page 7 of 15
SHANGHAI BIOMATERIALS RESEARCH & TEST CENTER
Add: 201, Building 2, No 427 Jumen Road, Shanghai, China
Zip Code: 200023
TEL: 0086-21-63034903
FAX: 00
1
Web site: www.sbrtc.com
E-mail:
163.com
Lab Na L 1538
SBRTC-2016-0335-2
APPENDIX 2
HISTOPATHOLOGY REPORT
The tissues samples from forty rats (twenty males and twenty females) received were fixed with formalin. Tissue received were Heart, Lung, Thymus, Liver, Spleen, Mesenteric Lymph Node, Kidneys, Adrenals, Thyroid gland, Esophagus, Trachea, Stomach, Duodenum, Jejunum, Ileum, Colon, Pancreas, Rectum, Bladder, Abdominal aorta, Peripheral nerve, Gonads, bone marrow, cecum, eyes, muscle, parathyroid gland, pituitary, prostate, salivary glands, salivary gland, skin, spinal cord, sternum, vagina and tissue with visible gross lesion. They are trimmed, embedded, sectioned and stained for routine HE histopathological evaluation. The summary of histopathological findings was showed as follow:
SUMMARY OF HISTOPATHOLOGICAL FINDINGS
Group Sex
N'2 of Animals Heart No significant findings Hyperplasy of interstitial cell
Control
Male
Female
10
10
10
10
Test
Male
Female
10
10
10
10
Thymus No significant findings
10
10
10
10
Liver
No significant findings
9
9
6
8
Infiltrate of inflammatory cell
1
1
Hyperplasy of lymphatic tissue
1
1
3
1
Atrophy, degeneration and necrosis
1
I
Spleen No significant findings
10
10
10
10
Lung
No significant findings
10
10
9
8
Hyperplasy of lymphatic tissue
1
3
Kidneys No significant findings
10
10
10
10
Adrenals No significant findings
10
10
10
10
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SHANGHAI BIOMATERIALS RESEARCH & TEST CENTER
Add: 201, Building 2, Ng 427 Jumen Road, Shanghai, China
Zip Code: 200023
TEL: 0086-21-63034903
FAX: 001
Web site: www.sbrtc.com
E-mail:
163.com
Lab Na L 1538
SBRTC-2016-0335-2
Group Sex
X2 of Animals Stomach No significant findings Infiltrate of eosinophile granulocyte
Pancreas No significant findings Hyperplasy of lymphatic tissue
Bladder No significant findings
Abdominal aorta No significant findings
Mesenteric Lymph Node No significant findings
Trachea No significant findings Lymphocytic infiltrate Infiltrate of plasma cells Granular leukocyte Gland hyperplasia Hyperplasy of lymphatic tissue
Thyroid gland No significant findings
Esophagus No significant findings
Duodenum No significant findings
Jejunum No significant findings
Ileum No significant findings
Colon No significant findings
Rectum No significant findings
Control
Male
Female
10
10
10
10
8
10
2
10
10
10
10
10
10
8
10
2
10
10
10
10
10
10
10
10
10
10
10
10
10
10
Test
Male
Female
10
10
9
10
1
10
10
10
10
10
10
10
10
8
8
2
1
1
2
1
1
10
10
10
10
10
10
10
10
10
10
10
10
10
10
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SHANGHAI BIOMATERIALS RESEARCH & TEST CENTER
Add: 201, Building 2, N4 427 Jumen Road, Shanghai, China
Zip Code: 200023
TEL: 0086-21-63034903
FAX: 00
Web site: www.sbrtc.com
E-mail:
163.com
Lab /\12 L 1538
SBR1C-2016-0335-2
Group Sex
N2 of Animals Testes No significant findings
Ovaries No significant findings
Uterus (including cervix and oviducts) No significant findings Infiltrate of eosinophile granulocyte
Peripheral nerve No significant findings
Brain No si nificant findings
All gross lesions of treatment sites No significant findings Implant material Lymphocytic infiltrate Granular leukocyte Infiltrate of plasma cells Monocyte infiltration
Bone marrow of sternum No significant findings
Sternum No significant findings
Cecum No significant findings
Epididymides No significant findings
Eyes No significant findings
Mammary gland (female) No significant findings
Control
Male
Female
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
Test
Male
Female
10
10
10
10
8 1
10
10
0
0
10
10
10
10
2
1
1
1
1
1
10
10
10
10
10
10
10
10
10
10
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SHANGHAI BIOMATERIALS RESEARCH & TEST CENTER
Add: 201, Building 2, NQ 427 Jumen Road, Shanghai, China
Zip Code: 200023
TEL: 0086-21-63034903
FAX: 0086-21-63011643
Web site: www.sbrtc.com
E-mail: biomatercenter@l63.com
Lab Na L 1538
SBRTC-2016-0335-2
Group Sex
N2 of Animals Skeletal muscle No significant findings
Parathyroid No significant findings
Pituitary No significant findings
Prostate No significant fi ndings
Salivary glands No significant findings
Seminal vesicles No significant fi ndings
Skin No significant findings
Spinal cord No significant findings
Vagina No significant findings
Control
Male
Female
10
10
10
10
Test
Male
Female
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
Tissue examined was within normal histomorphological limits and essentially comparable between test and control animals, except for the residual material accompanied by local inflammatory reaction at the implant sites in the test group.
Page 15 of 15
SHANGHAI BIOMATERIALS RESEARCH & TEST CENTER
Add: 201, Building 2, NQ 427 Jumen Road, Shanghai, China
Zip Code: 200023
TEL: 0086-21-63034903
FAX: 00Mlit
Web site: www.sbrtc.com
E-mail:
163.com