Chrome antimony titanium buff rutile

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

In the combined repeated dose and reproductive/ developmental toxicity screening test according to OECD guideline 422 with the read across substance Pigment Yellow 53, no reproductive toxicity was observed and a NOAEL >= 1000 mg/kg bw/d was determined.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

HYPOTHESIS FOR THE ANALOGUE APPROACH
The substance belongs to the group of inorganic pigments with a rutile lattice in which titanium ions are partially replaced by other metal ions (antimony, nickel, chrome). The solubility of the target and source substance in water is very low. Bioavailability is regarded as negligible for both, target and source substance.
For further information, please refer to the Read across justification attached in IUCLID section 13.2.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No reproductive toxicity was observed.

Key result

Critical effects observed:

no

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

>= 1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No fetal toxicity was observed.

Key result

Critical effects observed:

no

Key result

Reproductive effects observed:

no

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Guideline compliant study report

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 combined repeated dose and reproductive/ developmental toxicity screening test according to OECD guideline 422 (MHLW, 2002), the structural analogue C.I. Pigment Yellow 53 was administered to groups of Sprague Dawley rats (12/sex) at concentrations of 0 (vehicle), 250, 500, 1000 mg/kg bw/d. Males were treated for 46 days and females from 14 days before mating to day 4 of lactation.

No changes were found in female estrous cycle, male and female copulation index, conception index, delivery index, gestation length, and nursing index on day 4 of lactation, and no changes were observed in the weight of the genital organs (testis, epididymis and ovary) and endocrine organ (adrenal glands) as well as in the necropsy thereof, in each dosing group. In addition, abnormalities were not observed in the histopathological examination of the genital organs in the 1000 mg/kg group.

From the above, no effects of test substance administration on the male and female reproduction were observed in any of the dosing groups. Therefore, the no-observed-adverse-effect level (NOAEL) of test substance administration with repeated dose under this test conditions for the reproduction of parent animals was considered to be 1000 mg/kg/day or more.

Effects on developmental toxicity

Description of key information

The test compound was tested for its prenatal developmental toxicity in Wistar rats (OECD 414, GLP) at concentrations of 100, 300 and 1000 mg/kg bw administered by gavage. No test substance-related adverse effects on dams, gestational parameters or fetuses were seen at any dose level. The no observed adverse effect level (NOAEL) for maternal and prenatal developmental toxicology is 1000 mg/kg bw/d.

 

In addition, a dose range finding (DRF) study was performed for a pre-natal developmental toxicity study in the second species (equivalent or similar to OECD 414 (2018, non-GLP). Groups of female New Zealand White rabbits received the test compound daily via gavage at dose levels of 100, 300 and 1000 mg/kg bw/day. Based on this DRF study, it was concluded that up to the highest dose level of 1000 mg/kg bw/day, no test item-related effects were observed in maternal animals. Also, reproductive data from dams were not affected by treatment with the test item. There was no embryo-toxicity observed and foetal development was not affected by test compound treatment. No malformation or variations were observed in foetuses on macroscopic inspection at necropsy (external examinations only). Based on the results, the dose levels for a prenatal developmental toxicity study with the test compound were selected to be 100, 300 and 1000 mg/kg bw/day.

However, an analogue read-across to the substance antimony nickel titanium rutile has been proposed and therefore no full PNDT study in rabbit will be conducted with the test compound. The PNDT study in rabbit with the analogue substance antimony nickel titanium rutile is ongoing and upon availiability of the final report of the study this endpoint will be updated.  For further information on the read-across concept, please refer to the Read across justification attached in IUCLID section 13.2.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2017

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
- Age at study initiation: About 11-13 weeks
- Fasting period before study: no
- Housing: single
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: From GD 0 (day of supply) to the beginning of administration (GD 6), the animals will be accustomed to the environmental
conditions and to the diet.

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:

CMC (carboxymethyl cellulose)

Details on exposure:

Route of administration: Orally by gavage
Reason for the selection of the route of administration: The oral administration of a test substance has been proven useful worldwide in numerous studies for discovering a potential toxicological profile.
Frequency of administration/number of administrations: Once daily (GD 6-19)/14
Volume to be administered: 10 ml/kg body weight; the body weight determined most recently will be used to calculate the administration volume.
Preparation: For the test substance preparations, the specific amount of test substance will be weighed, topped up with 0.5% Carboxymethylcellulose suspension in drinking water in a calibrated beaker and intensely mixed with a homogenizer. Before and during administration, the preparations will be kept homogeneous with a magnetic stirrer.
Preparation frequency: daily
Storage conditions of the preparations: RT

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The analytical investigations of the test substance preparations will be carried out as a
separate study at the test facility Competence Center Analytics of BASF SE, 67056
Ludwigshafen, Germany, under the responsibility of the study director of this test facility.
The study will be carried out in compliance with the Principles of Good Laboratory
Practice.

