Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No study is available investigating fertility after exposure to 3-hydroxy-2-(3-hydroxy-2-quinolyl)-1H-inden-1-one. No additional screening study for reproductive/developmental toxicity is scientifically justified, since the physic-chemical parameter, the toxicokinetic assumption, and the experimental data including the developmental toxicity study according to OECD TG 414, oral and dermal acute data and oral sub-acute toxicity data indicate that the compound is not significantly absorbed and not toxic. No maternal or fetal toxicity was observed in the developmental toxicity study up to the highest dose tested (limit dose 1000 mg/kg/day). In an acute oral toxicity study no deaths, no clinical signs and no gross pathological findings were reported after dosing of 5 male and 5 female rats with 5000 mg/kg. In an acute dermal study 5 male and 5 female rats received a single dose of 2000 mg/kg of the test item applied semiocclusively for 24 hours. Rats tolerated the dose without toxicologically relevant clinical signs, mortalities, toxicological effects on body weight development and gross pathological findings. Oral administration of 3-hydroxy-2-(3-hydroxy-2-quinolyl)-1H-inden-1-one to Wistar rats at doses of 100, 300 and 1000 mg/kg/day for 28 days resulted in no changes of toxicological relevance. The orange discoloration of the feces noted in all treated groups represents a typical finding in gavage studies with colored substances or dyestuffs. Although the slight increase in the incidence of dark yellow urine implies that a minimal absorption cannot be excluded, no discoloration was noted in any organ and there were no correlating macroscopical or microscopical findings. Based on the results of this study, the no-observed-effect-level (NOEL) and no-observed-adverse-effect-level (NOAEL) were considered to be 1000 mg/kg body weight/day of 3-hydroxy-2-(3-hydroxy-2-quinolyl)-1H-inden-1-one, the highest dose tested.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because a pre-natal developmental toxicity study is available
Reproductive effects observed:
not specified
Effect on fertility: via oral route
Endpoint conclusion:
no study available
Quality of whole database:
No study is available investigating fertility after exposure to 3-hydroxy-2-(3-hydroxy-2-quinolyl)-1H-inden-1-one. No additional screening study for reproductive/developmental toxicity is scientifically justified, since the physic-chemical parameter, the toxicokinetic assumption, and the experimental data including the developmental toxicity study according to OECD TG 414, oral and dermal acute data and oral sub-acute toxicity data indicate that the compound is not significantly absorbed and not toxic. No maternal or fetal toxicity was observed in the developmental toxicity study up to the highest dose tested (limit dose 1000 mg/kg/day). In an acute oral toxicity study no deaths, no clinical signs and no gross pathological findings were reported after dosing of 5 male and 5 female rats with 5000 mg/kg. In an acute dermal study 5 male and 5 female rats received a single dose of 2000 mg/kg of the test item applied semiocclusively for 24 hours. Rats tolerated the dose without toxicologically relevant clinical signs, mortalities, toxicological effects on body weight development and gross pathological findings. Oral administration of 3-hydroxy-2-(3-hydroxy-2-quinolyl)-1H-inden-1-one to Wistar rats at doses of 100, 300 and 1000 mg/kg/day for 28 days resulted in no changes of toxicological relevance. The orange discoloration of the feces noted in all treated groups represents a typical finding in gavage studies with colored substances or dyestuffs. Although the slight increase in the incidence of dark yellow urine implies that a minimal absorption cannot be excluded, no discoloration was noted in any organ and there were no correlating macroscopical or microscopical findings. Based on the results of this study, the no-observed-effect-level (NOEL) and no-observed-adverse-effect-level (NOAEL) were considered to be 1000 mg/kg body weight/day of 3-hydroxy-2-(3-hydroxy-2-quinolyl)-1H-inden-1-one, the highest dose tested.
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 additional screening study for reproductive/developmental toxicity is scientifically justified, since the physic-chemical parameter, the toxicokinetic assumption, and the experimental data including the developmental toxicity study according to OECD TG 414, oral and dermal acute data and oral sub-acute toxicity data indicate that the compound is not significantly absorbed and not toxic. No maternal or fetal toxicity was observed in the developmental toxicity study up to the highest dose tested (limit dose 1000 mg/kg/day). In an acute oral toxicity study no deaths, no clinical signs and no gross pathological findings were reported after dosing of 5 male and 5 female rats with 5000 mg/kg. In an acute dermal study 5 male and 5 female rats received a single dose of 2000 mg/kg of the test item applied semiocclusively for 24 hours. Rats tolerated the dose without toxicologically relevant clinical signs, mortalities, toxicological effects on body weight development and gross pathological findings. Oral administration of 3-hydroxy-2-(3-hydroxy-2-quinolyl)-1H-inden-1-one to Wistar rats at doses of 100, 300 and 1000 mg/kg/day for 28 days resulted in no changes of toxicological relevance. The orange discoloration of the feces noted in all treated groups represents a typical finding in gavage studies with colored substances or dyestuffs. Although the slight increase in the incidence of dark yellow urine implies that a minimal absorption cannot be excluded, no discoloration was noted in any organ and there were no correlating macroscopical or microscopical findings. Based on the results of this study, the no-observed-effect-level (NOEL) and no-observed-adverse-effect-level (NOAEL) were considered to be 1000 mg/kg body weight/day of 3-hydroxy-2-(3-hydroxy-2-quinolyl)-1H-inden-1-one, the highest dose tested.

