natgillin/translations-raw huggingface dataset:
However, a second mating of the P males with untreated females is always an option to clarify equivocal findings or for further characterisation of effects on fertility observed in the first mating.
Rezultate preskusov nevrotoksičnosti je treba razlagati v povezavi z ustreznimi referenčnimi razponi preteklih kontrol.
IN-LIFE OBSERVATIONS
Živali kohorte 2B je treba uporabiti za nevropatološko oceno 21. ali 22. poporodni dan (glej odstavka 74–75).
For the P and the selected F1 animals, a general clinical observation is made once a day.
Preskus slušnega dražljaja se opravi 24. poporodni dan (± 1 dan) z živalmi v kohorti 2A.
In the case of gavage dosing, the timing of clinical observations should be prior to and post dosing (for possible signs of toxicity associated with peak plasma concentration).
Izvajanje preskušanja na dan preskušanja mora biti uravnoteženo po tretiranih in kontrolnih skupinah.
Pertinent behavioural changes, signs of difficult or prolonged parturition and all signs of toxicity are recorded.
Vsako preskušanje je sestavljeno iz 50 preskusov.
Twice daily, during the weekend once daily, all animals are observed for severe toxicity, morbidity and mortality.
Pri izvajanju preskusa slušnih dražljajev je treba določiti srednjo amplitudo odziva pri vsakem sklopu po 10 preskusov (5 sklopov po 10 preskusov), pri čemer morajo biti preskusni pogoji optimizirani za habituacijo znotraj preskušanja.
In addition, a more detailed examination of all P and F1 animals (after weaning) is conducted on a weekly basis and could conveniently be performed on an occasion when the animal is weighed, which would minimise handling stress.
Ti postopki morajo biti v skladu s preskusno metodo B.53 (35).
Observations should be carefully conducted and recorded using scoring systems that have been defined by the testing laboratory.
Ob primernem času med 63. in 75. poporodnim dnem se pri živalih iz kohorte 2A opravi sklop funkcionalnih opazovanj in avtomatizirani preskus motorične aktivnosti.
Efforts should be made to ensure that variations in the test conditions are minimal.
Ti postopki morajo biti v skladu s preskusnima metodama B.43 (33) in B.53 (35).
Signs noted should include, but not be limited to, changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions and autonomic activity (e.g. lacrimation, piloerection, pupil size, unusual respiratory pattern).
Sklop funkcionalnih opazovanj vključuje temeljit opis videza, vedenja in funkcionalne neokrnjenosti subjekta.
Changes in gait, posture, response to handling, as well as the presence of clonic or tonic movements, stereotypy (e.g. excessive grooming, repetitive circling) or bizarre behaviour (e.g. self-mutilation, walking backwards) should also be recorded.
To se oceni z opazovanjem v domači kletki, po prenosu na standardno mesto (na terenu), kjer se žival prosto giblje, in z gibalnimi preskusi.
Body weight and food/water consumption
Preskušanje naj se izvaja od najmanj do najbolj interaktivnega.
P animals are weighed on the first day of dosing and at least weekly thereafter.
Seznam meril je naveden v Dodatku 1.
In addition, P females are weighed during lactation on the same days as the weighing of the pups in their litters (see paragraph 44).
Vse živali morajo skrbno opazovati usposobljeni opazovalci, ki niso seznanjeni s tretiranjem živali, in sicer po standardiziranih postopkih, s katerimi se zmanjša variabilnost opazovalca.
All F1 animals are weighed individually at weaning (PND 21) and at least weekly thereafter.
Če je to mogoče, naj živali v zadevnem preskusu vrednoti isti opazovalec.
Body weight is also recorded on the day when they attain puberty (completion of preputial separation or vaginal patency).
Če to ni mogoče, je potreben dokaz o enaki zanesljivosti opazovalcev.
All animals are weighed at sacrifice.
Za vsak parameter v sklopu vedenjskega preskušanja je treba uporabiti izrecne operativno opredeljene lestvice in merila za točkovanje.
During the study, food and water consumption (in the case of test chemical administration in the drinking water) are recorded at least weekly on the same days as animal body weights (except during cohabitation).
