Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

NOAEL for reproductive toxicity = 1000 mg/kg bw (OECD421 study; 2012). Furthermore, no adverse findings in reproductive organs in both RDT studies (OECD407 study, 1999; OECD408 study, 2019).

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
December 2011 - October 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes (incl. certificate)
Remarks:
BASF SE, Experimental Toxicology end Ecology, 67056 Ludwigshafen, Germany
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Germany
- Age at study initiation: (P) 11-13 wks
- Weight at study initiation: (P) Males: 293-321 g; Females: 201-226 g
- Housing: individually in Makrolon type M III cages; exceptions: male and female partners were housed together during overnight matings, pregnant animals and their litters were housed together until PND 4
- Diet (ad libitum): groudn Kliba maintenance diet mouse/rat "GLP meal, Provimi Klibi SA, Kaiseraugust, CH
- Water (ad libitum): in water bottles
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 / 12
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
- The test substance was weighed in a graduated measuring flask depending on the dose group, topped up with highly deionized water and intensely mixed by shaking until completely dissolved.
- Volume administered each day: 10 ml/kg bw
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: overnight (about 04:00 p.m. until 07:00 - 09:00 a.m.)
- Proof of pregnancy: [sperm in vaginal smear] referred to as GD0 = day 0 of pregnancy
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
once during the study period
Duration of treatment / exposure:
- females: 14 days before mating, during pregnancy, until PND4
- males: 28 days
Frequency of treatment:
once daily
Remarks:
Doses / Concentrations:
0, 40, 200, 1000 mg/kg bw/d
Basis:
nominal in water
No. of animals per sex per dose:
10 per sex and group
Control animals:
yes, concurrent vehicle
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes, at least daily

DETAILED CLINICAL OBSERVATIONS: Yes / No / No data

BODY WEIGHT: Yes, weekly

FOOD CONSUMPTION: Yes, weekly, but not determined during mating period of F0 animals

WATER CONSUMPTION: No
Oestrous cyclicity (parental animals):
-
Sperm parameters (parental animals):
-
Litter observations:
PARAMETERS EXAMINED in F1 offspring: number and sex of pups, stillbirths, live births, postnatal mortality up to PND4, clinical observation, presence of gross anomalies, weight gain PND1-4

GROSS EXAMINATION OF DEAD PUPS:
[yes, for external and internal abnormalities]
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals [the next day after 28 days of exposure]
- Maternal animals: All surviving animals [at PND4]

GROSS NECROPSY
- Gross necropsy, special attention was given to the reproductive organs

HISTOPATHOLOGY / ORGAN WEIGHTS
- Weights in all animals: anesthetized animals, epididymes, testes
- Fixation in 4% formaldehyde or in modified Davidson´s solution: all gross lesions, cervix, coagulating gland, epididymes, ovaries, oviducts, prostate gland, seminal vesicles, testes, vagina, uterus
- Histopathology: Testes, epididymes, ovaries of control and high dose group
Postmortem examinations (offspring):
SACRIFICE: on PND4
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:
GROSS NECROPSY: external examination and eviceration, macroscopic assessment of organs
Animals with notable findings or abnormalities were evaluated on a case-by-case basis, depending on the type of finding.
Statistics:
DUNNETT-test, FISHER´s EXACT test, WILCOXON-test, KRUSKAL-WALLIS test
Reproductive indices:
- Male mating index (%), male fertility index
- Female mating index (%), female fertility index (%), gestation index (%), live birth index (%), postimplantation loss (%)


Females: determination of the number of implantations and calculation of the postimplantation loss
Offspring viability indices:
- Viability index (%), sex ratio
There were no test substance-related adverse findings in any of the groups.

