Registration Dossier
Registration Dossier
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EC number: 413-090-5 | CAS number: -
Toxicological information
Toxicity to reproduction
Administrative data
- Endpoint:
- one-generation reproductive toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 29 June 2006 to 10 November 2006
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 007
- Report date:
- 2007
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- lithium sodium 2-amino-4-{[4-(cyanoazanidyl)-6-[(3-sulfonatophenyl)amino]-1,3,5-triazin-2-yl]amino}-5-(2-{4-[2-(sulfonatooxy)ethanesulfonyl]phenyl}diazen-1-yl)benzene-1-sulfonate
- EC Number:
- 413-090-5
- Cas Number:
- 189574-45-6
- Molecular formula:
- Hill formula: C24H18LixN10NayO12S4
- IUPAC Name:
- lithium sodium 2-amino-4-{[4-(cyanoazanidyl)-6-[(3-sulfonatophenyl)amino]-1,3,5-triazin-2-yl]amino}-5-(2-{4-[2-(sulfonatooxy)ethanesulfonyl]phenyl}diazen-1-yl)benzene-1-sulfonate
- Test material form:
- solid: particulate/powder
- Details on test material:
- See below
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: TOXI COOP Ltd. 1032 Budapest, Cserkesz u. 90.
- Age at study initiation: Males: less than 9 weeks old
Females: at least 9 weeks old
- Housing: Before mating: 4 male animals/ cage
5 female animals/ cage
Mating period: male animals: individual caging,
Mating hours: 1 male and 1 female / cage
During pregnancy: in groups of 1 to 4 animals
Delivery and nursing: individual caging
- Diet (ad libitum): sniff SM R/M-Z+H autoclavable complete feed for rats and mice - breeding and maintenance
- Water (ad libitum): tap
- Acclimation period: 29 days for male rats
6 days for female rats
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25
- Humidity (%): 30 to 70
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 29 June 2006 To: 10 November 2006
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Remarks:
- distilled.
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test item was dissolved in distilled water in concentrations of 10 mg/mL, 30 mg/mL and 75 mg/mL. The pH of dosing solutions were adjusted to pH=7.0 with 10 M NaOH (solid NaOH: Batch No.: KBM 5080902, Expiry date: November 2009) during the first three weeks treatment. The results of the preliminary study (two days treatment) regarding the pH influence on digestive system were not supported by the observations after two weeks treatment therefore pH was not adjusted after three weeks treatment. Formulations were prepared daily except weekends. Dosing solutions were stable for at least 24 hours at room temperature and 4 days refrigerated. The stock solution was stable for at least 10 days at 2 to 8°C. Homogeneity of test item in this vehicle was analytically proven. Analytical control of dosing solutions was performed five times during the treatment period on Days 0, 56, 77, 99, and 131.
VEHICLE: Distilled water
- Concentration in vehicle: 10 mg/mL, 30 mg/mL and 75 mg/mL
- Amount of vehicle: 10 mL/kg body weight
- Lot/batch nos.: 0503-0306; 85 10604; 3490306; 3530306; 3630306; 53 10506; 6650706 - Details on mating procedure:
- Mating of the animals began approximately 11 weeks after starting of the treatment of male animals and 4 weeks after starting of the treatment of female animals.
One female was placed to the male of the same dose group (1:1 mating) until copulation occurred or two weeks had elapsed. Mating time was about 3 hours a day in the morning. Thereafter each morning vaginal smear was prepared and stained with 1 % aqueous methylene blue solution.
The day of mating (presence of vaginal plug or sperms in the vaginal smear) was considered as day 0 of pregnancy (as defined by OECD's TG 415). Sperm positive females were separated. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analytical control of dosing solutions was performed five times during the treatment period on Days 0, 56, 77, 99, and 131 with a validated HPLC method.
- Duration of treatment / exposure:
- Males: pre-mating: 81 days
pairing: 12 days
post-mating: 4 to 5 days
Females: pre-mating: 27 days
pairing: 12 days
gestation: 22 to 24 days
lactation: 21 to 23 days - Frequency of treatment:
- daily
- Details on study schedule:
- Pre-treatment period
Animal arriving: Male (M): 31 May 2006; Female (F): 16 August 2006
Veterinary control, acclimatisation: M: 31 May - 28 June 2006 (29 days); F: 16 - 21 August 2006 (6 days)
Animal identification/body weight measurement/randomisation: M: 28 June 2006; F: 21 August 2006
Treatment period
Pre-mating period: M: 29 June - 17 September 2006 (81 days); F: 22 August - 17 September 2006 (27 days)
Examination of estrous cycle: 22 August - 29 September 2006
Pairing period: 18 - 29 September 2006 (12 days)
Mating period: 18 - 27 September 2006 (10 days)
Gestation periods: 18 September - 19 October 2006 (32 days)
Lactation periods: 10 October - 10 November 2006 (32 days)
Clinical observation: M: Daily from 29 June 2006 - up to the necropsy; F: Daily from 22 August 2006 - up to the necropsy
Body weight measurement: M: 29 June 2006, then weekly
F: 22 August 2006, then weekly prior to and during the mating period,
- On gestational days 0, 4, 7, 10, 14, 17 and 21
- On postpartal days 0, 4, 7, 10, 14, 17 and 21
Food consumption measurement: M: 06 July 2006, then weekly prior to the mating
F: 29 August 2006, then weekly prior to the mating
- On gestational days 0, 7, 14 and 21
- On postpartal days 0, 4, 7, 14 and 21
PUPS
Body weight measurement: 10 October - 09 November 2006
- On postnatal days 0, 4, 7, 14 and 21
Surface righting reflex: 10 - 20 October 2006 - At the birthday
Pinna detachment: 12 - 22 October - On postnatal day 2
Eye opening: 24 October - 03 November 2006 - On postnatal day 14
Termination
Necropsy: M: 03, 04 October 2006
Dead animals: No.: 408: 28 September 2006
No.: 418: 05 August 2006
Dams delivered: 31 October - 10 November 2006
Dams not delivered: 25 October 2006
Females not mated: 04 October 2006
Offspring: sacrificed on postnatal day 21, 22 or 23
The end of the in life phase: 10 November 2006
Doses / concentrationsopen allclose all
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Remarks:
- 10 mg/ml analytical conc.
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- Remarks:
- 30 mg/ml analytical conc.
- Dose / conc.:
- 750 mg/kg bw/day (actual dose received)
- Remarks:
- 75 mg/ml analytical conc.