Če je mogoče, je treba razviti objektivna kvantitativna merila za opazovane končne točke, ki vključujejo subjektivno razvrščanje.
The food consumption of each cage of F1 animals is recorded weekly commencing with selection to a respective cohort.
Za motorično aktivnost se vsaka žival preskuša posamično.
Oestrous cycles
Preskušanje mora biti dovolj dolgo, da se za kontrolne vzorce dokaže habituacija znotraj preskušanja.
Preliminary information of test chemical-related effects on the oestrous cycle may already be available from previous repeat-dose toxicity studies, and may be used in designing a test chemical-specific protocol for the Extended One-Generation Reproductive Toxicity Study.
Če so v skladu z obstoječimi informacijami potrebni drugi funkcionalni preskusi (npr. senzorični, socialni, kognitivni), jih je treba vključiti, ne da bi bila pri tem ogrožena celovitost drugih vrednotenj v okviru študije.
Normally the assessment of oestrous cyclicity (by vaginal cytology) will start at the beginning of the treatment period and continue until confirmation of mating or the end of the 2-week mating period.
Če se ti preskusi izvajajo na istih živalih kot standardno preskušanje slušnega dražljaja, sklop funkcionalnih opazovanj in preskušanje motorične aktivnosti, je treba pripraviti časovni razpored različnih preskusov, da bi bila celovitost teh preskusov čim manj ogrožena.
If females have been screened for normal oestrous cycles before treatment, then it is useful to continue smearing as treatment starts, but if there is concern about non-specific effects at the start of treatment (such as an initial marked reduction in food consumption) then animals may be allowed to adapt to treatment for up to two weeks before the start of the 2-week smearing period leading into pairing.
Dopolnilni postopki so lahko posebno koristni, kadar empirična opazovanja, pričakovani učinki ali mehanizem/način delovanja kažejo posebno vrsto nevrotoksičnosti.
If the female treatment period is extended in this way (i.e. to a 4-week pre-mating treatment) then consideration should be made to purchasing animals younger and to extending the period of male treatment before pairing.
Ocena morebitne razvojne nevrotoksičnosti (kohorta 3)
When obtaining vaginal/cervical cells, care should be taken to avoid disturbance of mucosa and subsequently, the induction of pseudopregnancy (10) (11).
Na 56. poporodni dan (± 3 dni) je treba 10 samcev in 10 samic iz kohorte 3 iz vsake tretirane skupine (1 samec ali 1 samica na leglo; iz vsakega legla je naključno izbran vsaj 1 mladič) uporabiti v preskusu protitelesnega odziva na osnovi T-celic (TDAR), tj. primarni odziv protitelesa razreda IgM na antigen na osnovi T-celic, kot so SRBC (ovčje rdeče krvničke) ali KLH (hemocianin iz morskega polža), v skladu z veljavnimi postopki preskušanja imunotoksičnosti (14) (15).
Vaginal smears should be examined daily for all F1 females in cohort 1A, after the onset of vaginal patency, until the first cornified smear is recorded, in order to determine the time interval between these two events.
Odziv je mogoče ovrednotiti s štetjem celic, ki delajo plake (celice PFC), v vranici, ali določanjem titra protitelesa IgM, značilnega za SRBC ali KLH, v serumu s preskusom ELISA ob vrhuncu odziva.
Oestrous cycles for all F1 females in cohort 1A should also be monitored for a period of two weeks, commencing around PND 75.
Vrhunec odziva je običajno štiri (odziv celic PFC) ali pet (preskus ELISA) dni po intravenozni imunizaciji.
In addition, should mating of the F1 generation be necessary, the vaginal cytology in cohort 1B will be followed from the time of pairing until mating evidence is detected.