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
One male animal (#32) of the high-dose group was found dead in study week 3 without any abnormal clinical or pathological findings. Therefore, this was considered to be incidential and not treatment-related.
Some animals of the high-dose group showed transient salivation, perstisting only for some minutes after daily dosing.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Body weight of the high-dose males (up to -6% during study week 1 and 2) and food consumption of the high-dose males and females (-21% or -19% during study week 1) were statistically significantly reduced. Later on, both parameters were comparable to the control.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
- Male/female mating index = 100% (control, low-, mid-, high-dose). One low- and one mid-dose female (#117, 121) were not detected as being sperm positive. However, both had pups, giving evidence for successful copulation.
- Male/female fertility index = 100 % (control), 90% (low-, mid-dose), 80 % (high-dose). This is in the normal range of biological variation, inherent in the used rat strain. The infertile males (#17, 25, 34, 37) showed no relevant gross lesions. Minimal changes in testicles and epididymes were observed in male #34, but not severe enough to explain infertility. The non-pregnant femalse (#115, 125, 134, 137) had no relevant gross lesions.
- Mean duration of gestation: similar in all groups (22.0 - 22.5 d)
- Gestation index = 100 % in all groups
- Mean numer of implantation sites: comparable between control, low-, mid-, high-dose groups (13.5, 12.4, 13.0, 12.1)
- Post-implantation loss: comparable between control, low-, mid-, high-dose groups (10.7%, 7.7%, 6.7%, 7.4%)
- Mean number of F1 pups, delivered per dam: comparable between control, low-, mid-, high-dose groups (12.0, 11.4, 12.0, 11.3)
- Live birth index: 100% (control, low-dose), 99% (mid-dose), 94%* (p<= 0.05, high-dose); mainly caused by dam #138 with 4/10 stillborn pups.
- Number of stillborn pups: statistically increased in high-dose group (0, 0, 1, 5*); mainly caused by dam #138 with 4/10 stillborn pups. However, all respective values were in the historical control range and thus relect the normal range of biological variation inherent in the used rat strain.

ORGAN WEIGHTS (PARENTAL ANIMALS)
All mean absolute and relative weight parameters did not show significant differences compared to the control.

GROSS PATHOLOGY (PARENTAL ANIMALS)
All findings occured either indivdually or were biologically equally distributed over all groups and were not considered treatment-related.

HISTOPATHOLOGY (PARENTAL ANIMALS)
No findings were observed in the high-dose group, that could explain the lack of offspring in males (#34, 37) or lack of pregnancy in females (#134, 137). Minimal changes observed in the testicles (multifocal tubular degeneration) and epididymes (cell debris) of male #34 frequently occur as background lesions in male rats without impairing fertility. These changes were not considered treatment-related. All other findings occured either indivdually or were biologically equally distributed over all groups and were not considered treatment-related.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no test substance-related adverse findings at any dose
Critical effects observed:
no
There were no test substance-related adverse findings in any of the groups.

VIABILITY (OFFSPRING)
- Mean number of F1 pups, delivered per dam: comparable between control, low-, mid-, high-dose groups (12.0, 11.4, 12.0, 11.3)
- Live birth index: 100% (control, low-dose), 99% (mid-dose), 94%* (p<= 0.05, high-dose); mainly caused by dam #138 with 4/10 stillborn pups.
- Number of stillborn pups: statistically increased in high-dose group (0, 0, 1, 5*); mainly caused by dam #138 with 4/10 stillborn pups. However, all respective values were in the historical control range and thus relect the normal range of biological variation inherent in the used rat strain.
- Viablilty index during lactation (PND0-4): no test substance related changes between control, low-, mid-, high-dose (99, 93%*, 99, 96%). The slightly reduced index in the low-dose group resulted of the accidental death of 6 pups, which were placed with the wrong dam after weighing and immediatly killed).
- Sex distribution and ratios did not show substational differences between the groups.

CLINICAL SIGNS (OFFSPRING)
No test substance-related adverse were observed.

BODY WEIGHT (OFFSPRING)
Mean pup bw and pup bw change of all groups were statistically comparable.
One female runt each was seen in the control and the high-dose group, one male runt in the mid-dose group.

