3-methyl-1-vinyl-1H-imidazolium methyl sulphate

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP Guideline Study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2013

Report date:

2013

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

3-methyl-1-vinyl-1H-imidazolium methyl sulphate

EC Number:

247-832-2

EC Name:

3-methyl-1-vinyl-1H-imidazolium methyl sulphate

Cas Number:

26591-72-0

Molecular formula:

C6H9N2.CH3O4S

IUPAC Name:

1-ethenyl-3-methyl-1H-imidazol-3-ium methyl sulfate

Details on test material:

- Name of test material (as cited in study report): 3-Methyl-1-vinyl-1 H-imidazolium methyl sulfate
- Physical state: solid
- Analytical purity: 99.97 area-% determined by HPLC-Fingerprint
- Lot/batch No.: 77761968E0
- Stability under test conditions: The stability of the test item under storage conditions over the study period was guaranteed by the sponsor,
and the sponsor holds this responsibility.
- Storage condition of test material: Room temperature

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
- Age at study initiation: 12 - 13 weeks
- Weight at study initiation: males: 339.0 g - 372.4g; females: 191.1 g - 225.1 g
- Housing: During the study period, the rats were housed individually in Makrolon type M III cages supplied by Becker & Co., Castrop-Rauxel, Germany (floor area of about 800 cm²), with the following exceptions:
- During overnight matings, male and female mating partners were housed together in Makrolon type M III cages.
- Pregnant animals and their litters were housed together until PND 4.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
The test substance solutions in drinking water were prepared at the beginning of the administration period and thereafter in intervals, which took into account the analytical results of the stability verification.
For the preparation of the administration solutions the test substance was weighed in a calibrated beaker depending on the dose group, topped up with drinking water and subsequently intensely mixed with a magnetic stirrer until it was completely dissolved.

VEHICLE
- Justification for use and choice of vehicle (if other than water): good sulubility in water
- Amount of vehicle (if gavage): 10 mL/kg bw (including test substance)

Details on mating procedure:

In general, each of the male and female animals was mated overnight in a 1:1 ratio for a maximum of 2 weeks. Throughout the mating period, each female animal was paired with a predetermined male animal from the same dose group.
The animals were paired by placing the female in the cage of the male mating partner from about 16.00 h until 07.00 - 09.00 h of the following morning. Deviations from the specified times were possible on weekends and public holidays and were reported in the raw data. A vaginal smear was prepared after each mating and examined for the presence of sperm. If sperm was detected, pairing of the animals was discontinued. The day on which sperm were detected was denoted "GD 0" and the following day "GD 1".

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The analyses were carried out at the Analytical Chemistry Laboratory of Experimental Toxicology and Ecology of BASF SE, Ludwigshafen, Germany.
Analytical verifications of the stability of the test substance in drinking water for a period of 7 days at room temperature were carried out prior to the start of the study.
Given that test substance was completely miscible with drinking water, solutions were considered to be homogenous without further analysis.
Samples of the test substance solutions were sent to the analytical laboratory once at the beginning of the study for verification of the concentrations.
Of each sample, one additional reserve sample was retained. Details of the sampling schedule were recorded with the raw data.

Duration of treatment / exposure:

The duration of treatment covered a 2-week pre-mating and a mating period in both sexes, approximately 3 weeks post-mating in males and in one not pregnant female, and the entire gestation period as well as approximately 2 weeks of the lactation period.

Frequency of treatment:

once daily

Details on study schedule:

N/A

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 100, 300 and 1000 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: based on range-finder
- Rationale for animal assignment (if not random): random

Positive control:

N/A

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS/DETAILED CLINICAL OBSERVATIONS: Yes
A check for moribund or dead animals was made twice daily on working days or once daily (Saturday, Sunday or on public holidays). If animals were in a moribund state, they were sacrificed and necropsied. The examinations of these animals were carried out according to the methods established at the BASF SE laboratory for pathology, Experimental Toxicology and Ecology, Ludwigshafen, Germany.
A cageside examination was conducted at least once daily for any signs of morbidity, pertinent behavioral changes and signs of overt toxicity. Abnormalities and changes were documented daily for each animal.
The parturition and lactation behavior of the dams was generally evaluated in the mornings in combination with the daily clinical inspection of the dams. Only particular findings (e.g. inability to deliver) were documented on an individual dam basis.
On weekdays (except Saturday, Sunday and public holidays) the parturition behavior of the dams was inspected in the afternoons in addition to the evaluations in the mornings. The day of parturition was considered the 24-hour period from about 15.00 h of one day until about 15.00 h of the following day.