- No. of animals per sex per dose:
- 24 males/group
25 females/group - Control animals:
- yes, concurrent vehicle
- Details on study design:
- Dose selection rationale: The doses were chosen on the basis of the results of previous rodent studies and a preliminary toxicity study with the test item in rats. A group of male animals was treated at 1000 mg/kg bw/day dose for about 2 weeks before mating. During this period, a decision was made to eliminate this dose level from main part of the study before the female treatment has been started because of deaths of several male rats (9/24) treated with 1000 mg/kg bw/day.
Examinations
- Parental animals: Observations and examinations:
- PARENTAL (P) GENERATION
Clinical observations
A general clinical observation was made once a day, after treatment at approximately the same time. Observations were performed on the skin, fur, eyes and mucous membranes, autonomic activity (lachryrnation, piloerection, pupil size, respiratory pattern, occurrence of secretions and excretions), circulatory and central nervous system, somatomotor activity and behaviour pattern, changes in gait, posture and response to handling.
Morbidity and mortality
Animals were inspected for signs of morbidity and mortality twice daily (at the beginning and end of each day). Animals found dead were subjected to gross pathology and all organs were preserved in 10 % buffered formalin solutions but testes were preserved in Bouin's solution.
Body weight
All parent animals were weighed with accuracy of 1 g.
Parent (P) male animals were weighed and evaluated weekly (on the same day) prior to and during the mating period.
Parent females were weighed and evaluated weekly (on the same day) prior to and during the mating, on gestation days 0, 7, 14 and 21 and on postpartal days 0, 7, 14 and 21. Body weight of the female animals was weighed on gestation and postpartal days 4, 10 and 17 in order to make sure the accurate treatment, but these data were not evaluated statistically.
Food consumption
Food consumption was determined weekly (on the same day) by reweighing the nonconsumed diet with accuracy of 1 g during the pre-mating period and during the gestation period. After parturition, the non-consumed diet was weighed on the same days as pups:
- On gestational days 0, 7, 14 and 2 1
- On postpartal days 0, 4, 7, 14 and 2 1 - Oestrous cyclicity (parental animals):
- Examination of the oestrous cycle
Vaginal smear of all the females was prepared daily during the pre-mating period four weeks before the mating period and during the mating period. The vaginal smears were stained with 1 % aqueous methylene blue solution and were examined with light microscope. - Sperm parameters (parental animals):
- Not assessed
- Litter observations:
- Females were allowed to litter and rear their offspring. Delivery process was observed as carefully as possible. All changes were recorded.
Observation of the delivery process
Females were allowed to litter and rear their offspring. Delivery process was observed as carefully as possible. All changes were recorded.
Observation of the nursing instinct
Dams were observed whether they made a nest from the bedding material and cover their new-born pups or not. The efficiency of the lactation and nursing was observed by the presence of milk in the pups' stomach. All observations were recorded.
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, development
GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was determined for pups born or found dead. - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals were subjected to necropsy following terminal anaesthesia 4 -5 days after the mating period
- Female animals:
- Non-mated female animals were subjected to necropsy following terminal anaesthesia 5 days after the mating period.
Occasional implantations in the uterus were checked. If there was implantation in the uterus, corpora lutea were counted, too
- Animals, which failed to deliver up to gestation day 24 were subjected to necropsy following terminal anaesthesia
- Dams with viable pups were subjected to necropsy following terminal anaesthesia after post-partal day 21
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGHTS
The following organs of parental animals or representative samples thereof were preserved all in 4% neutral formaldehyde solution but testis in Bouin's solution for histological examination:
Gross lesions, lymph nodes (submandibular, mesenteric) sternum, skin and female mammary gland, salivary glands (submandibular), larynx, femur + bone marrow, spinal cord (cervical, lumbar, thoracic level), pituitary, thymus, trachea, lungs (with main stem bronchi), heart, thyroid + parathyroid, oesophagus, stomach, caecum, duodenum, ileum, jejunum, colon, rectum, urinary bladder, liver, pancreas, spleen, kidneys, adrenals, prostate, epididymides, ovaries, uterus with vagina, brain (including cerebrum, cerebellum, pons and medulla oblongata), eyes with optic nerve, Harderian glands and lachrymal gland, seminal vesicle, muscle (quadriceps), sciatic nerve, aorta.
Gross lesions, the ovaries, uterus, cervix, vagina, testes, epididymides, seminal vesicles, prostate, coagulating gland and pituitary gland were subjected to histological examinations.
Histological examinations were conducted in all control and high dose treated animals. A full histological examination was performed for animals, which were found dead during the study.
Reproductive organs of animals suspected of fertility were subjected to microscopic examination in low and medium dose groups. - Postmortem examinations (offspring):
- SACRIFICE
- All dead pups were dissected to find the cause of the death. It was determined whether the dead newborn was live-born or stillborn by lung flotation test.
- The F1 offspring were sacrificed without necropsy following terminal anaesthesia on postnatal day 2 1,22 or 23. - Statistics:
- STATISTICAL EVALUATION
The following parameters were evaluated:
PARENTAL MALES (P)
- Clinical observations
- Body weight (g)
- Body weight gain (g)
- Food consumption (g)
- Number of pairings
- Number of fertile pairings
- Number of infertile males
- Fertility index (%)
- Necropsy findings (%)
PARENTAL FEMALES (P)
- Clinical observations
- Body weight (g)
- Body weight gain (g)
- Food consumption (g)
- Number of not mated females
- Number of pregnant females
- Number of sperm positive, but non-pregnant females
- Copulatory index (%)
- Fertility index (%)
- Gestation index (%)
- Number of oestrous periods (until mating)
- Oestrous length (day, until mating)
- Duration of pregnancy (day)
- Implantations 1 dams
- Intrauterine mortality
- Total mortality (intra and extra uterine mortality)
- Necropsy findings (%)
- Histopathological findings (%)
OFFSPRING (F1)
- Mean body weight per litter on postnatal days 0,4,7, 14 and 21
- Mean body weight gain per litter between postnatal days 0-4,4-7, 7-14, 14-21 and
0-2 1
- Number of live births per litter, and number of viable pups per litter on postnatal
days 0,7, 14 and 21
- Extra uterine mortality of pups on postnatal days 0,2 1
- Viability index (%)
- Lactation index (96)
- Sex ratio % (on postnatal days 0 and 21)
- Surface righting reflex (%)
- Pinna detachment (%)
- Eye-opening (%)
- Necropsy findings (%)
The statistical evaluation of appropriate data was done SPSS PC+4.0. The homogeneity of variance between groups was checked by Bartlett's homogeneity of variance test. Where no significant heterogeneity was detected a one-way analysis of variance (ANOVA) is carried out. If the obtained result was significant Duncan Multiple Range test was used to access the significance of inter-group differences. At significant result at Bartlett's test the Kruskal-Wallis analysis of variance was used and the inter-group comparisons was performed using Mann- Whitney U-test. The Chi² test was performed if feasible. - Reproductive indices:
- Copulatory index (%): Number of sperm positive females x 100 / Number of mated females
Fertility index - Males (%): Number of fertile males x 100 / Number of mated males
Fertility index - Females (%): Number of pregnant females x 100 / Number of mated females
Gestation index (%): Number of females with viable pups x 100 / Number of pregnant females
Sex ratio: (Number of pups examined - Number of males (females)) x 100 / Number of pups examined - Offspring viability indices:
- Intra uterine mortality: (Number of implantations - Number of newborns) x 100 / Number of implantations
Total mortality: (Number of implantations - Number of viable pups) x 100 / Number of newborns
Viability index (%): Number of viable pups on day 4 (7, 14, 21) x 100 / Number of viable pups on day 0 (4, 7, 14)
Lactation index (%): Number of viable pups on day 21 x 100 / Number of viable pups on day 0 of lactation
Surface righting reflex, Pinna detachment, Eye-opening: (Number of pups examined - Number of pups with negative response) x 100 / Number of pups examined
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- An increased water consumption and urine excretion related to the test item was found at 750 mg bw/day group (male and female animals) from day 2 until the termination of the treatment. This is due to the high lithium salt content, as polyuria and polydidpsia are a common side-effect for lithium.
