YY/T 1292.4-2017 (YY/T1292.4-2017, YYT 1292.4-2017, YYT1292.4-2017) & related versions
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Test for reproductive and developmental toxicity of medical devices—Part 4: Two-generation reproductive toxicity test
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YY/T 1292.4-2017
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YYT 1292.4-2017
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YY/T 1292.4-2017
YY
PHARMACEUTICAL INDUSTRY STANDARD
OF THE PEOPLE’S REPUBLIC OF CHINA
ICS 11.040.01
C 30
Test for Reproductive and Developmental Toxicity of Medical
Devices - Part 4. Two-generation Reproductive Toxicity Test
ISSUED ON. FEBRUARY 28, 2017
IMPLEMENTED ON. JANUARY 1, 2018
Issued by. China Food and Drug Administration
Table of Contents
Foreword ... 3
Introduction ... 4
1 Scope ... 6
2 Normative References ... 6
3 Terms and Definitions ... 6
4 Main Equipment ... 6
5 Test Principle ... 7
6 Experimental Animals ... 7
7 Sample Preparation ... 8
8 Test Procedure ... 8
9 Result Observation ... 10
10 Test Data and Report ... 14
11 Result Explanation ... 17
Test for Reproductive and Developmental Toxicity of Medical
Devices - Part 4. Two-generation Reproductive Toxicity Test
1 Scope
This Part of YY/T 1292 specifies methods of testing two-generation reproductive
toxicity of medical devices/materials.
This Part is applicable to two-generation reproductive and developmental toxicity
evaluation of medical devices/materials.
2 Normative References
The following documents are indispensable to the application of this Standard. In terms
of references with a specified date, only versions with a specified date are applicable
to this Standard. The latest version (including all the modifications) of references
without a specified date is also applicable to this Standard.
GB/T 16886.1 Biological Evaluation of Medical Devices - Part 1. Evaluation and
Testing (GB/T 16886.1-2011, ISO 10993-1.2009, IDT)
GB/T 16886.2 Biological Evaluation of Medical Devices - Part 2. Animal Welfare
Requirements (GB/T 16886.2-2011, ISO 10993-2.2006, IDT)
GB/T 16886.3 Biological Evaluation of Medical Devices - Part 3. Tests for
Genotoxicity, Carcinogenicity and Reproductive Toxicity (GB/T 16886.3-2008, ISO
10993-3.2003, IDT)
GB/T 16886.12 Biological Evaluation of Medical Devices - Part 12. Sample
Preparation and Reference Materials (GB/T 16886.12-2005, ISO 10993-12.2002,
IDT)
3 Terms and Definitions
Terms and definitions defined in GB/T 16886.1, GB/T 16886.3 and GB/T 16886.12 are
applicable to this document.
4 Main Equipment
Common equipment in the laboratory, biological microscope, stereomicroscope,
Vernier caliper, animal sperm analyzer (optional), pathological examination instrument.
the maximum exposure dose can be adopted to determine whether toxic hazards
exist. However, corresponding supportive data of the range of dose adopted in the
test shall be provided.
8.3 Selection of Dose Level
If it is deemed that the test sample might generate two-generation reproductive toxicity
on the experimental animals, at least 3 experimental groups and 1 control group shall
be adopted. Other than there is limitation of physical and chemical properties, and
biological effect, the maximum selected dose shall trigger toxicity; however, it shall not
lead to the death of parental animals or cause severe pain to parental animals. During
the test, if there is death, the death rate of parental animals (P) shall be controlled <
10%. Decreasing dose level shall be designed in the other 2 groups, which can display
any effect that is related with sample processing and no observed adverse effect level
(NOAEL). Generally speaking, 2 ~ 4 times of the interval of the decrement groups shall
be selected. If a fourth dose group needs to be built, the interval of this dose group can
be huge (for example, 10 times). If medium is adopted in the test sample, a control
group of the medium shall be built. Apart from the supply of the test sample, animals
in the control group shall be handled in the same mode as the experimental group.
8.4 Test Progress
The test sample shall be provided to parental male and female animals every day after
5 weeks ~ 9 weeks. The test sample shall be provided to filial generation F1 male and
female mice after they wean. In terms of parental and filial generation F1 male and
female mice, the supply of test sample shall at least include 10 weeks before mating
and 2 weeks of mating. In terms of male mice that do not need the evaluation of
reproductive function, execute them in a humane way and dissect them. The supply of
test sample shall be continued among parental female mice from pregnancy to filial
generation F1’s weaning. The respective dose shall be confirmed in accordance with
the weight of each animal; the dose shall be prudently adjusted in one third time after
the pregnancy.
The supply of test sample shall be continued among parental and filial generation F1’s
male and female mice, till the test is completed. When parental and filial generation
F1’s male and female mice are no longer needed, execute all of them in a humane
way. Execute filial generation F1 mice that are not adopted for mating, and all the filial
generation F2’s mice in a humane way.
8.5 Animal Mating
8.5.1 Parental mating
Before each mating, female mouse shall always be kept in the same cage with a male
mouse that is provided with the same dose but not from the same litter, till the female
mouse is pregnant (or 2 weeks maximum). Examine sperm or vaginal plug every
Parental animals (P and F1) shall be weighted on the same day when the test is about
to be conducted; weigh them at least once a week after that. Parental female mice (P
and F1) shall be weighted on Day 0, Day 7, Day 14, Day 20 or Day 21 during their
pregnancy. During the breast-feeding period, they shall be weighted on the same day
when the litter is weighted and the day when animals are executed. The observation
result of each adult animal shall be reported one by one. In the early stage of mating
and pregnancy, measure food intake at least once a week.
