Niobium pentachloride

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

Study period:

2015-06-22 to 2016-02-09

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study according to OECD 422.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2016

Report date:

2016

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 (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Niobium pentachloride

EC Number:

233-059-8

EC Name:

Niobium pentachloride

Cas Number:

10026-12-7

Molecular formula:

Cl5Nb

IUPAC Name:

Niobium(V) chloride

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

- Name of test material (as cited in study report): Niobium pentachloride
- Physical state: solid at room temperature
- Colour: yellow
- Analytical purity: 99.9%
- Lot/batch No.: 146149
- Expiration date of the lot/batch: 2016-05-14
- Stability in water at room temperature: hydrolysis
- Storage condition of test material: at < -5 °C, protected from light and humidity
- Other: Due to its physical properties (fast hydrolysis and pH-shift) it was not possible to use the test item as delivered in a repeated dose toxicity study. In consultation with the sponsor it was decided that the test item was further processed at BSL by hydrolysis and neutralisation in order to prepare a formulation that was feasible for oral dose administration (for detailed information please see chapter "details on oral exposure").

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, 97633 Sulzfeld, Germany
- Age at start of the treatment period: males/females: 10-11 weeks
- Weight at study initiation: males: 246-290 g, females: 172-205 g
- Fasting period before study: no data
- Housing: in groups of two animals/sex/cage in IVC cages (type III H, polysulphone cages). During mating period males and females were housed together 1:1. After the confirmation of mating, females were kept individually during gestation/lactation period
- Diet (e.g. ad libitum): Altromin 1324 , ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 55 +/- 10
- Air changes (per hr): 10
- 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 item formulation (high dose) was prepared by slowly suspending the respective test item in Aqua ad iniectabilia/10M NaOH (approx. 4:1) for hydrolysis. The neutralising agent was used to adjust the pH-value to approximately 8. Both vehicle and neutralising agent were added to give the appropriate final concentration of the test item. The preparation procedure was performed on a magnetic stirrer while cooling on ice water.
Subsequent dose levels were achieved by further diluting the prepared test item formulation with the respective volume of vehicle.
The test item formulations were prepared at least once every ten days. Prepared formulations were stored at room temperature and protected from light.

PREPARATION OF THE SHAM CONTROL FORMULATION:
The sham control formulation was prepared by adding NaCl to Aqua ad iniectabilia, which based on a theoretically calculated amount of NaCl that may be assumed to be formed at higher dose groups (BSL study 145145 and 145146) during the dose formulation preparation. The calculation of NaCl in the high dose was made only once before the treatment initiation and the same calculated quantity of NaCl was used in every new batch of sham control formulation.

VEHICLE
- Vehicle used: Aqua ad iniectabilia
- Amount of vehicle (if gavage): 7 mL/kg bw
- Lot/batch no. (if required): 405559 and 405701

CHARACTERISATION of the NEUTRALISING AGENT
The pH-value of the test item was adjusted by sodium hydroxide solution (NaOH). The specifications provided by the supplier are listed as follows:
- Name: sodium hydroxide solution
- Concentration: 10M in H2O
- Batch No: 4F017374 and 0000557447

SHAM CONTROL FORMULATION:
- Name: NaCl
- Batch: 15A120009

Details on mating procedure:

- M/F ratio per cage: 1:1
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged (how): females were kept individually during gestation/lactation period and males were returned to its original cage.
- Any other deviations from standard protocol: no