Detailed clinical observations were performed in all animals once prior to the first administration and at weekly intervals during the administration period. The examinations started in the morning. The findings were ranked according to the degree of severity, if applicable.
For observation, the animals were removed from their cages by the investigator and placed in a standard arena (50 x 37.5 cm wide, with side borders which are 25 cm high). The following parameters listed were assessed:
1. Abnormal behavior in “handling”
2. Fur
3. Skin
4. Posture
5. Salivation
6. Respiration
7. Activity/arousal level
8. Tremors
9. Convulsions
10. Abnormal movements
11. Gait abnormalities
12. Lacrimation
13. Palpebral closure
14. Exophthalmos
15. Assessment of the feces discharged during the examination (appearance/consistency)
16. Assessment of the urine discharged during the examination
17. Pupil size

BODY WEIGHT: Yes
In general, the body weight of the male and female parental animals was determined once a week at the same time of the day (in the morning) until sacrifice.
The body weight change of the animals was calculated from these results.
The following exceptions are notable for the female animals:
- During the mating period the parental females were weighed on the day of positive evidence of sperm (GD 0) and on GD 7, 14 and 20.
- Females with litter were weighed on the day of parturition (PND 0) and on PND 4.
Females without positive evidence of sperm, without litter or waiting for necropsy, were weighed weekly. These body weight data were solely used for the calculations of the dose volume; therefore these values are not reported in the Summary but in the Individual Tables.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data

Oestrous cyclicity (parental animals):

N/A

Sperm parameters (parental animals):

N/A

Litter observations:

LITTER DATA
Pup number and status at delivery
All pups delivered from the F0 parents (F1 litter) were examined as soon as possible on the day of birth to determine the total number of pups, the sex and the number of liveborn and stillborn pups in each litter. At the same time, the pups were also being examined for macroscopically evident changes. Pups, which died before this initial examination, were defined as stillborn pups.

Pup viability/mortality
In general, a check was made for any dead or moribund pups twice daily on workdays (once in the morning and once in the afternoon) or as a rule, only in the morning on Saturdays, Sundays or public holidays. Dead pups were evaluated by the methods, which are described in detail in section “Necropsy observations”.
The number and percentage of dead pups on the day of birth (PND 0) and of pups dying between PND 1-4 (lactation period) were determined. Pups which died accidentally or were sacrificed due to maternal death, were not included in these calculations. The number of live pups/litter was calculated on the day after birth, and on lactation day 4. The viability index was calculated.

Sex ratio
On the day of birth (PND 0) the sex of the pups was determined by observing the distance between the anus and the base of the genital tubercle; normally, the anogenital distance is considerably greater in male than in female pups. The sex of the pups was finally confirmed at necropsy. The sex ratio was calculated at day 0 and day 4 after birth.

Pup clinical observations
The live pups were examined daily for clinical symptoms (including gross-morphological findings) during the clinical inspection of the dams and documented for each pup.

Pup body weight data
The pups were weighed on the day after birth (PND 1) and on PND 4.
Pups' body weight change was calculated from these results.
The individual weights were always determined at about the same time of the day (in the morning).
“Runts” were defined on the basis of the body weights on PND 1. "Runts" are pups that weigh less than 75% of the mean weight of the respective control pups.

Postmortem examinations (parental animals):

Necropsy
With one exception, all parental animals were sacrificed by decapitation under isoflurane anesthesia. The exsanguinated animals were necropsied and assessed by gross pathology; special attention was given to the reproductive organs. Female animal 137 was the exception, which was found dead on study day 12 in phase pre-mating.