Če se primarni odziv protiteles preskuša s štetjem celic, ki delajo plake, ni treba vseh podskupin živali vrednotiti na isti dan, pod pogojem, da:
Mating and pregnancy
so imunizacija in usmrtitev podskupin načrtovani tako, da se celice PFC prešteje ob vrhuncu odziva;
In addition to the standard endpoints (e.g. body weight, food consumption, clinical observations including mortality/morbidity checks), the dates of pairing, the date of insemination and the date of parturition are recorded and the precoital interval (pairing to insemination) and the duration of pregnancy (insemination to parturition) are calculated.
je v podskupinah enako število potomcev moškega in ženskega spola iz vseh skupin z odmerkom, vključno s kontrolnimi skupinami;
The P females should be examined carefully at the time of expected parturition for any signs of dystocia.
in so podskupine vrednotene približno ob isti poporodni starosti.
Any abnormalities in nesting behaviour or nursing performance should be recorded.
Izpostavljenost preskusni kemikaliji se nadaljuje do dneva pred odvzemom vranic za preskus odziva celic PFC ali seruma za preskus ELISA.
The day on which parturition occurs is lactation day 0 (LD 0) for the dam and postnatal day 0 (PND 0) for the offspring.
Nadaljnja ocena morebitne strupenosti za razmnoževanje (kohorta 1B)
Alternatively, all comparisons may also be based on post-coital time to eliminate confounding of postnatal development data, by differences in the duration of pregnancy;
Živali iz kohorte 1B se lahko po potrebi tretirajo še po 90. poporodnem dnevu in parijo za produkcijo generacije F2.
however, timing relative to parturition should also be recorded.
Glede na tehtnost dokazov pa se legla morda lahko usmrtijo na 4. poporodni dan, namesto da bi se jih spremljalo do odstavitve ali še dlje.
This is especially important when the test chemical exerts an influence on the duration of pregnancy.
OPAZOVANJA OB USMRTITVI
Offspring parameters
Klinična biokemija/hematologija
Each litter should be examined as soon as possible after parturition (PND 0 or 1) to establish the number and sex of pups, stillbirths, live births, and the presence of gross anomalies (externally visible abnormalities, including cleft palate; subcutaneous haemorrhages; abnormal skin colour or texture; presence of umbilical cord; lack of milk in stomach; presence of dried secretions).
Pregledati je treba naslednje hematološke parametre:
In addition, the first clinical examination of the neonates should include a qualitative assessment of body temperature, state of activity and reaction to handling.
hematokrit, koncentracijo hemoglobina, število eritrocitov, skupno število levkocitov in diferencialno sliko levkocitov, število trombocitov in čas/potencial koagulacije krvi.
Pups found dead on PND 0 or at a later time should be examined for possible defects and cause of death.
Preiskave plazme ali seruma morajo vključevati:
Live pups are counted and weighed individually on PND 0 or PND 1, and regularly thereafter, e.g. at least on PND 4, 7, 14, and 21.
glukozo, skupni holesterol, sečnino, kreatinin, skupne beljakovine, albumin in najmanj dva encima, ki sta kazalnika hepatoceličnih učinkov (kot so alanin-aminotransferaza, aspartat-aminotransferaza, alkalna fosfataza, gamaglutamil transpeptidaza in sorbitol dehidrogenaza).
Clinical examinations, as applicable for the age of the animals, should be repeated when the offspring are weighed, or more often if case-specific findings have been made at birth.
Meritve dodatnih encimov in žolčnih kislin lahko včasih dajo koristne informacije.
Signs noted could include, but may not be limited to, external abnormalities, changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions and autonomic activity.
Poleg tega se lahko vsem živalim tudi odvzame kri in se shrani za morebitno poznejšo analizo, da se razjasnijo dvoumni učinki ali zberejo podatki o notranji izpostavljenosti.
Changes in gait, posture, response to handling, as well as the presence of clonic or tonic movements, stereotypy or bizarre behaviour, should also be recorded.
Če drugo parjenje starševskih (P) živali ni načrtovano, se vzorci krvi zberejo tik pred postopkom ob načrtovani usmrtitvi ali v sklopu le-tega.
The anogenital distance (AGD) of each pup should be measured on at least one occasion from PND 0 through PND 4.
Če se živali ne usmrtijo, se vzorce krvi odvzame nekaj dni pred drugim parjenjem živali.