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Samples for the nominal concentration verification were taken in study week 1 (first week of pre-mating period), 3 (first week of mating) and in the last week of the study (gestation/lactation) from all groups (15 samples). However, the sham control samples were not analyzed for concentration of test item as it was not considered necessary.
Samples for homogeneity analysis were taken from the top, middle and bottom of the high dose and the low dose formulation in study week 1 (first week of pre-mating period) and 5 (gestation) (12 samples).
Samples for stability analysis were taken before the start of the study, 0 hours after the preparation and another sample 10 days after the preparation (at room temperature), from high and low dose formulations (4 samples).
DOSE FORMULATION ANALYSIS
The recoveries of analytical samples collected from LD, MD and HD groups at various intervals for the concentration verification, homogeneity and stability analysis were within the acceptance criteria (70% to 110%) except for homogeneity and concentration verification samples of LD group on week 1 (sample code 5a, 6a, 7a and 18a). The recoveries of these samples were below the acceptance criteria. As there were no adverse toxicity observed in the study, the NOAEL considered at 1000 mg/ kg body weight and the recoveries of nominal concentration of HD group during the study being within acceptance criteira i.e all HD group individual values ranging from 79% to 102%, the lower recoveries in the LD group was not considered to impact the validity of the study.

Duration of treatment / exposure:

The animals were treated with the test item formulation, vehicle or sham control formulation on 7 days per week for a period of 54 days, i.e. during 14 days of pre-mating and maximum 14 days of mating in both males and females, during the gestation period and up to post-natal day 3 in females. Males were dosed after the mating period until the minimum total dosing period of 28 days was completed.

Frequency of treatment:

once daily, 7 days a week

Details on study schedule:

not relevant

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 100, 300 and 1000 mg/kg bw/day
Basis:
nominal in water

No. of animals per sex per dose:

10 (6 per sex for sthe sham control)

Control animals:

yes, concurrent vehicle

yes, sham-exposed

Details on study design:

- Dose selection rationale: based on the results of a previous dose range finding study
- Rationale for animal assignment: random

Positive control:

not necessary

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: General clinical observations were made once a day, preferably at the same time each day. The health condition of the animals was recorded. Twice daily all animals were observed for morbidity and mortality except on weekends and public holidays when observations were made once daily.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once before the first exposure, and once a week thereafter, detailed clinical observations were made in all animals (except animal no. 36 of MD group, which was inadvertently missed) outside the home cage in a standard arena. Clinical observations included spontaneous activity, lethargy, recumbent position, convulsions, tremors, apnoea, asphyxia, vocalisation, diarrhoea, changes in the skin and fur, eyes and mucous membranes (salivation, discharge), piloerection and pupil size. Changes in gait, posture, response to handling as well as the presence of clonic or tonic movements, stereotypes, difficult or prolonged parturition or bizarre behaviour were recorded.

BODY WEIGHT: Yes
- Time schedule for examinations: The animals were weighed once before the assignment to the experimental groups, on the first day of administration and weekly thereafter as well as at the end of the study. During pregnancy, females were weighed on gestation days (GD) 0, 7, 14 and 20 and within 24 hours of parturition (day 0 post-partum) as well as day 4 post-partum along with pups.

FOOD CONSUMPTION: Yes
Food consumption was measured on the corresponding days of the body weight measurements after the beginning of the dose administration. Food consumption was not measured during the mating period in males and females and the post-mating period in males.

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: Yes, see chapter (neuro)behavioural examination.

HAEMATOLOGY: Yes
Haematological parameters from 5 randomly selected males and females (only lactating females were evaluated) from each group were examined at the end of the treatment as part of the sacrifice of the animals. In case of sham control animals haematology was measured on all males and lactating females. Blood from the abdominal aorta of the animals was collected in EDTA-coated tubes. Parameters checked in table 1 were examined.

CLINICAL CHEMISTRY: Yes
Parameters of clinical biochemistry from 5 randomly selected males and females (only lactating females were evaluated) from each group were examined at the end of the treatment priot to or as part of the sacrifice of the animals. In case of sham control animals clinical biochemistry was measured on all males and lactating females. Blood from the abdominal aorta of the animals was collected in serum separator tubes. Parameters checked in table 3 were examined.

URINALYSIS: Yes
A urinalysis was performed with samples collected from 5 randomly selected males and females (only lactating females were evaluated) from each group as part of the sacrifice of the animals. Additionally, urine colour/ appearance were recorded. In case of sham control animals urinalysis was made on all males and lactating females. Parameters checked in table 4 were examined.