Weight parameters
Weight assessment was carried out on all animals. The following weights were determined:

1. Anesthetized animals
2. Epididymides
3. Testes

The following weights were determined in 5 animals/sex and test group (females with litters, same animals as used for clinical pathology examinations):

1. Adrenal glands
2. Brain
3. Heart
4. Kidneys
5. Liver
6. Spleen
7. Thymus

Organ / Tissue preservation list
The following organs / tissues were preserved in neutral-buffered 4% formaldehyde or in modified Davidson’s solution:
1. All gross lesions
2. Adrenal glands
3. Aorta
4. Bone marrow (femur)
5. Brain
6. Cecum
7. Cervix
8. Coagulating gland
9. Colon
10. Duodenum
11. Eyes with optic nerve
12. Esophagus
13. Extraorbital lacrimal glands
14. Epididymides (modified Davidson’s solution)
15. Femur with knee joint
16. Heart
17. Ileum
18. Jejunum (with Peyer’s patches)
19. Kidneys
20. Larynx
21. Liver
22. Lungs
23. Lymph nodes (axillary and mesenteric)
24. Mammary gland (male and female)
25. Nose (nasal cavity)
26. Ovaries (modified Davidson’s solution)
27. Oviducts
28. Pancreas
29. Parathyroid glands
30. Pharynx
31. Pituitary gland
32. Prostate gland
33. Rectum
34. Salivary glands (mandibular and sublingual)
35. Sciatic nerve
36. Seminal vesicles
37. Skeletal muscle
38. Spinal cord (cervical, thoracic and lumbar cord)
39. Spleen
40. Sternum with marrow
41. Stomach (forestomach and glandular stomach)
42. Testes (modified Davidson’s solution)
43. Thymus
44. Thyroid glands
45. Trachea
46. Urinary bladder
47. Uterus
48. Vagina

The ovaries of animal 137 that died were fixed in 4% buffered formaldehyde solution.
The uteri of all female F0 parental animals were examined for the presence and number of implantation sites. The uteri of apparently non-pregnant animals or empty corpora uteri were placed in 1% ammonium sulfide solutions for about 5 minutes in order to be able to identify
early resorptions or implantations (SALEWSKI's method). Then the uteri were rinsed carefully with 0.9% NaCl solution. When the examinations were completed, the uteri were transferred to the Pathology Laboratory for further processing.

Paraffin embedding, sectioning and staining
After the organs were fixed, processing, examination by light microscopy and evaluation of findings were performed, staining with Hematoxylin-eosin (H&E):
all gross lesions (all affected animals per group),
control and high dose animals only:
Adrenal glands (5 animals per sex per group, females with litters only, same animals as used for clinical pathology examination)
Bone marrow (femur) (5 animals per sex per group, females with litters only, same animals as used for clinical pathology examination)
Brain (5 animals per sex per group, females with litters only, same animals as used for clinical pathology examination)
Cecum (5 animals per sex per group, females with litters only, same animals as used for clinical pathology examination)
Cervix (all animals per group)
Coagulation glands (all animals per group)
Colon (5 animals per sex per group, females with litters only, same animals as used for clinical pathology examination)
Duodenum (5 animals per sex per group, females with litters only, same animals as used for clinical pathology examination)
Epididymides (all animals per group)
Heart (5 animals per sex per group, females with litters only, same animals as used for clinical pathology examination)
Ileum (5 animals per sex per group, females with litters only, same animals as used for clinical pathology examination)
Jejunum (5 animals per sex per group, females with litters only, same animals as used for clinical pathology examination)
Kidneys (5 animals per sex per group, females with litters only, same animals as used for clinical pathology examination)
Liver (5 animals per sex per group, females with litters only, same animals as used for clinical pathology examination)
Lung (5 animals per sex per group, females with litters only, same animals as used for clinical pathology examination)
Lymph nodes (mesenteric and axillary lymph nodes) (5 animals per sex per group, females with litters only, same animals as used for clinical pathology examination)
Ovaries (all animals per group)
Oviducts (all animals per group)
Peyer’s patches (5 animals per sex per group, females with litters only, same animals as used for clinical pathology examination)
Prostate (all animals per group)
Rectum (5 animals per sex per group, females with litters only, same animals as used for clinical pathology examination)
Sciatic nerve (5 animals per sex per group, females with litters only, same animals as used for clinical pathology examination)
Seminal vesicles (all animals per group)
Spinal cord (cervical, thoracic and lumbar cords) (5 animals per sex per group, females with litters only, same animals as used for clinical pathology examination)
Spleen (5 animals per sex per group, females with litters only, same animals as used for clinical pathology examination)
Stomach (forestomach and glandular stomach) (5 animals per sex per group, females with litters only, same animals as used for clinical pathology examination)
Testes (all animals per group)
Thymus (5 animals per sex per group, females with litters only, same animals as used for clinical pathology examination)
Thyroid glands (5 animals per sex per group, females with litters only, same animals as used for clinical pathology examination)
Trachea (5 animals per sex per group, females with litters only, same animals as used for clinical pathology examination)
Urinary bladder (5 animals per sex per group, females with litters only, same animals as used for clinical pathology examination)
Uterus (all animals per group)
Vagina (all animals per group)

