Niobium dioxide

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422) the read across partner 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. No treatment-related effects were observed. Thus, the NOAEL for maternal and reproductive/developmental toxicity is considered to be 1000 mg/kg bw/day

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

Combined with repeated dose study

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

For justification of read-across please refer to the read-across report attached to IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Clinical signs:

no effects observed

Description (incidence and severity):

see below

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

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

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Description (incidence and severity):

see below

Haematological findings:

no effects observed

Description (incidence and severity):

see below

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

see below

Urinalysis findings:

no effects observed

Description (incidence and severity):

see below

Behaviour (functional findings):

no effects observed

Description (incidence and severity):

see below

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

see below

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Reproductive function: oestrous cycle:

no effects observed

Description (incidence and severity):

see below

Reproductive function: sperm measures:

no effects observed

Description (incidence and severity):

see below

Reproductive performance:

no effects observed

Description (incidence and severity):

see below

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 significant higher absolute liver weight in the sham control (higher by 15% vs control) and non significant 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.

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 were observed

Critical effects observed:

no

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

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

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Description (incidence and severity):

see below

Histopathological findings:

no effects observed

Description (incidence and severity):

see below

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.

Key result

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

Critical effects observed:

no

Reproductive effects observed:

not specified

Conclusions:

In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test no adverse effects were found after oral administration of hydrolysed and neutralysed 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 after hydrolysis and neutralisation 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.

This information is used in a read-across approach in the assessment of the target substance.

For justification of read-across please refer to the attached read-across report (see IUCLID section 13).

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

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

No data is available for Niobium dioxide (target substance). Thus, data from Niobium pentachloride (source substance) was used in a read-across approach. Details on the read-across rational are provided in section 13.

In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422) Niobium pentachloride 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, histopathology, organ weights, 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.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the result of a GLP study according to OECD 422 conducted with the source substance niobium pentachloride, the target substance niobium dioxide does not warrant classification for reproductive toxicity.