(NEURO)BEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: in the week before the first treatment and during the last week of the treatment in 5 randomly selected males and during the lactation period in 5 randomly selected females (only lactating females were evaluated)
- Battery of functions tested: Sensory reactivity to different modalities, grip strength and motor activity assessments and other behavioural observations as well as rearing supported and not supported, urination, defecation, startle/ auditory response, equilibrium reflex, positional passivity, visual placing, fore and hind limb grip strength, tail pinch response, toe pinch reflex, extensor thrust/limb tone, hind limb reflex, righting reflex on the ground, air righting reflex, pupil response, body temperature and ophthalmoscopy (anterior chamber of the eye and fundus of eye).

OTHER:
BLOOD COAGULATION:
Coagulation parameters from 5 randomly selected males and females (only lactating females were evaluated) from each group were examined at the end of the treatment prior or as part of the sacrifice of the animals. In case of sham control animals blood coagulation was measured on all males and lactating females. Blood from the abdominal aorta of the animals was collected in citrate tubes. Parameters checked in table 2 were examined.

Oestrous cyclicity (parental animals):

If the vaginal smear of a particular female was not found to be sperm-positive, the actual stage of the estrus cycle on that day was documented.

Sperm parameters (parental animals):

Parameters examined male parental generation: testis weight, epididymis weight, for the testes, a detailed qualitative examination was made; taking into account the tubular stages of the spermatogenic cycle at evaluation of additional hematoxylin-PAS (Periodic Acid Schiff) stained slides

Litter observations:

LITTER OBSERVATIONS:
Each litter was examined as soon as possible after delivery of the dam to establish the number and sex of pups, stillbirths, live births, runts and the presence of gross abnormalities.
Live pups were counted and sexed and litters weighed within 24 hours of parturition (day 0 post-partum) and on day 4 post-partum. Live pups were identified by tattoo marked on the paws. In addition to the observations of the parent animals, any abnormal behaviour of the offspring was recorded.

Postmortem examinations (parental animals):

GROSS PATHOLOGY: Yes
All male animals were sacrificed after the completion of the mating period (total dosing period: 28 days) on study day 29, while female animals were sacrificed on the respective post-natal day 4. The surviving pups were sacrificed by decapitation on PND 4. Dead pups and pups sacrificed on day 4 post-partum were carefully examined externally for gross abnormalities. Four females (no. 55 of control, no. 133, 136 of MD and no. 151 of HD group) were sacrificed on study day 26 from the day of sperm-positive vaginal smear or from the last day of the mating period due to non-delivery.
All animals were subjected to a detailed gross necropsy which includes careful examination of the external surface of the body, all orifices and the cranial, thoracic and abdominal cavities and their contents. Special attention was paid to the organs of the reproductive system. The ovaries, uterus with cervix, vagina, testes, epididymides, accessory sex organs (prostate, seminal vesicles with coagulating glands as a whole). The number of implantation sites and corpora lutea was recorded for each parental female at necropsy. The number of corpora lutea and implantation sites was also recorded for one female sacrificed on day 26 post-coitum due to non-delivery.

ORGAN WEIGHTS: Yes
The wet weight of the organs (table 5) of 5 sacrificed adult males and 5 females (only lactating females were evaluated) randomly selected from each group was recorded as soon as possible. Paired organs were weighed together. In case of sham control animals the wet weight of the organs of all males and lactating females were recorded. In addition reproductive organs of all animals were weighed and preserved.

HISTOPATHOLOGY: Yes
A full histopathology was carried out on the preserved organs and tissues according to Table 6 of 5 randomly selected male and female animals (only lactating females were evaluated) of the control and high dose groups which were sacrificed at the end of the treatment period.
Because of possible treatment-related changes noted in the high dose group, stomach from animals of the low- and mid-dose groups (groups 3 and 4, respectively) pre-selected for the examination of full list organs/tissues, as well as stomach from all sham control animals was examined.

Postmortem examinations (offspring):

SACRIFICE
-The F1 offspring was sacrificed at 4 days of age.