Details on mating procedure:

The animals are paired by the breeder and will be supplied at noon on the day of evidence of mating; this day is referred to as GD O and the following day as GD 1.

Duration of treatment / exposure:

The day of evidence of mating is referred to as GD O and the following day as GD 1.
The test substance will be administered to the animals orally by gavage from GD 6 through GD 19

Frequency of treatment:

daily

Dose / conc.:

100 mg/kg bw/day (actual dose received)

Dose / conc.:

300 mg/kg bw/day (actual dose received)

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

25

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: based on information of the combined reprotox / repeated dose study and the 90d study, 100, 300 and 1000 mg/kg bw were chose.

The random distribution of the animals to the individual groups will be carried out on the day of supply (= GD 0) by randomly removing the animals from the transport boxes.

On GD 20, all surviving dams will be sacrificed and examined. All evaluations except for the gross-pathological evaluation and the determination of the uterus weights will be carried out by technicians unaware of the treatment groups using coded animal numbers. The fetuses will be removed from the uterus, which has been opened before and examined.

Maternal examinations:

Mortality
A check for moribund and dead animals will be made twice daily from Mondays to Fridays and once daily on Saturdays, Sundays and public holidays (GD 0 to 20).

Clinical signs
A cageside examination will be conducted at least once daily for any signs of morbidity, pertinent behavioral changes and/or signs of overt toxicity.
During the administration period (GD 6 - 19) all animals will be checked daily for any abnormal clinically signs before the administration as well as within 2 hours and within 5 hours after the administration. Abnormalities and changes will be documented for each animal.

Food consumption
Food consumption will be recorded for GD 0-1, 1-3, 3-6, 6-8, 8-10, 10-13, 13-15, 15-17, 17-19 and 19-20.

Body weight
Body weights will be recorded on GD 0, 1, 3, 6, 8, 10, 13, 15, 17, 19 and 20.

POST-MORTEM EXAMINATIONS
On GD 20, the surviving dams will be anesthetized with isoflurane, sacrificed by cervical dislocation in a randomized sequence and examined. The fetuses will be removed from the uterus, which has been opened before and examined.
Moribund animals and animals that die intercurrently will be examined if possible (with the exception of the uterus weight).

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes / No / No data
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
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter

Statistics:

Means and standard deviations will be calculated. In addition, the following statistical analyses will be carried out:

Food consumption, body weight, body weight change, corrected body weight gain, carcass weight, weight of the unopened uterus, weight of the placentas and
fetuses, corpora lutea, implantations, pre- and postimplantation losses, resorptions and live fetuses --> DUNNETT's test

Number of pregnant animals at the end of the study, mortality rate (of the dams) and number of litters with fetal findings --> FISHER's exact test

Proportion of fetuses with findings per litter --> WILCOXON test

Indices:

conception rate (in %) = (number of pregnant animals / number of fertilized animals) x 100
preimplantation loss (in %) for each individual pregnant animal which underwent scheduled sacrifice = ((number of corpora lutea – number of implantations)/number of corpora lutea) x 100
The postimplantation loss (in %) for each individual pregnant animal which underwent scheduled sacrifice = ((number of implantations – number of live fetuses) / number of implantations) x 100

Historical control data:

OECD 414 studies in wistar rats between 2012 - 2016 (n=34)

Clinical signs:

no effects observed

Description (incidence and severity):

Yellowish discolored feces were recorded for all females of the high-dose group (1000 mg/kg bw/d) from GD 14 onwards until terminal sacrifice (GD 20). This feces discoloration mirrors the presence of the test substance (or its metabolites) in the gastrointestinal tract. It is not considered as an adverse toxic effect.
No further clinical signs or changes of general behavior, which may be attributed to the test substance, were detected in any female at dose levels of 100, 300 or 1000 mg/kg bw/d during the entire study period.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

The mean body weights and average body weight gain of the low-, mid- and high-dose dams (100, 300 or 1000 mg/kg bw/d) were in general comparable to the concurrent control group throughout the entire study period. This includes the slightly higher weight gain of the mid-dose dams on GD 19-20.