GROSS PATHOLOGY (OFFSPRING)
- One F1 pup showed a spontaneous finding (dilated renal pelvis). There were no further findings.
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 test substance-related findings at any dose
Critical effects observed:
no
Reproductive effects observed:
no

In conclusion, under the conditions of this study the NOAEL for general systemix toxicity, reproductive toxicity performance and fertility is 1000 mg/kg bw/d for the F0 parental rats. Furthermore, the NOAEL for developmental toxicity was also 1000 mg/kg bw/d.

Conclusions:
In conclusion, under the conditions of this OECD421 study the NOAEL for general systemix toxicity, reproductive toxicity performance and fertility is 1000 mg/kg bw/d for the F0 parental rats. Furthermore, the NOAEL for developmental toxicity was also 1000 mg/kg bw/d. Therefore, Aminopropyl-imidazol is considered to be non-toxic to reproduction (neither fertility, nor developmental toxicity) in this study.
Executive summary:

In a GLP compliant OECD421 study, N-(3-Aminopropyl)-imidazole was given daily to 10 Wistar rats per sex and group per gavage at doses of 0, 40, 200 and 1000 mg/kg bw/d (BASF SE, 2012) to screen fo potential reproductive and developmental toxicity. The exposure lasted for at least 28 days in males and for at least 38 days in females (2 weeks prior to mating, during the mating period of max. 2 weeks, about 1 week post-mating for males and for the entire gestation period up to PND 4 in females). The examination of clinical signs and mortality, of food consumption, body weight and organ weights, the gross pathology, histopathology and the reproductive performance relvealed no toxicologically relevant adveres effects in parental animals up to 1000 mg/kg bw/d. Furthermore, no toxicologically relevant developmental differences in the F1 pups were detected during this study considering viability, clincial signs, body weight and gross pathology of the F1 pups. Therefore, under the conditions of this study, the NOAEL for reproductive toxicity as well as for developmental toxicity in the F1 offspring is 1000 mg/kg bw/d.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

In a GLP compliant OECD421 study, N-(3-Aminopropyl)-imidazol was given daily to 10 Wistar rats per sex and group per gavage at doses of 0, 40, 200 and 1000 mg/kg bw/d (2012; RL1) to screen for potential reproductive and developmental toxicity. The exposure lasted for at least 28 days in males and for at least 38 days in females (2 weeks prior to mating, during the mating period of max. 2 weeks, about 1 week post-mating for males and for the entire gestation period up to PND 4 in females). The examination of clinical signs and mortality, of food consumption, body weight and organ weights, the gross pathology, histopathology and the reproductive performance revealed no toxicologically relevant adverse effects in parental animals up to 1000 mg/kg bw/d. Furthermore, no toxicologically relevant developmental differences in the F1 pups were detected during this study considering viability, clincial signs, body weight and gross pathology of the F1 pups. Therefore, under the conditions of this study, the NOAEL for reproductive toxicity as well as for developmental toxicity in the F1 offspring is 1000 mg/kg bw/d.

Furthermore, no adverse findings in reproductive organs were detected in both RDT studies (OECD407 study, 1999, RL1; OECD408 study, 2019, RL1).