Statistics:

A statistical assessment of the results of the body weight, food consumption, parameters of haematology, blood coagulation and clinical biochemistry and absolute and relative organ weights were performed for each gender by comparing values of dosed with control animals of the main groups using a one-way ANOVA and a post-hoc Dunnett Test and additionally Tukey test for absolute liver weight of females as the Dunnett test indicated statistical significance for SC and MD groups compared to control. These statistics were performed with GraphPad Prism V.6.01 software (p<0.05 was considered as statistically significant).

Reproductive indices:

Copulation, fertility, delivery and viability

Offspring viability indices:

Viability index

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Description (incidence and severity):

see below

Body weight and weight changes:

no effects observed

Description (incidence and severity):

see below

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

see below

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

see below

Other effects:

not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

no effects observed

Description (incidence and severity):

see below

Reproductive performance:

no effects observed

Description (incidence and severity):

see below

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
No mortality occurred in the control, sham control or any of the dose groups during the treatment period of this study except one female of HD group was found dead on PND 0. Histopathologically, the cause of death was revealed an accidental influx of the dosing solution into the respiratory tract, and it was not test item-related effect.
Slight to severe salivation was noted in few males and females of the HD group and one female of the SC group on single occasion of treatment. Furthermore, moving the bedding was observed transiently in all males and all females of the HD and the SC group and in three male of the MD group. The clinical signs salivation and moving the bedding were observed immediately after the dose administration and therefore were considered to be a sign of discomfort due to a local reaction to the test item rather than a systemic adverse effect and has no toxicological relevance.
Isolated incidence of abnormal breathing irrespective of the dose group on single occasion of treatment were considered to be incidental.
Partial regurgitation of formulation was noted in isolated males and/or females of the dose groups and/or control groups. This clinical sign was transient in appearance and showed up irrespective of the groups. Therefore, it was considered to be incidental.
None of the females showed signs of abortion or premature delivery.
During the weekly detailed clinical observation, no relevant differences between the groups were found.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
In both males and females, there was no test item treatment related effect on body weight in the dose groups during the study period. There were no statistically significant differences between the dose groups, sham control group and the control group.
In correlation to the body weight and body weight change, the food consumption in both males and females tended to increase with the progress of the study in the control, the SC, the LD, the MD and the HD group. No test item related or statistically significant effect on food consumption was observed in males and females during the whole study period.

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
By the detailed testicular examination, it was judged that there were no treatment-related effects on the testicular histomorphology including spermatogenesis as well.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
There were no test item related effects on the reproductive indices (copulation, fertility, delivery and viability indices) in the dose groups when compared to the control group. However, a slightly reduced fertility index (number of females pregnant / No. of females copulated X 100) of 80 and 90 % in the MD and HD group compared to 100 % in all other groups. In the absence of dose response dependency, the finding was not considered to be of toxicological relevance. The viability index was marginally lower in the HD group (98.21%) as compared to the control group (100%). This was due to missing (probably cannibalized) one single pup (no. 4) of female no. 145. As this finding was limited to a single pup it was considered as incidental.

PRECOITAL INTERVAL AND DURATION OF GESTATION
There were no effects on the duration of precoital interval and the duration of gestation in the dose groups and sham control group, when compared to the control group.

PRE-AND POST-NATAL DATA
There were no test item treatment related effects on the number of corpora lutea, number of implantation sites, number of live pups (PND 0 and PND 4) and percentage of pre-and post-implantation loss in the dose groups and sham control group, when compared to the control group.