Special attention was given on stages of spermatogenesis in the male gonads.
Female animal 137 that died unscheduled was processed histotechnically and assessed like planned.
A correlation between gross lesions and histopathological findings was attempted.

Postmortem examinations (offspring):

Pup necropsy observations
All pups with scheduled sacrifice on PND 4 were sacrificed under isoflurane anesthesia with CO2. All pups were examined externally and eviscerated; their organs were assessed macroscopically.
All stillborn pups and all pups that died before PND 4 were examined externally, eviscerated and their organs were assessed macroscopically.
All pups without notable findings or abnormalities were discarded after their macroscopic evaluation. Animals with notable findings or abnormalities were evaluated on a case-by-case basis, depending on the type of finding.

Statistics:

Detailed statistical analyses were conducted

Reproductive indices:

For the males, mating and fertility indices were calculated. For the females, mating, fertility and gestation indices were calculated. The live birth index was calculated for F1 litters and the postimplantation loss (in %) was calculated.

Offspring viability indices:

The viability index and the sex ratio were calculated

Results and discussion

Results: P0 (first parental generation)

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
There were no substance-related mortalities in any of the male and female parental animals in any of the groups.
On premating day 12, one high dose F0 female (No. 137 - 1000 mg/kg body weight/day) was found dead after a gavage error.
With the exception of salivation after treatment, no clinical signs or changes of general behavior, which may be attributed to the test substance, were detected in any male or female F0 generation parental animals during the whole study including gestation and lactation periods.
Several male and female animals of dose group 3 (1000 mg/kg bw/d) showed salivation after treatment. This transient salivation for a few minutes immediately after each treatment was likely to be induced by the unpleasant taste of the test substance or by local irritation of the upper digestive tract. It is not considered to be a sign of systemic toxicity.
One sperm positive high-dose female (1000 mg/kg bw/d - No. 136), one sperm positive lowdose female (100 mg/kg bw/d - No. 118) and one sperm negative low-dose female (No. 116) did not deliver F1 pups.
One high-dose female (No. 135) showed complete litter loss (all pups stillborn or found dead on PND 0)
Male and female animals of all dose groups (1000, 300 and 100 mg/kg bw/d) did not show any abnormalities during detailed clinical observations.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Mean body weights and mean body weight change of the male and female F0 generation parental animals in all test substance-treated groups (test groups 1 - 3) were comparable to the concurrent control group during the entire study period.
Food consumption of the male and female F0 generation parental animals in all test substance-treated groups (test groups 1 - 3; 100, 300 and 1000 mg/kg bw/d) was comparable to the concurrent control group during the entire study period.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
Male reproduction data
For all F0 parental males (except male No. 16), which were placed with females to generate F1 pups, copulation was confirmed. Thus, the male mating index was 100% in all groups (except test group 1 – 90%) including the controls.
Fertility was proven for most of the F0 parental males within the scheduled mating interval for F1 litter.
One high-dose male (1000 mg/kg bw/d - No. 36) and two low-dose males (100 mg/kg bw/d - No. 16 and 18) did not generate F1 pups.
Thus, the male fertility index ranged between 80% and 100% without showing any relation to dosing. This reflects the normal range of biological variation inherent in the strain of rats used for this study.
The apparently infertile male rats of test groups 3 (No. 36) and 1 (No. 18) did not show relevant gross lesions. The male No. 16 of test group 1 had epididymides moderately and testes severely reduced in size.