9.3 Estrus Cycle
Before mating and at any time during the mating period, conduct vaginal smear
observation of the duration and state of P and F1 female mice’s estrus cycle, till mating
is successful. If vaginal/cervical cell is found in vaginal smear, identify whether it is
caused by mucosal disorder or pseudopregnancy.
9.4 Sperm Parameters
9.4.1 When the test is completed, record the weight of testis and epididymis of all the
P and F1 male mice. Take and fixate one-side organ for histopathological examination.
When there are ≥ 10 male mice in each group of P and F1 male mice, unfixed testis
and epididymis can be used to count sperm in the tail of epididymis. Gather sperms in
the tail of epididymis or vas deferens to evaluate the vitality and form of sperms. If any
treatment-related influence is observed, or the influence on sperm morphology is found
in test substances in other tests, all the male mice in each dose group shall receive
sperm evaluation; otherwise, sperm count is merely restricted to P and F1 animals in
the control group and the high dose group.
9.4.2 The total number of sperms in the tail of epididymis shall be counted. Sperms
stored in the tail of epididymis can be calculated through the concentration and volume
count of sperms in suspensions for qualitative evaluation, or sperms recovered from
the remaining tissue fluid of the tail of epididymis of homogenate. Sperms shall be
counted immediately once all the male mice selected from the dose group are
executed, unless there is already recording through images or figures, or specimen
has already been frozen for subsequent analysis. The maximum dose group and
control group shall be analyzed first. If no treatment-related influence is found in the
maximum dose group (for example, the study of sperm count, vitality and morphology),
it is unnecessary to analyze other dose groups. On the contrary, if treatment-related
influence is found in the maximum dose group, further analysis and evaluation is also
necessary in other dose groups.
9.4.3 Evaluate the vitality of sperms in testis (or vas deferens) or record a video of this
immediately after animals are executed. Minimize damage during the recovery of
sperms; use an acceptable method to dilute them for the analysis of sperm vitality.
Determine the percentage of sperms engaged in sexual activity. If computer is adopted
to assist the analysis, the generation of sperms’ sexual vitality depends on the average
channel rate and the threshold of straight-line or linear index defined by the users. If
tissues of all the P and F1 animals that are selected for mating from the high dose
group and the control group. The ovary examination of parental animals P shall be
considered as an option. If necessary, examine organ changes in the low dose group
and medium dose group. Furthermore, conduct pathological examination of genital
organs of animals with doubtful reduced fertility (for example, difficulty in mating,
getting pregnant or normally giving birth to the filial generation, or with affected estrus
cycle, sperm quantity, vitality or morphology) in the low dose group and medium dose
group. Examine all the visible damages, for example, shrink or tumor.
Conduct specific histopathological examination of testis [for example, fixate with with
Bouini’s antiseptic solution, use paraffin embedding and cut slices (thickness. 4 μm ~
5 μm)] to identify treatment-related influence; for instance, retained sperm cells,
deficiency of germ cell layer or the accumulative access of unknown types and
multinucleated giant cell or spermatogenic cell to spermatogenic lumen. A complete
epididymis examination shall include head, body and tail, which can be examined
through the longitudinal section of epididymis. Epididymis shall be evaluated in
accordance with leukocyte infiltration, degree of changes of cell type, types of
abnormal cells and the state of sperm phagocytosis. Para-amino salicylic acid (PAS)
and hematoxylin can be adopted to dye and examine the genital organs of male
animals.
After lactation, the histopathological examination of ovary shall include primitive and
growing follicles, and luteum during the lactation period. In the histopathological
examination, the quantity of primitive follicles shall be qualitatively analyzed. Conduct
quantitative analysis of primitive follicles of filial generation F1 female mice; the
selection of the quantity of animals and ovary slices, and the sample size the slices
shall comply with the statistical requirements of the evaluation procedure. This
examination shall include the count of primitive follicles (this type of primitive follicles
is often mixed with small growing follicles); compare the result of the experimental
group and the control group.
9.8.2 Weaning animals
Generally, examine visible abnormal tissues and target organs of filial mice that
manifest external defects or clinical symptoms, and 1 filial mouse of each litter and
each gender that is randomly selected from F1 and F2 animals that are not selected
for mating. Fixate and preserve them for histopathological examination. During the
comprehensive histopathological examination of the preserved tissues, place an
emphasis on the examination of organs of the reproductive system.
10 Test Data and Report
10.1 Data
Data shall be listed and reported individually, so that the quantity of animals in each
......
| Standard ID | YY/T 1292.4-2017 (YY/T1292.4-2017) | | Description (Translated English) | Test for reproductive and developmental toxicity of medical devices--Part 4: Two-generation reproductive toxicity test | | Sector / Industry | Medical Device & Pharmaceutical Industry Standard (Recommended) | | Classification of Chinese Standard | C30 | | Classification of International Standard | 11.040.01 | | Word Count Estimation | 10,115 | | Date of Issue | 2017-02-28 | | Date of Implementation | 2018-01-01 | | Drafting Organization | Shandong Province Medical Device Product Quality Inspection Center, Shenzhen Medical Device Testing Center | | Administrative Organization | National Medical Device Biology Evaluation Standardization Technical Committee (SAC/TC 248) | | Proposing organization | China Food and Drug Administration | | Issuing agency(ies) | State Food and Drug Administration |
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