Effects on developmental toxicity

Description of key information

The maternal NOAEL is 300 mg/kg bw/d based on several animals with ulceration(s) in stomach treated with 1000 mg/kg bw/d N-(3-Aminopropyl)imidazole. The (NOAEL for prenatal developmental toxicity is the highest tested dose of 1000 mg/kg bw/d.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
May 2018 - November 2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes (incl. certificate)
Remarks:
BASF SE, Experimental Toxicology and Ecology, 67056 Ludwigshafen, Germany
Limit test:
no
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL:
Batch identification: C520/090/2017/F3
- Purity: 100.0 area-% (GC, DB-1), 99.9 area-% (GC, DB-1701)
- Content: 99.3 g/100 g (Final Report. 17L00242)
Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
- Age at study initiation: 10-12 weeks
- Weight at study initiation: 138.7 – 186.7 g.
- Fasting period before study: No
- Housing: The rats were housed individually in Polycarbonate cages.Individual housing is preferred over group housing as the close individual monitoring of food and water consumption as well as of clinical signs of toxicity in pregnant animals is crucial during this period of increased sensitivity.
- Diet (e.g. ad libitum): Ground Kliba maintenance diet mouse/rat “GLP”, meal, supplied by Provimi Kliba SA (new name Granovit AG), Kaiseraugst, Switzerland ground Kliba maintenance diet mouse/rat “GLP”, meal, supplied by Provimi Kliba SA (new name Granovit AG), Kaiseraugst, Switzerland
- Water (e.g. ad libitum):Drinking water ad libitum.
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 45-65%
- Air changes (per hr): 15 times per hour
- Photoperiod (hrs dark / hrs light):12 hours

Route of administration:
oral: gavage
Vehicle:
other: ultrapure water
Details on exposure:
The test substance preparations were prepared at the beginning of the administration period and thereafter at intervals, which took into account the period of established stability. The preparations were kept at room temperature. For the test substance preparations, the specific amount of test substance was weighed, topped up with ultrapure water in a graduated flask and intensely mixed with a magnetic stirrer until it was completely dissolved.Before and during administration, the preparations were kept homogeneous with a magneticstirrer. The test substance was administered as an aqueous preparation to groups of 25 time-mated female Wistar rats by gavage at doses of 100, 300 and 1000 mg/kg body weight/day (mg/kg bw/d) on gestation days (GD) 6 through 19. The control group, consisting of 25 females, was dosed with the vehicle (ultrapure water) in parallel. A standard dose volume of 10 mL/kg body weight was used for each test group.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The analytical investigations of the test substance preparations (concentration control) were carried out as a separate study at the external test facility Institut Kuhlmann GmbH, Germany under the responsibility of the study director of this test facility (02Y0387/98X013); Institut Kuhlmann ID: GLP-008/18). The study was carried out in compliance with the Principles of Good Laboratory Practice: The analyses of the test-substance preparations were carried out at the Analytical Chemistry Laboratory. The study was carried out in compliance with the Principles of Good Laboratory Practice.The stability of the test substance in ultrapure water at room temperature for a period of 7 days demonstrated. Analytical verifications of the stability of the test substance in ultrapure water over a period of 7 days at room temperature had been verified prior to the start of the study in a similar batch. Samples of the test substance preparations were sent once (at the beginning of administration) to the analytical laboratory for verification of the concentrations. Given that the test substance was completely miscible with ultrapure water, solutions were considered to be homogenous without further analysis.
Duration of treatment / exposure:
GD 6-19
Frequency of treatment:
once dailly
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: A cage-side examination was conducted at least once daily before and after treatment period.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: During treatment period (GD 6-19) all rats were checked daily for any signs of morbidity, pertinent behavioral changes and/or signs of overt toxicity before administration as well as within 2 hours and within 5 hours after administration.

BODY WEIGHT: Yes
- Time schedule for examinations:GD 0, 1, 3, 6, 8, 10, 13, 15, 17, 19 and 20