ORGAN WEIGHTS (PARENTAL ANIMALS)
In males, there were no statistically significant differences in the absolute and relative organ weights of the dose groups and sham control group except statistically significantly higher relative kidney weights in the HD group when compared to the corresponding control group. However, there was a moderately lower absolute and relative mean weight of thyroid/parathyroid glands in the male HD group (lower by approx. 28% vs controls). As no macroscopic and microscopic findings were associated with the thyroid/parathyroid glands, the findings were considered to have no toxicological relevance.
There was also a higher absolute and relative weight of pituitary gland (higher by approx.51% vs controls) noted in the male HD group without achieving statistical significance when compared to the control group. In the absence of a dose response relationship and an absence of macroscopic and microscopic findings, this was not considered to have toxicological relevance.
In females, there was a statistically significantly higher absolute liver weight in the sham control (higher by 15% vs control) and non significantly higher absolute weights in treatment groups compared to the control group animals. In the absence of a dose response relationship and an absence of macroscopic and microscopic findings, this was not considered to have toxicological relevance.
There was also a marginally higher absolute and relative pituitary weight in the HD group (higher by up to 15% vs control) and a moderately higher absolute and relative spleen weight in all treatment groups (higher by up to 22 % vs control). In the absence of statistical significance and absence of macroscopic and microscopic findings, these changes were not considered to be of toxicological relevance.

GROSS PATHOLOGY (PARENTAL ANIMALS)
Few specific macroscopic changes were recorded for the male and female animals, which based on microscopic examination, and were not considered to be of test item treatment relevance.
The macroscopic changes observed were dilated ureter (male no. 12 of SC), spotted red thymus (male no. 13 of SC), yellow spots on right side of epididymides (male no. 102 of LD group), and dilated renal pelvis of kidney (female no. 62 of SC). Other findings observed were liver grown in to diaphragm (female no.137 of MD and 144 of HD), fluid distention in uterus and cyst at right ovary (female no.151 of HD), discoloured red stomach, gased intestine and blood filled lung (female no. 152 of HD). These changes were within the range of normal background alterations which may be recorded in animals of this strain and age.

HISTOPATHOLOGY (PARENTAL ANIMALS)
Under the conditions of this study, histomorphologic changes, which were considered to be associated with properties of the dose formulation, were observed in the stomach of Groups 2, 3, 4, and 5 (Sham control, Low-dose, Medium-dose, and High-dose, respectively). They consisted of mucous neck cell hypertrophy with/without increased submucosal inflammatory cell infiltrate in the glandular stomach. Mucous neck cell hypertrophy/proliferation was considered to be an adaptive response to protect the mucosa, and there was no specific direction in incidence and severity between groups under the condition of this study. Increased inflammatory cell infiltrate recorded in some animals is also a response to irritation to gastric glandular mucosa.
Multifocal mucosal surface necrosis with hemorrhage was observed in the glandular stomach of 2 males of the high-dose group (1000 mg/kg bw/day), and minimal increase in incidence and severity of submucosal inflammatory cell infiltrate in the glandular stomach were recorded in males of the medium-dose (300 mg/kg bw/day) and the high-dose group. Although actual intra-gastric state after dosing (e.g., actual pH value of gastric juice, gastric potential difference, retention time of contents) was unknown, the intra-gastric environment might become more irritative status than that in other groups, when the higher-dose(s) of the test item were administered per os with the condition of this formation.
The above-mentioned changes appeared more prominently in males compared with females. It is thought that female gastric mucosa during pregnancy/lactation has high tolerance to irritative alteration of intra-gastric environment after dosing compared to that of males, and this was considered to be the reason that there were differences in incidence and severity between males and females of the medium- and high-dose groups.
In any event, it was considered that histologic findings recorded in the stomach were changes due to local irritation associated with properties of dose formation, and were not caused by systemic toxicological effects of the test item. The test item produced no histomorphologic evidence of toxicological properties in the male and female reproductive organs including testes, epididymides, prostate glands, coagulating glands, seminal vesicles, ovaries, uterus with cervix and vagina. Furthermore, by the detailed testicular examination, it was judged that there were no treatment-related effects on the testicular histomorphology including spermatogenesis as well.
The remainder of findings recorded was within the range of normal background lesions which may be recorded in animals of this strain and age, or was incidental lesions that were not related to treatment with the test item.