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- In the 750 mg/kg bw/day group, decreased activity and piloerection were noted for
animal No.: 408 on days 89 and 90 resulting in death of this animal next day.
One animal (No.: 418) was found in prone position with closed eyes and onvulsions
immediately after the treatment (day 37) and then was died. Histopathology reveled misdosing for both animals.
There were no clinical sings in female animals except for one pregnant rat (No.: 338) at 300 mg/kg bw/day. Paleness and piloerection were observed from gestational day 21 to gestational day 23 and 27, respectively. Enlarged spleen and early death was recorded at the gross pathology on gestation day 28. Histological examination revealed splenic hyperplasia as individual disorder. - Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Other effects:
- not examined
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
Details on results (P0)
CLINICAL SYMPTOMS AND MORTALITY
An increased water consumption and urine excretion related to the test item was found at 750 mg bw/day group (male and female animals) from day 2 until the termination of the treatment. There were no other test item related clinical signs at 100,300 or 750 mgkg bw/day doses.
Individual clinical observations noted for single male animals at all doses were as follows:
In the 100 mg/kg bw/day group, damage of the left eye was observed from day 70 up to the termination.
In the 300 mg/lg bw/day group, alopecia was found on the forelimbs from day 28 up to the necropsy.
Mortality
In the 750 mg/kg bw/day group, decreased activity and piloerection were noted for One animal on days 89 and 90 resulting in death of this animal next day. One animal was found in prone position with closed eyes and convulsions immediately after the treatment (day 37) and then was died.
There were no clinical signs in female animals except for one pregnant rat at 300 mg/kg bw/day. Paleness and piloerection were observed from gestational day 21 to gestational day 23 and 27, respectively. Enlarged spleen and early death was recorded at the gross pathology on gestation day 28. Histological examination revealed splenic hyperplasia as individual disorder.
BODY WEIGHT AND BODY WEIGHT GAIN
Pre-mating period.
100 mg/kg bw/day
In the male animals, the mean body weight gain slightly exceeded the control value on week 11.
In the female animals, the mean body weight gain was slightly higher on week 4.
300 mg/kg bw/day
In the male animals, the mean body weight gain was slightly above the mean control value on week 11.
In the female animals, the mean body weight gain was slightly higher than the control on week 4.
750 mg/kg bw/day
In the male animals, the mean body weight gain slightly exceeded the control value on weeks 2,3, and 9 and it was less on week 6.
In the female animals, the mean body weight gain was slightly exceeded the control value on week 2.
Gestation period
There were no differences in the body weight and body weight gain between the control and Reaktiv Gelb F68072 treated animals at any dose level.
Lactation period
300 mg/kg bw/day
A slightly less body weight gain was noted on the first week.
750 mg/kg bw/day
The mean body weight gain was slightly exceeded the control value on week 2. In summary: No test item influence on the body weight development was found. The body weight was comparable in the control and Reaktiv Gelb F68072 FW treated animals in the course of the study. There were no differences between the control and test item treated groups either during the gestation or lactation periods. The summarised body weight gain was similar in the control and test item treated groups during the pre-mating, gestation and lactation periods. Slight deviations from the control value occurred in some cases without any dose relevance and these were not considered to be test item related.
FOOD CONSUMPTION
Pre-mating period
100 mg/kg bw/day
There were no differences in the mean daily food intake between the control and Reaktiv Gelb F68072 FW treated animals (male and female).
300 mg/kg bw/day
In the male animals, the mean daily food consumption was slightly above the mean control value on week 8.
In the female animals, the mean daily food consumption exceeded the mean control value on week 3.
750 mg/kg bw/day
In the male animals, the mean daily food consumption was higher (8-12 %) than the mean control value during the entire pre-mating period except weeks 1 and 6. In the female animals, the mean daily food consumption was less on week 1 and was higher than the mean control value on weeks 3 and 4 of the pre-mating period.
Gestation period
100 mg/kg bw/day
There were no differences in the mean daily food intake between the control and Reaktiv Gelb F68072 FW treated animals.
300 mg/kg bw/day, 750 mg/kg bw/day
The mean food consumption was higher during the whole gestation period with statistical significance on week 2.
Lactation period
100 mg/kg bw/day
There were no differences in the mean daily food consumption between the control and Reaktiv Gelb F68072 FW treated animals.
300 mg/kg bw/day
The mean daily food intake was less than the control value on week 1.
750 mg/kg bw/day
The mean food consumption was slightly less than the control value on week 1 of the lactation period.
In summary: A slightly higher mean daily food consumption was noted for male and female animals at 750 mg/kg bw/day almost the entire pre-mating period and for female animals during the gestation period. Considering that there were no body weight differences, a test item influence on the efficacy of feeding or on the metabolism cannot be excluded. It should be mentioned however, the food consumption was not influenced during the lactation period.