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day: GD 20
- Organs examined: The uteri and the ovaries were removed and the following data were recorded: Weight of the unopened uterus, Number of corpora lutea, Number and distribution of implantation sites classified as: Live fetuses
Dead implantations:a) Early resorptions (only decidual or placental tissues visible or according to SALEWSKI from uteri from apparently non-pregnant animals and the empty uterus horn in the case of single horn pregnancy), b) Late resorptions (embryonic or fetal tissue in addition to placental tissue visible), c) Dead fetuses (hypoxemic fetuses which did not breathe spontaneously after the uterus had been opened). After the weight of the uterus had been determined, all subsequent evaluations of the dams and the gestational parameters (except of gross pathology including organ weights) were conducted by technicians unaware of treatment group in order to minimize bias. For this purpose animal numbers were encoded.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
Statistics:
DUNNETT-test (two-sided), FISHER'S EXACT test (one-sided), WILCOXONtest (one-sided)
Indices:
The conception rate (in %) was calculated according to the following formula:
(number of pregnant animals/number of fertilized animals) x100
The preimplantation loss (in %) for each individual pregnant animal which underwent scheduled sacrifice was calculated according to the following formula:
((number of corpora lutea – number of implantations)/number of corpora lutea) x100
The postimplantation loss (in %) for each individual pregnant animal which underwent scheduled sacrifice was calculated according to the following formula:
((number of implantations – number of live fetuses)/number of implantations) x100
Historical control data:
Historical contraol data were available
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Some (12 out of 25) females of the high-dose group (1000 mg/kg bw/d) showed occasional salivation during the treatment period. Salivation occurred in the respective animals only shortly, i.e. within 0-2h, after treatment and was observed during GD 15-19. No clinical signs or changes of general behavior were detected in any female of all test groups beyond 2 hours after treatment. The temporary salivation around the daily treatment was most probably caused by the local irritating effect of the test substance and was assessed as treatment related.
Mortality:
no mortality observed
Description (incidence):
There were no test substance-related or spontaneous mortalities in any females of all test groups (0, 100, 300 or 1000 mg/kg bw/d).
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Mean body weight change of the high-dose dams (1000 mg/kg bw/d) was statistically significantly reduced during GD 8-10 (36% below control) but recovered afterwards. The high-dose values even exceeded the control value during GD 10-13 (attaining statistical significance) and were comparable again for the rest of the study period. However, the mean body weights of these females were comparable to the concurrent control group throughout the entire study period. Therefore, it was assessed as incidental and toxicologically not relevant. The mean body weights and the average body weight gain of the low- and mid-dose dams (100 and 300 mg/kg bw/d) were generally comparable to the concurrent control group throughout the entire study period. The statistically significantly increased body weight gain value in test group 3 during GD 3-6 (pretreatment period) was assessed as incidental. The corrected body weight gain of test groups 1, 2 and 3 (100, 300 and 1000 mg/kg bw/d) revealed no difference of any biological relevance to the corresponding control group.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
The mean food consumption of the high-dose dams (1000 mg/kg bw/d) was statistically significantly reduced during GD 6-8 (17% below control) but recovered afterwards and was comparable to the control values again throughout the remaining study period (GD 7-20). If calculated for the entire treatment period (GD 6-19), the mean food consumption of the high-dose dams was comparable to the concurrent control group. Therefore, it was assessed as incidental and toxicologically not relevant. The mean food consumption of the mid- and low-dose dams (300 and 100 mg/kg bw/d) was generally comparable to the concurrent control group throughout the entire study period.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
The mean gravid uterus weights of the animals of test groups 1-3 (100, 300 and 1000 mg/kg bw/d) were not influenced by the test substance. The differences between these groups and the control group revealed no dose-dependency and were assessed to be without biological relevance.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
In test group 3 during necropsy in the stomach ulceration(s) (single) in 6/25 dams (Nos. 81, 82, 87, 89, 93, 94) were noted. This was assessed as a treatment related and adverse finding. One finding in test group 3 (dilated renal pelvis (right) in dam No. 92) was assessed as incidental and not treatment-related. There is no evidence for any association of these scattered finding with the treatment. For one finding in test group 2 (stomach: erosion(s) in dam No. 71) a relation to treatment cannot be excluded. Due to the single occurrence it was not assessed as an adverse effect of treatment in this dose group. No further necropsy findings which could be attributed to the test substance were seen in any dam.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
A vaginal hemorrhage occurred on GD 14. On cesarean section, for this female 10 early resorptions were recorded after staining (i.e. pregnant by stain).. Hence, the postimplantation loss of this dam was 100% whereas for the other test group 3 dams, the mean postimplantation loss and the number of early resorptions were comparable to the control. The effects occurred in single animals are assessed as incidental findings and not related to treatment.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
see "Description for pre- and post-implantation loss"
Early or late resorptions:
no effects observed
Description (incidence and severity):
see "Description for pre- and post-implantation loss"
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
Only pregnant dams were used for the calculations of mean maternal food consumption, body weight and body weight change. Only pregnant dams with scheduled sacrifice (GD 20) were used for the calculation of mean gravid uterine weights, corrected (net) body weight gain and summary of reproduction data. The following females were excluded from the above-mentioned calculations:
Test group 1 (100 mg/kg bw/d): Female No. 41 – not pregnant
Test group 3 (1000 mg/kg bw/d): Female No. 91 – not pregnant
Other effects:
no effects observed
Description (incidence and severity):
The mean placental weights of test groups 1-3 were comparable to the concurrent control group.
Key result
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
gross pathology
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
not examined
Reduction in number of live offspring:
not examined
Changes in sex ratio:
no effects observed
Description (incidence and severity):
The sex distribution of the fetuses in test groups 1-3 (100, 300 and 1000 mg/kg bw/d) was comparable to the control fetuses
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
The mean fetal weights of test groups 1, 2 and 3 were not influenced by the test substance and did not show any biologically relevant differences in comparison to the control group.
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
External malformations did not occur in any of the fetuses in this study. There were noted soft tissue and skeletal) malformations in test groups 0, 2 and 3 (0, 300 and 1000 mg/kg bw/d).Two fetuses of the control group carried more than one malformation, i.e. male fetus No. 14- 05 (additional vertebral arch and corresponding rib, branched rib) and male fetus No. 23-09 (shortened scapula, bent rib). Further malformations, such as abnormal lung lobation, misshapenbasisphenoid and cleft sternum were observed in individual fetuses, unrelated to the dose and all of them can be found in the historical control data. All these findings were single cases, no ontogenetic pattern is recognizable for all these individual malformations nor was there any cluster of any of these individual malformations seen in the other offspring of these test groups. They also do neither form a pattern or syndrome with other minor anomalies which may raise toxicological concern nor do they influence the overall rate of malformations in this study. There is no evidence for any association of these scattered findings with the treatment.
Skeletal malformations:
no effects observed
Description (incidence and severity):
Skeletal malformations were recorded for four control, one mid- and one high-dose fetuses. The mean values of total incidences of skeletal malformations did not differ significantly and were within the historical control data. The finding ‘misshapen basisphenoid’ in the fetuses of test groups 2 and 3 were single events in individual fetuses and the mean values were within the historical control data (affected fetuses per litter, mean: 0.1%, range: 0.0 - 1.0%). Therefore, the observed malformation in substance-treated fetuses was not assessed as treatment-related and adverse. For all test groups, skeletal variations of different bone structures were observed, with or without effects on corresponding cartilages. The observed skeletal variations were related to several parts of fetal skeletons and appeared without a relation to dose. The overall incidences of skeletal variations were comparable to the historical control data.
Visceral malformations:
no effects observed
Other effects:
no effects observed
Details on embryotoxic / teratogenic effects:
No differences of toxicological relevance between the control and the treated groups (100, 300 or 1000 mg/kg bw/d) were determined for any reproductive parameters, such as conception rate, mean number of corpora lutea, mean number of implantations, as well as pre- and postimplantation loss. Similarly, no influence of the test substance on fetal weight and sex distribution of the fetuses was noted at any dose.
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects up to the highest dose
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Conclusions:
Under the conditions of this prenatal developmental toxicity study, the oral administration of N-(3-Aminopropyl)imidazole to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19), the no observed adverse effect level (NOAEL) for maternal toxicity is 300 mg/kgbody weight/day based on several animals with ulceration(s) in stomach treated with 1000 mg/kg body weight/day N-(3-Aminopropyl)imidazole. The no observed adverse effect level (NOAEL) for prenatal developmental toxicity is the highest tested dose of 1000 mg/kg bw/d.
Executive summary:

In a prenatal developmental toxicity study, the test substance N-(3-Aminopropyl)imidazole was administered to pregnant Wistar rats daily by gavage from implantation to one day prior to the expected day of parturition (GD 6-19) to evaluate its potential maternal and prenatal developmental toxicity. Analyses confirmed the correctness of the prepared concentrations and the stability of the test substance in the vehicle. Generally, clinical observations including food consumption and body weight gain revealed no toxicologically relevant difference between the animals receiving 100, 300 or 1000 mg/kg bw/d N-(3-Aminopropyl)imidazole and controls. Some (12 out of 25) females of the high-dose group (1000 mg/kg bw/d) showed transient salivation during the treatment period. Salivation persisted in the respective animals only for some time after daily gavage dosing (maximum up to 2 hours) and was initially observed on GD 15. The temporary salivation around the daily treatment was not assessed as a sign of systemic toxicity. It was most probably caused by the local irritating effect of the test substance and in conjunction with the observed ulceration(s) in the stomach (6/25 animals) during necropsy in this dose group assessed as treatment related adverse effect. No differences of toxicological relevance between the control and the treated groups (100, 300 or 1000 mg/kg bw/d) were determined for any reproductive parameters, such as conception rate, mean number of corpora lutea, mean number of implantations, as well as pre- and postimplantation loss. Similarly, no influence of the test substance on fetal weight and sex distribution of the fetuses was noted at any dose. Overall, there was no evidence for toxicologically relevant adverse effects of the test substance on fetal morphology at any dose.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