Food consumption and compound intake (if feeding study):

no effects observed

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:

no effects observed

Description (incidence and severity):

A yellow discolored content of the stomach was recorded in 9 out of 25 mid-dose females (36%) and in 14 high-dose females (56%), while a yellow discolored content of the small intestine was seen in 2 mid-dose (8%) and 5 high-dose females (20%). These yellow discolorations mirror presence of the test substance (or its metabolites) in the gastrointestinal tract. They are not considered as adverse, toxic effects by themselves.
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

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

no effects observed

Early or late resorptions:

effects observed, non-treatment-related

Description (incidence and severity):

There were lower numbers of (early) resorptions than control in all treatment groups, producing higher live litter sizes in return. However, all observed differences are considered to reflect the normal range of fluctuations for animals of this strain and age. Hence, they are considered to be sporadical findings, neither related to treatment nor adverse.

Dead fetuses:

no effects observed

Changes in pregnancy duration:

no effects observed

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed

Changes in number of pregnant:

no effects observed

Other effects:

no effects observed

Details on maternal toxic effects:

The conception rate reached 88% in the control and the mid-dose groups (0 and 300 mg/kg bw/d) and 100% in the low- and high-dose groups (100 and 1000 mg/kg bw/d). With these rates, a sufficient number of pregnant females were available for the purpose of the study. There were no test substance-related and/or biologically relevant differences between test groups 0-3 in conception rate, in the mean number of corpora lutea and implantation sites or in the values calculated for the pre- and the postimplantation losses, the number of resorptions and viable fetuses.

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: no maternal toxicity at any dose level observed

Key result

Abnormalities:

no effects observed

Fetal body weight changes:

no effects observed

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

no effects observed

Description (incidence and severity):

There were lower numbers of (early) resorptions than control in all treatment groups, producing higher live litter sizes in return. However, all observed differences are considered to reflect the normal range of fluctuations for animals of this strain and age for historical control data. Hence, they are considered to be sporadical findings, neither related to treatment nor adverse.

Changes in postnatal survival:

not specified

External malformations:

effects observed, non-treatment-related

Description (incidence and severity):

External malformations were detected in test groups 1 and 2 (100 and 300 mg/kg bw/d). In each case, these external malformations were associated with either soft tissue or skeletal malformations. None of these malformations are considered to be related to the treatment.
The total incidence of external malformations in treated animals did not differ significantly from the concurrent control group and was covered by the historical control data
No external variations were recorded.
One unclassified external observation, i.e. blood coagulum around placenta, was recorded in two fetuses of the mid-dose group (300 mg/kg bw/d). Since the finding was without statistical significance and not related to dose, it is not considered to be test substance-related.

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

Some skeletal malformations were detected in all test groups including the control (test groups 0-3; 0, 100, 300 and 1000 mg/kg bw/d). Two fetuses had associated external findings. The incidences of these malformations were neither statistically significantly different from control nor dose dependent and therefore not considered biologically relevant.
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 dosing.
The rate of affected fetuses per litter with skeletal variations was statistically significantly higher in the low- and mid-dose groups (100 and 300 mg/kg bw/d, however, the incidences of all test groups were well within the historical control range and the variations neither showed a specific pattern nor a dose-response.
In addition to the findings tabulated above, the litter incidence for ‘misshapen sternebra; unchanged cartilage’ was statistically significantly increased in test group 2 (n=20*, 91%). However, the increase was not dose-related and the value was well within the range of the historical control data (mean 92.2%, range of 62.5 - 100.0%). Therefore, it is not assessed as being treatment-related.
designated as unclassified cartilage observations, occurred in all test groups. The observed unclassified cartilage findings were related to the skull, the ribs and the sternum. The rate of ‘bipartite processus xiphoideus’ was statistically significantly higher in all test substance-treated groups (test groups 1-3: 62.4%*/65.6%*/57.6%*[p<=0.05]). As a consequence of these increases, the incidence of total fetal skeletal unclassified cartilage observations was statistically significantly higher in test groups 1 and 2 (Tab. 4.3.4.3.1.). However, the incidences of all test substance-treated groups were well within the historical control range (mean 72.2% [52.5% - 89.4%]), while the concurrent control incidence was unusually low, below the historical control range (test group 0: 42.0%). Therefore and as there is no dose-response relationship an association to the treatment and a toxicological relevance is not assumed.