OESTROUS CYCLE
There were no test item related differences in the oestrous cycle during the four weeks of the pre-treatment period. The number of animals with regular cycles, the number of animals with irregular cycles, the number of cycles, the number of days in prooestrous, the number of days in oestrous, the number of days in diestrous and number of animals in prolonged oestrous diestrous were considered to be normal in all groups.
DELIVERY DATA
There were no differences between the control and test item treated groups in percentage of dams delivered (calculated by the number of pregnant females), percentage of dams with viable foetuses, in live birth index and in lactation index. No test item effect were found either in the litter mean of the number of implantations, number of total births, number of liveborns and stillborns. No stillborns were found in the 100 mg/kg bw/day and 750 mg/kg bw/day groups.
The mean duration of pregnancy (22.55 days) was slightly longer in dams treated with 750 mg/kg bw/day dose of Reaktiv Gelb F68072 FW than in the control.
In summary: The gestation period was slightly prolonged at 750 mg/kg bw/lday: 10/22 dams delivered on day 23, one on day 24 in whereas the control group had 2/23 dams delivered on gestation day 23 all other on gestation day 22 or 21. However, this was not considered to be significant biologically, because it is specific for this species strain according to the laboratories Historical Control data (Gestation length: 22.17 +/-0.44 days, min: 2 1 days, Max 23 days, n= 41).
There were no test item related alterations in the delivery data of Reaktiv Gelb F68072
FW treated dams as compared to the control value.
REPRODUCTIVE PERFORMANCE
The number and percentage of mated and fertile male animals, the copulatory and fertility indices were not affected by the treatment. The number and percentage of fertile males and fertility index were the lowest in 100 mg/kg bw/day group. There were no differences between the control and test item treated groups in the number and percentage of sperm positive (mated) female animals and copulatory index. The number and percentage of non-pregnant females was the highest in the low dose group (100 mg/kg bw/day group). The percentage of pregnant animals was less than the control, consequently the fertility index was less in the 100 mg/kg bw/day group than that in the control group. The percentage of pregnants with liveborn was less than the control value and number of pregnants not delivered exceeded the control value in 300 mg/kg bw/day group, consecutively the gestation index was less in 300 mg/kg bw/day group than that in the control group. The mean precoital interval was similar in the experimental groups.
In summary: No test item effect was found on the reproductive ability of male and female animals. There were no significant differences between the control and Reaktiv Gelb F68072 FW treated groups. The above detailed slight deviations from control were observed in the low (100 mg/kg bw/day ) and middle (300 mg/kg bw/day ) groups but not in the high (750 mg/kg bw/day ) dose group and were considered to be accidental and independent from the treatment.
NECROPSY
Male animals
Control group
In the lungs sporadic pinhead-sized greyish white foci, pinprick-sized haemorrhages and in the kidneys unilateral pyelectasia (were observed.
100 mg/kg bw/day
The eye of single animal was traumatised and pinprick-sized haemorrhages in the lungs were noted for several rats . Pale and nutmeg-like patterned liver and unilateral renal pyelectasia were found in single animals.
300 mg/kg bw/day
Pinprick-sized haemorrhages were observed in the lungs.
750 mg/kg bw/day
In animals found dead, dark red lungs, yellow content in the stomach and empty intestines were observed. In the surviving animals, reddish mottled colour and pinprick-sized haemorrhages were noted in the lungs.
Female animals
Dams
Control
In the lungs pinprick-sized haemorrhages were noted for several dams. Pinprick-sized haemorrhages in the lungs and early embryonic death in the uterine horns were observed in animal No.: 150 (not delivered) on gestational day 31.
100 mg/kg bw/day
In the lungs pinprick-sized haemorrhages were noted.
300 mg/kg bw/day
In the lungs pinprick-sized haemorrhages were found . Enlarged spleen and early embryonic death in the uterine horn were observed in two dams,
which not delivered. Late embryonic death was noted for animal No.: 335.
750 mg/kg bw/day
In the lungs pinprick-sized haemorrhages and pale liver were observed.
Non-pregnant and not mated animals
Control
In the only non-pregnant control animal (No.: 136) pinprick-sized haemorrhages were found in the lungs.
100 mg/kg bw/day
In the non-pregnant animals, in the lungs pinprick-sized haemorrhages, in the not mated rat severe hydrometra were observed.
300 mg/kg bw/day
Pinprick-sized haemorrhages in the lungs were observed in the only non-pregnant animal.
In the not mated rat, pinprick-sized haemorrhages in the lungs and severe hydrometra in the uterus were noted.
750 mg/kg bw/day
No macroscopic findings were found in non-pregnant and not mated animals.
In summary: Gross necropsy revealed no test item related macroscopic findings. Pulmonary alterations of the dead animals are indicative of suffocation as cause of the death. In surviving animals, reddish mottled colour and pinprick-sized haemorrhages in the lungs were related to the exsanguination process. These commonly occur in untreated animals after exsanguination. Sporadic pinhead-sized greyish white foci in the lungs, pale and nutmeg-like pattern of liver, enlargement of the spleen, renal pyelectasia, trauma on the eye were considered as individual alterations commonly seen in untreated experimental and rats.
HISTOPATHOLOGY
Male animals
In the dead animals, (750 mg/kg bw/day , No.: 408 and 418) in the lungs diffuse congestion and alveolar oedema were related to suffocation as the cause of death. In animal No.: 408, subacute focal purulent-necrotic inflammation in the wall of oesophagus due to mechanical injury at the oral gavage and serous-purulent inflammation in the adventitia of thoracic aorta as an accompanying reaction of oesophageal lesion were observed. These lesions were independent of the test item.
Control group
In the lungs foamy cells and unilateral pyelectasia in the kidneys were observed.
100 mg/kg bw/day
One-side pyelectasia (in the kidney and zonal vacuolisation of hepatocytes were noted for single animals subjected to histological examinations on the basis of the results of macroscopic findings.
750 mg/kg bw/day
There were no histological lesions in male animals. The examined organs of reproductive system (testes, epididymides, seminal vesicles, prostate, coagulate gland) were considered to be normal histologically in all (control and treated) groups. The various spermatogenic cells, representing different phases in the development and differentiation of the spermatozoons were the same in quantity and morphologically in the testes and epididyrnides of animals belonging to the control and treated groups. The histological picture of seminal vesicles, prostate and coagulating gland was
normal in all cases.
Female animals
Dams
Control group,
In dams which delivered, the ovaries had a normal structure characteristic of the species, age and phase of the active sexual cycle. The cortex of ovaries in all female animals contained primordial, secondary and tertiary follicles and corpora lutea, indicating the active maturation of oocytes and ovulation. The uterus, cervix, and vagina had a normal structure in accordance with the phase of sexual cycle in the investigated animals. Purulent endometritis, necrotic debris and dilatation of uterus (1124) were observed in the dam not delivered (No.: 150).