OTHER FINDINGS (PARENTAL ANIMALS):

Haematology and Coagulation:
In males and females, no test item treatment related effects were observed for haematological parameters. However, there was a statistically significantly increase of large unstained cells (LUC) in male sham control group compared to control animals. By considering that no statistically significant changes in LUC of dose groups compared to control animals and also that no dose response relationship were observed, no effect in LUC was considered. All mean and most of the individual values were within the historical control data range. There was also higher LUC in male and female MD and HD group, but in the absence of statistical significance, the finding was not considered to be adverse.
Blood coagulation was not affected in males and females due to test item treatment.

Clinical Chemistry:
There were no test item treatment related effects on clinical biochemistry parameters. All parameters were within the historical control data range.

Urinalysis:
The urinalysis performed in male and female animals revealed no test item treatment related effect.

(Neuro)Behaviour:
No relevant effects were observed in any of the parameters of the functional observation battery before and at the end of the treatment period. There were no biologically relevant differences in body temperature between the groups except slight but statistically significantly lower body temperature that was observed in HD group before initiation of the treatment. As this effect was observed before treatment, it has no toxicological relevance.

Effect levels (P0)

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 were observed

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings:

no effects observed

Details on results (F1)

LITTER DATA:
There were no test item treatment related effects on litter data including total number of pups born, number of live pups, still births and runts on PND 0 as well as number of male pups, number of female pups and sex ratio on PND 0 and PND 4. There were no statistically significant changes noted for these litter data.

LITTER WEIGHT DATA
There were no effects on pup mean weight, total litter weight, male and female litter weight on PND 0 and PND 4. There was no statistically significant change in dose groups compared to corresponding controls.

PUP SURVIVAL DATA
There were no effects on the survival of the pups from PND 1 through PND 4 in the dose groups and sham control group, when compared to the control group.
A marginally higher mean mortality of pups between PND 1 and PND 4 was observed in the HD group (1.79%) compared to the control group (0.00%). This outcome did not achieve statistical significance and was attributed to missing one single pup of one single dam (pup no. 4 of dam no. 145) on PND 1. Thus, it was considered as incidental and not related to the treatment with the test item.

PUP EXTERNAL FINDINGS
No test item related gross external abnormalities of toxicological relevance were observed in the pups of any of the groups.

REPRODUCTIVE INDICES
There were no test item related effects on the reproductive indices (copulation, fertility, delivery and viability indices) in the dose groups when compared to the control group. However, a slightly reduced fertility index (number of females pregnant / No. of females copulated X 100) of 80 and 90 % in the MD and HD group compared to 100 % in all other groups. In the absence of dose response dependency, the finding was not considered to be of toxicological relevance. The viability index was marginally lower in the HD group (98.21%) as compared to the control group (100%). This was due to missing (probably cannibalized) one single pup (no. 4) of female no. 145. As this finding was limited to a single pup it was considered as incidental.

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No abnormalities at any dose level

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test no adverse effects were found after oral administration of niobium pentachloride in male and female Wistar rats and in the male and female pups. Based on the results, the NOAEL is considered to be 1000 mg/kg bw/day.

Executive summary:

In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422) niobium pentachloride (99.9% purity) was administered orally to 10 male and female Wistar rats/dose in water by gavage at dose levels of 0, 100, 300, or 1000 mg/kg bw/day. The animals were treated with the test item formulation on 7 days per week for a period of 54 days, i.e. during 14 days of pre-mating and maximum 14 days of mating in both males and females, during the gestation period and up to post-natal day 3 in females. Males were dosed after the mating period until the minimum total dosing period of 28 days was completed. Litter was not exposed. There were no treatment-related effects found regarding to mortality, clinical signs, functional observations, food consumption, histopathology, body weights, organ weights, haematology, clinical chemistry, urinalysis, reproduction, breeding data and pup development up to 1000 mg/kg bw/day. Based on the results, the NOAEL for maternal and reproductive/developmental toxicity is considered to be 1000 mg/kg bw/day.

This study is acceptable and satisfies the guideline requirement for a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422) in rat.