Female reproduction and delivery data
The female mating index calculated after the mating period for F1 litter was 100% in all test groups except test group 1 (90%).
The mean duration until sperm was detected (GD 0) varied between 2.8 and 3.0 days without any relation to dosing.
All sperm positive rats delivered pups or had implants in utero with the following exception:
- High-dose female No. 136 (mated with male No. 36) did not become pregnant.
- Low-dose female No. 116 (mated with male No. 16) did not become pregnant.
- Low-dose female No. 118 (mated with male No. 18) did not become pregnant.
The fertility index varied between 88.9 % in test groups 3 and 1 and 100% in test group 2 and in control. These values reflect the normal range of biological variation inherent in the strain of rats used for this study.
The non-pregnant female of the low dose No. 118 had a severe dilatation of vagina with a suppurative content. The non-pregnant female of the high-dose female No. 136 did not have any relevant gross lesions.
The mean duration of gestation was similar in all test groups (i.e. between 21.9 and 22.4 days).
The gestation index was 100% in control and all dose groups.
Implantation was not affected by the treatment since the mean number of implantation sites was comparable between all test substance-treated groups and the controls, taking normal biological variation into account (12.9 / 12.9 / 13.1 and 11.8 implants/dam in test groups 0-3 (0, 100, 300 and 1000 mg/kg body weight/day)). There were no statistically significant differences in post-implantation loss between the groups (5.6% / 11.1% / 2.0% / 6.3%), and the mean number of F1 pups delivered per dam remained unaffected (12.1 / 11.6 / 12.8 and 10.9 pups/dam at 0, 100, 300 and 1000 mg/kg bw/d).
The rate of liveborn pups was also not affected by the test substance, as indicated by live birth indices of 100% (control), 98.9 (test group 1), 98.4 (test group 2) and 88.5% (test group 3). The number of litters with stillborn pups was comparable between control and all test
groups.
Thus, 3-Methyl-1-vinyl-1 H-imidazolium methyl sulfate did not adversely affect reproduction and delivery of the F0 generation parental females.

ORGAN WEIGHTS (PARENTAL ANIMALS)
Absolute weights
When compared to the control group 0 (set to 100%), the mean absolute liver weight was significantly increased in male animals of the high-dose group (111 %). All other mean absolute weight parameters in males and all weight parameters in females did not show significant differences when compared to the control group 0.

When compared to the control group 0 (set to 100%), the mean relative liver weights were significantly increased in male animals of the high-dose group (112 %).
All other mean relative weight parameters did not show significant differences when compared to the control group 0.
The increase in absolute and relative liver weights in test group 3 (1000 mg/kg bw/day) in male animals was considered to be treatment - related but not adverse due to lack of histopathological correlate.

GROSS PATHOLOGY (PARENTAL ANIMALS)
Female animal 137 that died showed a ruptured esophagus.
All other findings occurred individually. They were considered to be incidental or spontaneous in origin and without any relation to treatment.
Fertility:
Two mating pairs of test group 1 ([100 mg/kg bw/day] Nos. 16/116, 18/118) and two pairs of test group 3 ([1000 mg/kg bw/day] 36/136, 37/137) were recorded as no offspring/ not pregnant. Male animal 16 showed bilateral reduced size of testis and epididymis, female animal 118 showed dilation of the vagina, and female animal 137 died of ruptured esophagus before mating. The mating pair 36/136 did not show relevant gross lesions.

HISTOPATHOLOGY (PARENTAL ANIMALS)
Animal 137 showed rupture of the esophagus confirming the macroscopic diagnosis.
All other findings occurred either individually or were biologically equally distributed over control and treatment groups. They were considered to be incidental or spontaneous in origin and without any relation to treatment.
Fertility
Two mating pairs of test group 1 ([100 mg/kg bw/day] Nos. 16/116, 18/118) and two pairs of test group 3 ([1000 mg/kg bw/day] 36/136, 37/137) were recorded as no offspring/not pregnant. Male animal 16 showed bilateral tubular degeneration of the testes and immature ducts in the epididymides correlating to the macroscopically observed reduced size of testes and epididymides, explaining the absence of offspring in pair 16/116. Female animal 118 showed hydrovagina with persistent septum correlating to the macroscopically noted dilation of the vagina, explaining the absence of offspring in pair 18/118. Animal 137 showed rupture of the esophagus confirming the macroscopic diagnosis and died before mating. Pair 36/136
did not show relevant histological lesions.
These findings were not considered to be treatment - related and spontaneous in origin.