300 mglkg bwlday
Splenic hyperplasia was noted for animals not delivered (212, No.: 338 and 341) and subjected to histological examinations because of macroscopic findings.
750 mg/kg bw/day
Foetuses and dilatation of uterus were observed in pregnant animal not delivered (No.: 438).
There were no histological changes in dams with viable foetuses in the high dose group. The ovaries had a normal structure characteristic of the species, age and phase of the active sexual cycle. The cortex of ovaries in all female animals contained primordial, secondary and tertiary follicles and corpora lutea, indicating the active maturation of oocytes and ovulation. The uterus, cervix, and vagina had a normal structure in accordance with the phase of sexual cycle in the investigated animals.
Non-pregnant and not mated animals
Control
In the only non-pregnant animal, the ovaries had a normal structure characteristic of the species, age and phase of the active sexual cycle. The cortex of ovaries contained primordial, secondary and tertiary follicles and corpora lutea, indicating the active maturation of oocytes and ovulation. The uterus, cervix, and vagina had a normal structure in accordance with the phase of sexual cycle.
750 mg/kg bw/day
The ovaries had a normal structure characteristic of the species, age and phase of the active sexual cycle. The cortex of ovaries in all female animals contained primordial, secondary and tertiary follicles and corpora lutea, indicating the active maturation of oocytes and ovulation. The uterus, cervix, and vagina had a normal structure in accordance with the phase of sexual cycle in the investigated animals. In summary: No treatment related alterations were found at the investigation of the male and female reproductive organs, pituitary, and macroscopically altered organs.
750 mg/kg bw/day .
The zonal vacuolisation of hepatocytes in the liver (111 male animal, 100 mg/kg bw/day), the unilateral pyelectasia in the kidney without other pathological lesion (degeneration, inflammation or fibrosis, 212 male control animals, and 1 male animal at 100 mg/kg bw/day ), the foamy cells in the lung (111 male, control) and the hyperplasia in the spleen (300 mg/kg bw/day , two female animals) were considered as individual disorder. These are common alterations in this species and strain. The endometritis in this study was considered as sporadic individual disease.
An increased water consumption and urine excretion related to the test item was found at 750 mg bw/day group (male and female animals) from day 2 until the termination of the treatment. There were no other test item related clinical signs at 100,300 or 750 mgkg bw/day doses.
Individual clinical observations noted for single male animals at all doses were as follows:
In the 100 mg/kg bw/day group, damage of the left eye was observed from day 70 up to the termination.
In the 300 mg/lg bw/day group, alopecia was found on the forelimbs from day 28 up to the necropsy.
Mortality
In the 750 mg/kg bw/day group, decreased activity and piloerection were noted for One animal on days 89 and 90 resulting in death of this animal next day. One animal was found in prone position with closed eyes and convulsions immediately after the treatment (day 37) and then was died.
There were no clinical signs in female animals except for one pregnant rat at 300 mg/kg bw/day. Paleness and piloerection were observed from gestational day 21 to gestational day 23 and 27, respectively. Enlarged spleen and early death was recorded at the gross pathology on gestation day 28. Histological examination revealed splenic hyperplasia as individual disorder.
BODY WEIGHT AND BODY WEIGHT GAIN
Pre-mating period.
100 mg/kg bw/day
In the male animals, the mean body weight gain slightly exceeded the control value on week 11.
In the female animals, the mean body weight gain was slightly higher on week 4.
300 mg/kg bw/day
In the male animals, the mean body weight gain was slightly above the mean control value on week 11.
In the female animals, the mean body weight gain was slightly higher than the control on week 4.
750 mg/kg bw/day
In the male animals, the mean body weight gain slightly exceeded the control value on weeks 2,3, and 9 and it was less on week 6.
In the female animals, the mean body weight gain was slightly exceeded the control value on week 2.
Gestation period
There were no differences in the body weight and body weight gain between the control and Reaktiv Gelb F68072 treated animals at any dose level.
Lactation period
300 mg/kg bw/day
A slightly less body weight gain was noted on the first week.
750 mg/kg bw/day
The mean body weight gain was slightly exceeded the control value on week 2. In summary: No test item influence on the body weight development was found. The body weight was comparable in the control and Reaktiv Gelb F68072 FW treated animals in the course of the study. There were no differences between the control and test item treated groups either during the gestation or lactation periods. The summarised body weight gain was similar in the control and test item treated groups during the pre-mating, gestation and lactation periods. Slight deviations from the control value occurred in some cases without any dose relevance and these were not considered to be test item related.
FOOD CONSUMPTION
Pre-mating period
100 mg/kg bw/day
There were no differences in the mean daily food intake between the control and Reaktiv Gelb F68072 FW treated animals (male and female).
300 mg/kg bw/day
In the male animals, the mean daily food consumption was slightly above the mean control value on week 8.
In the female animals, the mean daily food consumption exceeded the mean control value on week 3.
750 mg/kg bw/day
In the male animals, the mean daily food consumption was higher (8-12 %) than the mean control value during the entire pre-mating period except weeks 1 and 6. In the female animals, the mean daily food consumption was less on week 1 and was higher than the mean control value on weeks 3 and 4 of the pre-mating period.
Gestation period
100 mg/kg bw/day
There were no differences in the mean daily food intake between the control and Reaktiv Gelb F68072 FW treated animals.
300 mg/kg bw/day, 750 mg/kg bw/day
The mean food consumption was higher during the whole gestation period with statistical significance on week 2.
Lactation period
100 mg/kg bw/day
There were no differences in the mean daily food consumption between the control and Reaktiv Gelb F68072 FW treated animals.
300 mg/kg bw/day
The mean daily food intake was less than the control value on week 1.
750 mg/kg bw/day
The mean food consumption was slightly less than the control value on week 1 of the lactation period.
In summary: A slightly higher mean daily food consumption was noted for male and female animals at 750 mg/kg bw/day almost the entire pre-mating period and for female animals during the gestation period. Considering that there were no body weight differences, a test item influence on the efficacy of feeding or on the metabolism cannot be excluded. It should be mentioned however, the food consumption was not influenced during the lactation period.
OESTROUS CYCLE
There were no test item related differences in the oestrous cycle during the four weeks of the pre-treatment period. The number of animals with regular cycles, the number of animals with irregular cycles, the number of cycles, the number of days in prooestrous, the number of days in oestrous, the number of days in diestrous and number of animals in prolonged oestrous diestrous were considered to be normal in all groups.