Visceral malformations:

no effects observed

Description (incidence and severity):

One fetus of test group 2 (300 mg/kg bw/d) had multiple soft tissue malformations, which were associated with an external malformation.
The total incidence of soft tissue malformations did not differ significantly from the concurrent control group. The findings were covered by the historical control data and, therefore, not assessed as treatment-related.
Three soft tissue variations were detected, i.e. short innominate, dilated renal pelvis and dilated ureter. These variations were neither significantly different from the concurrent control nor dose-dependently altered. Therefore, they were not considered biologically relevant.
No soft tissue unclassified observations were recorded.

Other effects:

no effects observed

Description (incidence and severity):

Weight of the placentae
The mean placental weights of test groups 1-3 were comparable to the concurrent control group.

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects at any dose level

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

Total external malformations

		Test group 0 0 mg/kg bw/d	Test group 1 100 mg/kg bw/d	Test group 2 300 mg/kg bw/d	Test group 3 1000 mg/kg bw/d
LitterFetuses	N N	22 218	25 251	22 237	25 253
Fetal incidence	N (%)	0.0	1 (0.4)	2 (0.8)	0.0
Litter incidence	N (%)	0.0	1 (4.0)	2 (9.1)	0.0
Affectedfetuses/litter	Mean%	0.0	0.5	0.8	0.0

mg/kg bw/d = milligram per kilogram body weight per day; N = number; % = per cent

Total soft tissue malformations

		Test group 0 0 mg/kg bw/d	Test group 1 100 mg/kg bw/d	Test group 2 300 mg/kg bw/d	Test group 3 1000 mg/kg bw/d
LitterFetuses	N N	21 105	25 119	22 114	25 118
Fetal incidence	N (%)	0.0	0.0	1 (0.9)	0.0
Litter incidence	N (%)	0.0	0.0	1 (4.5)	0.0
Affectedfetuses/litter	Mean%	0.0	0.0	0.8	0.0

mg/kg bw/d = milligram per kilogram body weight per day; N = number; % = per cent

Total skeletal malformations

		Test group 0 0 mg/kg bw/d	Test group 1 100 mg/kg bw/d	Test group 2 300 mg/kg bw/d	Test group 3 1000 mg/kg bw/d
LitterFetuses	NN	22 113	25 132	22 123	25 135
Fetal incidence	N (%)	1 (0.9)	1 (0.8)	2 (1.6)	2 (1.5)
Litter incidence	N (%)	1 (4.5)	1 (4.0)	2 (9.1)	2 (8.0)
Affectedfetuses/litter	Mean%	0.9	0.8	1.7	1.4

mg/kg bw/d = milligram per kilogram body weight per day; N = number; % = per cent

Total fetal skeletal variations

		Test group 0 0 mg/kg bw/d	Test group 1 100 mg/kg bw/d	Test group 2 300 mg/kg bw/d	Test group 3 1000 mg/kg bw/d
LitterFetuses	N N	22 113	25 132	22 123	25 135
Fetal incidence	N (%)	110 (97)	132 (100)	123 (100)	129 (96)
Litter incidence	N (%)	22 (100)	25 (100)	22 (100)	25 (100)
Affectedfetuses/litter	Mean%	97.6	100.0*	100.0*	95.7

mg/kg bw/d = milligram per kilogram body weight per day; N = number; % = per cent

* = p<=0.05 (Wilcoxon-test [one-sided])

Occurrence of statistically significantly increased skeletal variations (expressed as mean percentage of affected fetuses/litter)

Finding	Test group 0 0 mg/kg bw/d	Test group 1 100 mg/kg bw/d	Test group 2 300 mg/kg bw/d	Test group 3 1000 mg/kg bw/d	HCD Mean % (range)
Incomplete ossification of basisphenoid	20.3	29.8*	24.6	20.0	17.3 (7.3 - 37.6)
Bipartite ossification of tho- racic centrum; dumbbell- shaped cartilage of cen- trum	0.0	0.0	2.2*	0.0	0.5 (0.0 - 2.4)

mg/kg bw/d = milligram per kilogram body weight per day; HCD = Historical control data; % = per cent

* = p<= 0.05 (Wilcoxon-test [one-sided]) ** = p<=0.01 (Wilcoxon-test [one-sided])