Pup body weight should be collected on the day the AGD is measured and the AGD should be normalised to a measure of pup size, preferably the cube root of body weight (12).
Razen če je na podlagi obstoječih podatkov iz študij s ponavljajočim se odmerkom razvidno, da preskusna kemikalija ne vpliva na parameter, je treba pred usmrtitvijo opraviti analizo urina in ovrednotiti naslednje parametre:
The presence of nipples/areolae in male pups should be checked on PND 12 or 13.
videz, količino, osmolalnost ali specifično težo, pH, beljakovine, glukozo, kri in krvne celice ter celični drobir.
All selected F1 animals are evaluated daily for balano-preputial separation or vaginal patency for male/female respectively commencing before the expected day for achievement of these endpoints to detect if sexual maturation occurs early.
Odvzame se lahko tudi urin za spremljanje ekskrecije preskusne kemikalije in/ali metabolitov.
Any abnormalities of genital organs, such as persistent vaginal thread, hypospadia or cleft penis, should be noted.
Pri živalih F1 je treba spremljati tudi sistemske učinke.
Sexual maturity of F1 animals is compared to physical development by determining age and body weight at balano-preputial separation or vaginal opening for male/female respectively (13).
Ob usmrtitvi se desetim naključno izbranim samcem in samicam iz kohorte 1A na skupino z odmerkom, ki so se postili, vzamejo vzorci krvi z določenega mesta, ki se nato shranijo pod ustreznimi pogoji in na katerih se opravijo standardne klinične biokemijske preiskave, vključno z oceno serumske koncentracije hormonov ščitnice (T4 in TSH), hematološke preiskave (skupno število in diferencialna slika levkocitov ter število eritrocitov) in analiza urina.
Assessment of potential developmental neurotoxicity (cohorts 2A and 2B)
Na 4. poporodni dan se odvečne mladiče makroskopsko obducira in upoštevajo se meritve serumske koncentracije hormona ščitnice (T4).
Ten male and 10 female cohort 2A animals and 10 male and 10 female cohort 2B animals, from each treatment group (for each cohort: 1 male or 1 female per litter; all litters represented by at least 1 pup; randomly selected) should be used for neurotoxicity assessments.
Po potrebi se zarodu odvzame kri novorojenih mladičev (4. poporodni dan) za biokemično analizo/analizo hormonov ščitnice.
Cohort 2A animals should be subjected to auditory startle, functional observational battery, motor activity (see paragraphs 48-50), and neuropathology assessments (see paragraphs 74-75).
Za analizo T4 in TSH se kri odvzame tudi odstavljenim mladičem, ki se jih makroskopsko obducira na 22. poporodni dan (mladiči F1, ki niso izbrani za kohorte).
Efforts should be made to ensure that variations in all test conditions are minimal and are not systematically related to treatment.
Parametri semena
Among the variables that can affect behaviour are sound level (e.g. intermittent noise), temperature, humidity, lighting, odours, time of day, and environmental distractions.
Parametre semena se meri pri vseh samcih generacije P, razen če obstajajo podatki, ki dokazujejo, da so v 90-dnevni študiji parametri semena nespremenjeni.
Results of the neurotoxicity assays should be interpreted in relation to appropriate historical control reference ranges.
Pregled parametrov semena se opravi pri vseh samcih iz kohorte 1A.
Cohort 2B animals should be used for neuropathology assessment on PND 21 or PND 22 (see paragraphs 74-75).
Ob usmrtitvi se pri vseh starševskih (P) samcih in samcih F1 (kohorta 1A) zabeleži teža moda in obmodka.
An auditory startle test should be performed on PND 24 (± 1 day) using animals in cohort 2A.
Vsaj eno modo in en obmodek se shrani za histopatološki pregled.
The day of testing should be counterbalanced across treated and control groups.
Drugi obmodek se uporabi za štetje zalog semena v repu obmodka (16) (17).
Each session consists of 50 trials.
Poleg tega se odvzame seme iz repov obmodkov (ali semenovodov) z metodami, pri katerih so poškodbe za ovrednotenje gibljivosti in morfologije semena kar najmanjše (18).