DELIVERY DATA
There were no differences between the control and test item treated groups in percentage of dams delivered (calculated by the number of pregnant females), percentage of dams with viable foetuses, in live birth index and in lactation index. No test item effect were found either in the litter mean of the number of implantations, number of total births, number of liveborns and stillborns. No stillborns were found in the 100 mg/kg bw/day and 750 mg/kg bw/day groups.
The mean duration of pregnancy (22.55 days) was slightly longer in dams treated with 750 mg/kg bw/day dose of Reaktiv Gelb F68072 FW than in the control.
In summary: The gestation period was slightly prolonged at 750 mg/kg bw/lday: 10/22 dams delivered on day 23, one on day 24 in whereas the control group had 2/23 dams delivered on gestation day 23 all other on gestation day 22 or 21. However, this was not considered to be significant biologically, because it is specific for this species strain according to the laboratories Historical Control data (Gestation length: 22.17 +/-0.44 days, min: 2 1 days, Max 23 days, n= 41).
There were no test item related alterations in the delivery data of Reaktiv Gelb F68072
FW treated dams as compared to the control value.
REPRODUCTIVE PERFORMANCE
The number and percentage of mated and fertile male animals, the copulatory and fertility indices were not affected by the treatment. The number and percentage of fertile males and fertility index were the lowest in 100 mg/kg bw/day group. There were no differences between the control and test item treated groups in the number and percentage of sperm positive (mated) female animals and copulatory index. The number and percentage of non-pregnant females was the highest in the low dose group (100 mg/kg bw/day group). The percentage of pregnant animals was less than the control, consequently the fertility index was less in the 100 mg/kg bw/day group than that in the control group. The percentage of pregnants with liveborn was less than the control value and number of pregnants not delivered exceeded the control value in 300 mg/kg bw/day group, consecutively the gestation index was less in 300 mg/kg bw/day group than that in the control group. The mean precoital interval was similar in the experimental groups.
In summary: No test item effect was found on the reproductive ability of male and female animals. There were no significant differences between the control and Reaktiv Gelb F68072 FW treated groups. The above detailed slight deviations from control were observed in the low (100 mg/kg bw/day ) and middle (300 mg/kg bw/day ) groups but not in the high (750 mg/kg bw/day ) dose group and were considered to be accidental and independent from the treatment.
NECROPSY
Male animals
Control group
In the lungs sporadic pinhead-sized greyish white foci, pinprick-sized haemorrhages and in the kidneys unilateral pyelectasia (were observed.
100 mg/kg bw/day
The eye of single animal was traumatised and pinprick-sized haemorrhages in the lungs were noted for several rats . Pale and nutmeg-like patterned liver and unilateral renal pyelectasia were found in single animals.
300 mg/kg bw/day
Pinprick-sized haemorrhages were observed in the lungs.
750 mg/kg bw/day
In animals found dead, dark red lungs, yellow content in the stomach and empty intestines were observed. In the surviving animals, reddish mottled colour and pinprick-sized haemorrhages were noted in the lungs.
Female animals
Dams
Control
In the lungs pinprick-sized haemorrhages were noted for several dams. Pinprick-sized haemorrhages in the lungs and early embryonic death in the uterine horns were observed in animal No.: 150 (not delivered) on gestational day 31.
100 mg/kg bw/day
In the lungs pinprick-sized haemorrhages were noted.
300 mg/kg bw/day
In the lungs pinprick-sized haemorrhages were found . Enlarged spleen and early embryonic death in the uterine horn were observed in two dams,
which not delivered. Late embryonic death was noted for animal No.: 335.
750 mg/kg bw/day
In the lungs pinprick-sized haemorrhages and pale liver were observed.
Non-pregnant and not mated animals
Control
In the only non-pregnant control animal (No.: 136) pinprick-sized haemorrhages were found in the lungs.
100 mg/kg bw/day
In the non-pregnant animals, in the lungs pinprick-sized haemorrhages, in the not mated rat severe hydrometra were observed.
300 mg/kg bw/day
Pinprick-sized haemorrhages in the lungs were observed in the only non-pregnant animal.
In the not mated rat, pinprick-sized haemorrhages in the lungs and severe hydrometra in the uterus were noted.
750 mg/kg bw/day
No macroscopic findings were found in non-pregnant and not mated animals.
In summary: Gross necropsy revealed no test item related macroscopic findings. Pulmonary alterations of the dead animals are indicative of suffocation as cause of the death. In surviving animals, reddish mottled colour and pinprick-sized haemorrhages in the lungs were related to the exsanguination process. These commonly occur in untreated animals after exsanguination. Sporadic pinhead-sized greyish white foci in the lungs, pale and nutmeg-like pattern of liver, enlargement of the spleen, renal pyelectasia, trauma on the eye were considered as individual alterations commonly seen in untreated experimental and rats.
HISTOPATHOLOGY
Male animals
In the dead animals, (750 mg/kg bw/day , No.: 408 and 418) in the lungs diffuse congestion and alveolar oedema were related to suffocation as the cause of death. In animal No.: 408, subacute focal purulent-necrotic inflammation in the wall of oesophagus due to mechanical injury at the oral gavage and serous-purulent inflammation in the adventitia of thoracic aorta as an accompanying reaction of oesophageal lesion were observed. These lesions were independent of the test item.
Control group
In the lungs foamy cells and unilateral pyelectasia in the kidneys were observed.
100 mg/kg bw/day
One-side pyelectasia (in the kidney and zonal vacuolisation of hepatocytes were noted for single animals subjected to histological examinations on the basis of the results of macroscopic findings.
750 mg/kg bw/day
There were no histological lesions in male animals. The examined organs of reproductive system (testes, epididymides, seminal vesicles, prostate, coagulate gland) were considered to be normal histologically in all (control and treated) groups. The various spermatogenic cells, representing different phases in the development and differentiation of the spermatozoons were the same in quantity and morphologically in the testes and epididyrnides of animals belonging to the control and treated groups. The histological picture of seminal vesicles, prostate and coagulating gland was
normal in all cases.
Female animals
Dams
Control group,
In dams which delivered, the ovaries had a normal structure characteristic of the species, age and phase of the active sexual cycle. The cortex of ovaries in all female animals contained primordial, secondary and tertiary follicles and corpora lutea, indicating the active maturation of oocytes and ovulation. The uterus, cervix, and vagina had a normal structure in accordance with the phase of sexual cycle in the investigated animals. Purulent endometritis, necrotic debris and dilatation of uterus (1124) were observed in the dam not delivered (No.: 150).