Total unclassified cartilage observations

		Test group 0 0 mg/kg bw/d	Test group 1 100 mg/kg bw/d	Test group 2 300 mg/kg bw/d	Test group 3 1000 mg/kg bw/d
LitterFetuses	N N	22 113	25 132	22 123	25 135
Fetal incidence	N (%)	48 (42)	85 (64)	79 (64)	77 (57)
Litter incidence	N (%)	18 (82)	25 (100)*Fi	22 (100)	23 (92)
Affectedfetuses/litter	Mean%	44.7	64.8*Wi	65.6*Wi	58.1

mg/kg bw/d = milligram per kilogram body weight per day; N = number; % = per cent

* Fi= p ≤ 0.05 (Fisher’s exact test[one-sided])

* Wi= p ≤ 0.05 (Wilcoxon-test[one-sided])

Conclusions:

Under the conditions of this prenatal developmental toxicity study, the oral administration of the test item to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) at a dose of 1000 mg/kg bw/d caused neither evidence of maternal nor developmental toxicity.
In conclusion, the no observed adverse effect level (NOAEL) for maternal and prenatal developmental toxicology is 1000 mg/kg bw/d.

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 Sicotan Yellow K 2011 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 their homogeneous distribution 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 the test item and controls.

Clinical observations, food consumption and body weights/body weight gain (gross and corrected) revealed no toxicologically relevant effects in the animals receiving 100, 300 or 1000 mg/kg bw/d of the test compound. Yellowish discolored feces were recorded for all females of the high-dose group (1000 mg/kg bw/d) from GD 14 onwards until terminal sacrifice (GD 20). This feces discoloration mirrors the presence of the test substance (or its metabolites) in the gastrointestinal tract. It is not considered as an adverse toxic effect.

No differences of toxicological relevance between the control and the treated groups (100, 300 and 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 and live litter size. Similarly, no adverse effect of the test substance on uterine and placental weights as well as fetal weight and sex distribution of the fetuses was noted at any dose. Fetal external, soft tissue and skeletal examinations revealed that there is no effect of the test

substance on the respective morphological structures up to a dose of 1000 mg/kg bw/d.

Under the conditions of this prenatal developmental toxicity study, the oral administration of the test item to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) at a dose of 1000 mg/kg bw/d caused neither evidence of maternal nor developmental toxicity.

In conclusion, the no observed adverse effect level (NOAEL) for maternal and prenatal developmental toxicology is 1000 mg/kg bw/d.

 

In addition, a dose range finding (DRF) study with rabbits was performed for a pre-natal developmental toxicity study (equivalent or similar to OECD 414 (2018, non-GLP). Groups of six mated female New Zealand White rabbits were administered daily the test compound in an aqueous solution of carboxyl methylcellulose (0.5 % w/v) via gavage at dose levels of 100, 300 and 1000 mg/kg bw/day between gestation days 6 and 28. A vehicle control group was run concurrently. The results showed that no mortality was observed in the maternal animals during the study. No test item-related effects were observed in maternal animals for clinical signs, body weight, body weight gain, food consumption, gravid uterus weight and macroscopical examination. Furthermore, no test item-related effect was noted on the reproductive parameters (number of corpora lutea, number of dams pregnant, implantations, pre-implantation loss, post-implantation loss, resorption (early, late and total) and dead foetuses). No abortions occurred during the study. The examinations of the foetuses revealed that no test item-related effects were observed on foetal body weight (male, female and combined sexes), litter weight, number of live foetuses, sex ratio and external examinations. Based on the results, the dose levels for a prenatal developmental toxicity study with the test material were selected to be 100, 300 and 1000 mg/kg bw/day.

However, an analogue read-across to the substance antimony nickel titanium rutile has been proposed. The compound belongs to the group of inorganic pigments with a rutile lattice in which titanium ions are partially replaced by other metal ions (antimony, nickel, chrome). The solubility of the target and source substance in water is very low. Bioavailability is regarded as negligible for both, target and source substance. A PNDT study in rabbit with the analogue substance antimony nickel titanium rutile is ongoing and upon availiability of the final report of the study this endpoint will be updated.  For further information on the read-across concept, please refer to the Read across justification attached in IUCLID section 13.2.

Justification for classification or non-classification

The available studies are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance does not need to be classified and labelled for reproductive or developmental toxicity under Regulation (EC) No 1272/2008, as amended for the ninth time in Regulation EC No 2016/1179.