In performing the auditory startle test, the mean response amplitude on each block of 10 trials (5 blocks of 10 trials) should be determined, with test conditions optimised to produce intra-session habituation.
Gibljivost semena je treba ovrednotiti takoj po usmrtitvi ali zabeležiti za poznejšo analizo.
These procedures should be consistent with test method B.53 (35).
Odstotek progresivno gibljivega semena je treba subjektivno ali objektivno določiti z analizo gibanja s pomočjo računalnika (19) (20) (21) (22) (23) (24).
At an appropriate time between PND 63 and PND 75, the cohort 2A animals are subjected to a functional observational battery and an automated test of motor activity.
Za morfološko ovrednotenje semena je treba vzorce semena iz obmodka (ali semenovoda) proučiti kot fiksirane ali mokre preparate (25) in najmanj 200 semenčic na vzorec razvrstiti kot normalne (glavica in srednji del/repek so videti normalno) ali nenormalne.
These procedures should be consistent with test methods B.43 (33) and B.53 (35).
Primeri morfoloških anomalij semena vključujejo spojitev, ločene glavice ter glavice in/ali repke nepravilnih oblik (26).
The functional observational battery includes a thorough description of the subject's appearance, behaviour and functional integrity.
Glavice nepravilne oblike ali velike glavice lahko kažejo na okvare pri sprostitvi spermatidov v obmodek.
This is assessed through observations in the home cage, after removal to a standard arena for observation (open field) where the animal is moving freely, and through manipulative tests.
Če se ob obdukciji zamrznejo vzorci semena, fiksirajo brisi in posnamejo posnetki za analizo gibljivosti semena (27), se lahko naknadno analizirajo le samci iz kontrolne skupine in skupin z velikim odmerkom.
Testing should proceed from the least to the most interactive.
Če so opazni učinki, povezani s tretiranjem, je treba ovrednotiti tudi skupine z manjšim odmerkom.
A list of measures is presented in Appendix 1.
Makroskopska obdukcija
All animals should be observed carefully by trained observers who are unaware of the animals' treatment status, using standardised procedures to minimise observer variability.
Ob usmrtitvi ali prezgodnji smrti se vse starševske (P) živali in živali F1 makroskopsko obducirajo in makroskopsko pregledajo za odkrivanje kakršnih koli strukturnih anomalij ali patoloških sprememb.
Where possible, it is advisable that the same observer evaluates the animals in a given test.
Posebno pozornost je treba posvetiti organom razmnoževalnega sistema.
If this is not possible, some demonstration of inter-observer reliability is required.
Mladiče, ki so humano usmrčeni med poginjanjem, in mrtve mladiče je treba zabeležiti in, če se ne macerirajo, proučiti glede možnih okvar in/ali vzroka smrti ter konzervirati.
For each parameter in the behavioural testing battery, explicit operationally defined scales and scoring criteria are to be used.
Pri odraslih starševskih (P) samicah in samicah F1 se na dan obdukcije pregleda bris nožnice, da se ugotovi faza pojatvenega cikla in omogoči korelacija s histopatološkimi preiskavami razmnoževalnih organov.
If possible, objective quantitative measures should be developed for observational endpoints, which involve subjective ranking.
Maternice vseh starševskih (P) samic (in po potrebi samic F1) se pregledajo glede navzočnosti in števila vgnezditev na način, ki nima negativnega vpliva na histopatološko ovrednotenje.
For motor activity, each animal is tested individually.
Teža organov in shranjevanje tkiv – odrasle starševske (P) živali in odrasle živali F1
The test session should be long enough to demonstrate intra-session habituation for controls.
Po usmrtitvi se čim prej po seciranju, da ne pride do izsušitve, določita telesna teža in mokra teža v nadaljevanju navedenih organov vseh starševskih (P) živali in odraslih živali F1 iz zadevnih kohort (kakor je navedeno v nadaljevanju).
If existing information indicates the need for other functional testing (e.g. sensory, social, cognitive), these should be integrated without compromising the integrity of the other evaluations conducted in the study.