300 mglkg bwlday
Splenic hyperplasia was noted for animals not delivered (212, No.: 338 and 341) and subjected to histological examinations because of macroscopic findings.
750 mg/kg bw/day
Foetuses and dilatation of uterus were observed in pregnant animal not delivered (No.: 438).
There were no histological changes in dams with viable foetuses in the high dose group. The ovaries had a normal structure characteristic of the species, age and phase of the active sexual cycle. The cortex of ovaries in all female animals contained primordial, secondary and tertiary follicles and corpora lutea, indicating the active maturation of oocytes and ovulation. The uterus, cervix, and vagina had a normal structure in accordance with the phase of sexual cycle in the investigated animals.
Non-pregnant and not mated animals
Control
In the only non-pregnant animal, the ovaries had a normal structure characteristic of the species, age and phase of the active sexual cycle. The cortex of ovaries contained primordial, secondary and tertiary follicles and corpora lutea, indicating the active maturation of oocytes and ovulation. The uterus, cervix, and vagina had a normal structure in accordance with the phase of sexual cycle.
750 mg/kg bw/day
The ovaries had a normal structure characteristic of the species, age and phase of the active sexual cycle. The cortex of ovaries in all female animals contained primordial, secondary and tertiary follicles and corpora lutea, indicating the active maturation of oocytes and ovulation. The uterus, cervix, and vagina had a normal structure in accordance with the phase of sexual cycle in the investigated animals. In summary: No treatment related alterations were found at the investigation of the male and female reproductive organs, pituitary, and macroscopically altered organs.
750 mg/kg bw/day .
The zonal vacuolisation of hepatocytes in the liver (111 male animal, 100 mg/kg bw/day), the unilateral pyelectasia in the kidney without other pathological lesion (degeneration, inflammation or fibrosis, 212 male control animals, and 1 male animal at 100 mg/kg bw/day ), the foamy cells in the lung (111 male, control) and the hyperplasia in the spleen (300 mg/kg bw/day , two female animals) were considered as individual disorder. These are common alterations in this species and strain. The endometritis in this study was considered as sporadic individual disease.
Effect levels (P0)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 750 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Remarks:
- No adverse effects related to the substance were noted. The only effects seen were secondary effects related to the high lithium content of the substance.
Target system / organ toxicity (P0)
- Critical effects observed:
- no
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- mortality observed, treatment-related
- Description (incidence and severity):
- In the 750 mg/kg bw/day group, a slightly higher mortality rate was noted; 25/288
pups were found dead (9) or were cannibalised (15) between postnatal days 0 and 21 in comparison to 10/318 pups in the control group. This was considered not to be related to the toxicity of the substance but due to a secondary effect of the lithium side effects (polydipsia and polyurea) in dams. - Body weight and weight changes:
- no effects observed
- Gross pathological findings:
- no effects observed
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- no effects observed
Details on results (F1)
F1 GENERATION
MORTALITY AND CLINICAL SYMPTOMS
In the control, 100 mg/kg bw/day and 300 mg/kg bw/day groups, the mortality of pups was low between postnatal days 0 and 2 1 (1 013 18,6126 1 and 71256, respectively).
In the 750 mg/kg bw/day group, a slightly higher mortality rate was noted. Pups were found dead (9) or were cannibalised (15) between postnatal days 0 and 21.
Percentage of dead male pups was significantly higher than in the control group.
There were no differences between control and test item treated groups in the ratio of genders.
Viability indices and lactation indices were similar in the control, 100 mg/kg bw/day and 300 mg/kg bw/day groups during the 21 postnatal days. In the 750 mg/kg bw/day group, the viability index was slightly less on postnatal day 4.
There were no differences in the litter means of the examined parameters between the
control and dose groups.
In summary: A slightly higher mortality rate of male pups was found at 750 mg/kg bw/day between postnatal day 0 and 4, consequently the viability indices for this period was less. This difference was ascribed to treatment, but was probably related to maternal toxicity (observed as polyuria).
The percentage of non-suckled pups correlated with the percentage of dead or cannibalised (not found) pups at 750 mg/kg bw/day group. Pale, cold pups, congenital absence of tail and haemorrhage on the body were observed sporadically without any dose relation.
BODY WEIGHT
There were no differences in the mean body weight and body weight gain of pups between the experimental groups when calculated either individually or by litter.
DEVELOPMENTAL TESTS
The number and percentage of animals with a negative response in the surface righting reflex and in the suckling ability were comparable in all groups. The number of pups per litter with positive surface righting reflex was slightly less than the control.
The number and percentage of animals with detached pinna (negative response) was higher at 300 mg/kg bw/day and the number and percentage of animals with closed eyes (negative response) was less at 100 mg/kg bw/day . There were no differences in the litter means.
In summary: There was no test item influence on the development of pups. The differences in pinna detachment and eye opening at 300 and 100 mg/kg bw/day , respectively, were considered to be independent from the test item taking into account the normal values of the high dose group.
NECROPSY
In the control group, acute enteritis (115) empty stomach (115) and autolysed organs (115) were observed. The stomach was full of milk (1/5), the lung flotation test was positive in one rat (115) and was negative in another one (115) on postnatal day 0. In the 100 mg/kg bw/day group, autolysed organs (3/5), empty stomach (215) and dark red lungs (115) were found. The lung flotation test was positive in two pups. In the 300 mg/kg bw/day group, autolysed organs (211 l), empty stomach (111 1) were observed. The lung flotation test was negative in seven pups.
In the 750 mg/kg bw/day group, empty stomach (519) and dark red lungs (219) were found. The lung flotation test was positive in nine pups.
In summary: Test item related macroscopic alterations were not found in offspring subjected to gross pathology. Acute enteritis and content of stomach were considered to be individual findings causing death of the pups.
MORTALITY AND CLINICAL SYMPTOMS
In the control, 100 mg/kg bw/day and 300 mg/kg bw/day groups, the mortality of pups was low between postnatal days 0 and 2 1 (1 013 18,6126 1 and 71256, respectively).
In the 750 mg/kg bw/day group, a slightly higher mortality rate was noted. Pups were found dead (9) or were cannibalised (15) between postnatal days 0 and 21.
Percentage of dead male pups was significantly higher than in the control group.
There were no differences between control and test item treated groups in the ratio of genders.
Viability indices and lactation indices were similar in the control, 100 mg/kg bw/day and 300 mg/kg bw/day groups during the 21 postnatal days. In the 750 mg/kg bw/day group, the viability index was slightly less on postnatal day 4.