In a prenatal developmental toxicity study, the test substance N-(3-Aminopropyl)imidazole was administered to pregnant Wistar rats daily by gavage from implantation to one day prior to the expected day of parturition (GD 6-19) to evaluate its potential maternal and prenatal developmental toxicity (OECD414, 2019; RL1). Analyses confirmed the correctness of the prepared concentrations and the stability of the test substance in the vehicle. Generally, clinical observations including food consumption and body weight gain revealed no toxicologically relevant difference between the animals receiving 100, 300 or 1000 mg/kg bw/d N-(3-Aminopropyl)imidazole and controls. Some (12 out of 25) females of the high-dose group (1000 mg/kg bw/d) showed transient salivation during the treatment period. Salivation persisted in the respective animals only for some time after daily gavage dosing (maximum up to 2 hours) and was initially observed on GD 15. The temporary salivation around the daily treatment was not assessed as a sign of systemic toxicity. It was most probably caused by the local irritating effect of the test substance and in conjunction with the observed ulceration(s) in the stomach (6/25 animals) during necropsy in this dose group assessed as treatment related adverse effect. No differences of toxicological relevance between the control and the treated groups (100, 300 or 1000 mg/kg bw/d) were determined for any reproductive parameters, such as conception rate, mean number of corpora lutea, mean number of implantations, as well as pre- and postimplantation loss. Similarly, no influence of the test substance on fetal weight and sex distribution of the fetuses was noted at any dose. Overall, there was no evidence for toxicologically relevant adverse effects of the test substance on fetal morphology at any dose.

Under the conditions of this prenatal developmental toxicity study, the oral administration of N-(3-Aminopropyl)imidazole to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19), the no observed adverse effect level (NOAEL) for maternal toxicity is 300 mg/kg bw/d based on several animals with ulceration(s) in stomach treated with 1000 mg/kg bw/d N-(3-Aminopropyl)imidazole. The NOAEL for prenatal developmental toxicity is the highest tested dose of 1000 mg/kg bw/d.

Mode of Action Analysis / Human Relevance Framework

not specified

Justification for classification or non-classification

Classification of 1H-imidazole-1 -propylamine pure:

GHS classification according to Annex I of the Regulation EC/1272/2008: no classification required

Classification of 1H-imidazole-1 -propylamine crude:

GHS classification according to Annex I of the Regulation EC/1272/2008: Category 1B, H360

The classification of the crude specification is based on the presence of imidazole (< 1%).