Ti organi se nato shranijo pod ustreznimi pogoji.
Supplemental procedures may be particularly useful when empirical observation, anticipated effects, or mechanistic/mode-of-action indicate a specific type of neurotoxicity.
Maternica (z jajcevodoma in materničnim vratom), jajčniki.
Assessment of potential developmental immunotoxicity (cohort 3)
Moda, obmodki (v celoti in repi za vzorce za štetje semena).
At PND 56 (± 3 days), 10 male and 10 female cohort 3 animals from each treatment group (1 male or 1 female per litter; all litters represented by at least 1 pup; randomly selected) should be used in a T-cell dependant antibody response assay, i.e. the primary IgM antibody response to a T-cell dependent antigen, such as Sheep Red Blood Cells (SRBC) or Keyhole Limpet Hemocyanin (KLH), consistent with current immunotoxicity testing procedures (14) (15).
Prostata (dorzolateralni in ventralni del skupaj).
Responses typically peak four (PFC response) or five (ELISA) days after intravenous immunisation.
V primeru učinka na skupno težo prostate, povezanega s tretiranjem, je treba po fiksaciji previdno secirati dorzolateralni in ventralni segment in ju ločeno stehtati.
If the primary antibody response is assayed by counting plaque-forming cells, it is permissible to evaluate subgroups of animals on separate days, provided that:
Semenska mešička s koagulacijskimi žlezami in njihovimi tekočinami (kot ena enota).
subgroup immunisation and sacrifice are timed so that PFCs are counted at the peak of the response;
Možgani, jetra, ledvice, srce, vranica, priželjc, hipofiza, ščitnica (po fiksaciji), nadledvični žlezi in znani tarčni organi ali tkiva.
that subgroups contain an equal number of male and female offspring from all dose groups, including controls;
Poleg navedenih organov je treba pod ustreznimi pogoji shraniti vzorce perifernega živca, mišice, hrbtenjače, očesa z vidnim živcem, prebavnega trakta, sečnega mehurja, pljuč, sapnika (s pritrjeno ščitnico in obščitnicami), kostnega mozga, semenovoda (pri samcih), mlečnih žlez (pri samcih in samicah) in nožnice.
and that subgroups are evaluated at approximately the same postnatal age.Exposure to the test chemical will continue until the day before collecting spleens for the PFC response or serum for the ELISA assay.
Pri živalih kohorte 1A se vsi organi stehtajo in shranijo za histopatološke preiskave.
Follow-up assessment of potential reproductive toxicity (cohort 1B)
Pri preiskavi pred- in poporodno povzročenih imunotoksičnih učinkov se pri 10 samcih in 10 samicah iz kohorte 1A iz vsake tretirane skupine (1 samec ali 1 samica na leglo; iz vsakega legla je naključno izbran vsaj 1 mladič) ob usmrtitvi opravi naslednje:
Cohort 1B animals can be maintained on treatment beyond PND 90 and bred to obtain a F2 generation if necessary.
tehtanje bezgavk, ki so blizu predela poti izpostavljenosti, in tistih, ki so od njega oddaljene (poleg tehtanja nadledvičnih žlez, priželjca in vranice, ki je bilo pri vseh živalih iz kohorte 1A že opravljeno),
Males and females of the same dose group should be cohabited (avoiding the pairing of siblings) for up to two weeks, beginning on or after PND 90, but not exceeding PND 120.
analiza podskupin limfocitov v vranici (limfocitov T s površinskim označevalcem CD4+ in CD8+, limfocitov B in naravnih celic ubijalk) v eni polovici vranice, druga polovica se shrani za histopatološko ovrednotenje.
Procedures should be similar to those for the P animals.
Z analizo podskupin limfocitov v vranici pri neimuniziranih živalih (kohorta 1A) se bo ugotovilo, ali je izpostavljenost povezana s spremembo imunološke razporeditve celic 'pomagalk' (CD4+), citotoksičnih (CD8+) limfocitov iz priželjca ali naravnih celic ubijalk (hiter odziv na neoplastične celice in patogene).