Effect levels (P0)

Dose descriptor:

NOAEL

Remarks:

parental, reproductive performance, fertility and development

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects

Results: F1 generation

Details on results (F1)

LITTER DATA
Pup number and status at delivery
The mean number of delivered F1 pups per dam and the rates of liveborn and stillborn F1 pups were evenly distributed about the groups. The respective values reflect the normal range of biological variation inherent in the strain used in this study. The number of stillborn pups in the high dose group was relatively high but not significantly different in comparison to control. Furthermore, all stillborn pups were found in the litter of one dam. Therefore, this finding was considered as spontaneous in nature and not treatment related.
Pup viability/mortality
The viability index indicating pup mortality during lactation (PND 0 - 4) varied between 86.4% (test group 3), 100% (test group 2 and 1) and 99.2% (control) without showing any association to the treatment.
Mortality data are based on stillborn pups, dead pups, pups sacrificed moribund and cannibalized pups.
Sex ratio
The sex distribution and sex ratios of live F1 pups on the day of birth and PND 4 did not show substantial differences between the control and the test substance-treated groups; slight differences were regarded to be spontaneous in nature

CLINICAL SIGNS (OFFSPRING)
There were no test substance-related adverse clinical signs observed in any of the F1 generation pups of the different test groups.

BODY WEIGHT (OFFSPRING)
No test compound-related influence on F1 pup body weights and pup body weight change were noted in all dose groups.
Two male runts were seen in test group 3 (1000 mg/kg bw/d). This incidence was considered as spontaneous in nature and not treatment related.

GROSS PATHOLOGY (OFFSPRING)
A few pups showed spontaneous findings at gross necropsy, such as post mortem autolysis, situs inversus, reddish discolored testis, hydroureter and hydronephrosis. These findings occurred without any relation to dosing and/or can be found in the historical control data at comparable or even higher incidences. Thus, all these findings were not considered to be associated to the test substance.

Effect levels (F1)

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

>= 1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

In an OECD 422 study, the test compound 3-Methyl-1-vinyl-1 H-imidazolium methyl sulfate was administered daily by gavage to groups of 10 male and 10 female Wistar rats to screen for potential repeated dose, reproductive and developmental toxicity. The animals were dosed throughout the study. For females this included two weeks prior to mating, the variable time of conception, the duration of pregnancy and at least four days after delivery. Males were dosed for a minimum of four weeks. Thereby, both sexes were exposed up to and including the day before scheduled kill with 100, 300, and 1000 mg/kg bw/d. Analyses confirmed the overall accuracy of the prepared concentrations and demonstrated the stability of the test substance in drinking water over a period of 7 days at room temperature. In the clinical examinations of the parental animals F0 no toxicologically-relevant adverse differences were caused by 3-Methyl-1-vinyl-1 H-imidazolium methyl sulfate up to the limit dose of 1000 mg/kg bw/d. In the continuative investigations including the detailed clinical observation (DCO), the functional observational battery (FOB), and measurement of motor activity (MA) no significant differences to control were observed at any dose level. No treatment related findings were observed during mating, gestation, delivery and lactation. Concerning clinical pathology including the analyses of red and white blood cells, coagulations parameters, enzymes, substrates, electrolytes, and minerals no treatmentrelated, adverse effects were observed up to limit dose (1000 mg/kg bw/d). Regarding pathology, the liver of male animals of test group 3 (1000 mg/kg bw/day) showed an increase in absolute (+11%) and relative (+12%) weights which was regarded to be adaptive and non- adverse in the absence of histological findings. All other pathological findings recorded were considered to be incidental in nature and not related to treatment. The test substance led to no treatment-related changes in the genital organs of males (testes and epididymides) and females (ovaries) in the histotechnical assessment.