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Diss Factsheets

Administrative data

Description of key information

A guideline study according to OECD 422 was conducted. No adverse effects were observed after oral administration of the source substance Niobium pentachloride in male and female Wistar rats at the highest tested dose of 1000 mg/kg bw/day. Based on the results, the NOAEL can be considered to be 1000 mg/kg bw/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: oral, other
Remarks:
combined repeated dose and reproduction / developmental screening
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
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 specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
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
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
see below
Gross pathological findings:
no effects observed
Description (incidence and severity):
see below
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
see below
Histopathological findings: neoplastic:
no effects observed
Details on results:
MORTALITY
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.

CLINICAL SIGNS
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 WEIGHT GAIN
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.

FOOD CONSUMPTION
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.

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.

ORGAN WEIGHTS
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
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
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.

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 were no statistically significant change in dose groups compared to corresponding controls.

PRECOITAL INTERVAL AND DURATION OF GESTATION
There were no effects on the duration of pre-coital 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.

REPRODUCTIVE INDICES
There were no test item treatment 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 of female no. 145. As this finding was limited to a single pup it was considered as incidental.

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 the death of one single pup of one single dam on PND 1. Thus, it was considered 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.

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 criteria 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.
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
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. 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.

No adverse effects of Niobium pentachloride after hydrolysis and neutralisation were found up to the dose level of 1000 mg/kg body weight/day.

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 (no. 152) that was found dead on PND 0.

There were no clinical signs of toxicological relevance in the dose groups and sham control group when compared to the control group. However, predominant clinical signs like salivation and/or moving the bedding were observed transiently in all males and females of the HD and/ or SC group. These clinical signs were noted immediately after the dose administration, therefore, were considered to be signs of discomfort caused due to treatment.

During the weekly detailed clinical observation, no relevant differences between the groups were found.

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.

There were no effects of test item treatment on body weight development of both males and females during the treatment period.

There were no adverse effects on food consumption of males and females of dose groups or sham control compared to control animals during the study period.

The NOAEL in this study is considered to be 1000 mg/kg bw/day. This study is classified as acceptable and satisfies the guideline requirement for an oral repeated dose toxicity study 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).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
GLP guideline study

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

No data regarding the oral exposition is available for Niobium dioxide (target substance). Thus, available data from niobium pentachloride (source substance) were 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) the source substance (99.9% purity) was administered orally (after hydrolysis and neutralization) 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. No adverse effects of Niobium pentachloride were found up to the dose level of 1000 mg/kg body weight/day. Thus, the NOAEL in this study is considered to be 1000 mg/kg bw/day.

Justification for classification or non-classification

Based on the available data from the read-across partner Niobium pentachloride, the target substance Niobium dioxide does not warrant classification for specific target organ toxicity in accordance to CLP.