There were no differences in the litter means of the examined parameters between the
control and dose groups.
In summary: A slightly higher mortality rate of male pups was found at 750 mg/kg bw/day between postnatal day 0 and 4, consequently the viability indices for this period was less. This difference was ascribed to treatment, but was probably related to maternal toxicity (observed as polyuria).
The percentage of non-suckled pups correlated with the percentage of dead or cannibalised (not found) pups at 750 mg/kg bw/day group. Pale, cold pups, congenital absence of tail and haemorrhage on the body were observed sporadically without any dose relation.
BODY WEIGHT
There were no differences in the mean body weight and body weight gain of pups between the experimental groups when calculated either individually or by litter.
DEVELOPMENTAL TESTS
The number and percentage of animals with a negative response in the surface righting reflex and in the suckling ability were comparable in all groups. The number of pups per litter with positive surface righting reflex was slightly less than the control.
The number and percentage of animals with detached pinna (negative response) was higher at 300 mg/kg bw/day and the number and percentage of animals with closed eyes (negative response) was less at 100 mg/kg bw/day . There were no differences in the litter means.
In summary: There was no test item influence on the development of pups. The differences in pinna detachment and eye opening at 300 and 100 mg/kg bw/day , respectively, were considered to be independent from the test item taking into account the normal values of the high dose group.
NECROPSY
In the control group, acute enteritis (115) empty stomach (115) and autolysed organs (115) were observed. The stomach was full of milk (1/5), the lung flotation test was positive in one rat (115) and was negative in another one (115) on postnatal day 0. In the 100 mg/kg bw/day group, autolysed organs (3/5), empty stomach (215) and dark red lungs (115) were found. The lung flotation test was positive in two pups. In the 300 mg/kg bw/day group, autolysed organs (211 l), empty stomach (111 1) were observed. The lung flotation test was negative in seven pups.
In the 750 mg/kg bw/day group, empty stomach (519) and dark red lungs (219) were found. The lung flotation test was positive in nine pups.
In summary: Test item related macroscopic alterations were not found in offspring subjected to gross pathology. Acute enteritis and content of stomach were considered to be individual findings causing death of the pups.
Effect levels (F1)
open allclose all
- Dose descriptor:
- NOEL
- Generation:
- F1
- Effect level:
- 300 mg/kg bw/day (actual dose received)
- Sex:
- male/female
- Basis for effect level:
- viability
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- >= 750 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Remarks:
- No adverse effects related to the substance were noted. The only effects seen were secondary effects related to the effects caused in dams by the high lithium content of the substance.
Target system / organ toxicity (F1)
- Critical effects observed:
- no
Overall reproductive toxicity
- Reproductive effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- Reaktiv Gelb F68072 FW induced polyuria and polydipsia at 750 mg/kg/day dose level on parental generation of CRL:(WI)BR rats during the course of a one generation reproduction toxicity study. This is a reult of the hight lithium content in the test material, as polyuria and polydipsia are common side effects of lithium.
Reproductive performance of males and females were unaffected by the treatment. The mortality of pups was a slightly higher at 750 mg/kg bw/day, as a consequence of maternal lithium effects (polyuria). There was no effect on postnatal development of viable pups. - Executive summary:
The aim of the one-generation reproduction toxicity study was to provide general information concerning the effect of the test item Reaktiv Gelb F68072 FW on the male and female reproductive performance, such as gonadal function, estrous cycle, mating behavior, conception, parturition, gestation and lactation (P generation) and on the neonatal morbidity, mortality, growth and development of the offspring (F1 generation) following oral (by gavage) administration. CRL:(WI)BR rats (n=24 males/group and n=25 females/group) were involved in the study in a control and at three dose levels: 100 mg/kg/day, 300 mg/kg/day and 750 mg/kg/day. Treatment was carried out orally once a day in concentrations of 10 mg/ml, 30 mg/ml and 75 mg/ml corresponding to 10 ml/kg body weight volume. All animals of the P generation were treated prior to mating (male animals for 81 days, females for 27 days) and throughout mating. For females, treatment was continued though the gestation and lactation periods up to the necropsy. Observations included mortality, clinical symptoms, body weight, food consumption, estrous cycle, mating, and delivery process.
The dams of P generation were allowed to litter, and rear their young up to termination on day 21-23 postpartum. Developmental tests were evaluated on litters (surface righting reflex, suckling, pinna detachment and eye opening). All animals were subjected to gross pathology one day after the last treatment and offspring were sacrificed. Histopathology examination was performed on reproductive organs in the control and high dose groups and on gross lesions in the low and middle dose groups.
There were no test item related effect on the general state and behavior of animals, but an increased urine excretion and water consumption related to the test item was found at 750 mg/kg bw/day group (male and female animals) from day 2 until the termination of the treatment. The body weight, body weight gain of males and females were unaffected at the examined dose levels during the pre-mating period. There was no effect on body weight, body weight gain of dams during gestation and lactation period at the examined dose levels. The mean daily food consumption was higher than the control at 750 mg/kg bw/day dose in male animals and in female animals during the pre-mating and gestation periods. No test item influence on the estrous was found.
There were no test item related alterations in the delivery data of dams when compared with the control value.
Reproductive performance of males and females were unaffected by treatment with Reaktiv Gelb F68072 FW. Gross pathology revealed no alterations due to the effect of test item in P generation. No histological alterations related to the test item effect were found. In the male animals the investigated organs of reproductive system (testes, epididymides, seminal vesicles, prostate, coagulating gland) were histologically normal. In dams, the ovaries had a normal structure characteristic of the species, age and phase of the active sexual cycle. The uterus, cervix, and vagina had a normal structure in accordance with the phase of sexual cycle in the investigated animals.
Mortality of pups was slightly higher at 750 mg/kg bw/day group (9% vs. 3% of control value). Body weight, body weight gain and sex ratio of pups were not influenced by treatment with Reaktiv Gelb F68072 FW. There was no effect on postnatal development of pups.
Reaktiv Gelb F68072 FW induced polyuria and polydipsia at 750 mg/kg/day dose level on parental generation of CRL:(WI)BR rats during the course of a one generation reproduction toxicity study. This is a reult of the hight lithium content in the test material, as polyuria and polydipsia are common side effects of lithium.
Reproductive performance of males and females were unaffected by the treatment. The mortality of pups was a slightly higher at 750 mg/kg bw/day, as a consequence of maternal lithium effects (polyuria). There was no effect on postnatal development of viable pups.
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