Effects on developmental toxicity

Description of key information

A developmental toxicity study conducted according to OECD TG 414 and GLP is available. The purpose of this study was an assessment of the influence of Macrolex Gelb G (a colorant for plastics) on embryo-fetal survival and development when administered during the organogenesis and fetal growth phases of pregnancy in the Han Wistar rat.

It was concluded from this study that the dosage of 1000 mg/kg/day was the maternal no observed-adverse-effect-level (NOAEL) and 1000 mg/kg/day was the no-observed-effect-level (NOEL) for embryo-fetal survival and development.

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:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
rats, oral dosing
Principles of method if other than guideline:
The study was designed to meet the requirements of the following guidelines: Current EU, OECD 414 and EPA (OPPTS 870.3700) Guidelines.

The purpose of this study was an assessment of the influence of Macrolex Gelb G (a colorant for plastics) on embryo-fetal survival and development when administered during the organogenesis and fetal growth phases of pregnancy in the Han Wistar rat.

Three groups of 20 females received Macrolex Gelb G at doses of 250, 500 or 1000 mg/kg/day by oral gavage administration, from Day 6 to 19 after mating. A similarly constituted Control group received the vehicle, PEG 300 at the same volume dose as the treated groups. Animals were killed on Day 20 after mating for reproductive assessment and fetal examination.

Clinical observations, body weight and food consumption were recorded. Adult females were examined macroscopically at necropsy on Day 20 after mating and the gravid uterus weight recorded. All fetuses were examined macroscopically at necropsy and subsequently by detailed internal visceral examination or skeletal examination.
GLP compliance:
yes (incl. certificate)
Limit test:
no
Specific details on test material used for the study:
Test item identity (including alternative names):
Macrolex Gelb G
Macrolex Yellow G
3-hydroxy-2-(3-hydroxy-2-quinolyl)-1H-inden-1-one

CAS number:
17772-51-9

Empirical formula:
C18H11N O3

Molecular mass:
289.28 g/mole

Appearance:
Solid, powder, yellow.

Batch number:
CHT23240.

Purity: 98.8%.
Species:
rat
Strain:
Wistar
Remarks:
RccHan™;WIST (Han Wistar)
Details on test animals and environmental conditions:
Duration of acclimatization:
13 days before commencement of pairing.

Age of the animals at the start of the study (Day 0 of gestation):
78 to 84 days old.

Weight range of the animals at the start of the study (Day 0 of gestation:
180 to 228 g.

Allocation:
On the day of positive evidence of mating (Day 0). Only females showing at least two copulation plugs were allocated.

Identification of animals:
Each animal was assigned a number and identified uniquely within the study by a tail tattoo.

Air supply:
Filtered fresh air which was passed to atmosphere and not recirculated.

Temperature and relative humidity:
Monitored and maintained within the range of 20-24ºC and 40-70%.

Bedding:
Solid bottom cages contained softwood based bark-free fiber bedding, which was changed at appropriate intervals each week.

Number of animals per cage:
Acclimatization: up to four animals
During pairing:one (stock) male and one female
Gestation: one female

Environmental enrichment:
Aspen chew block:
A soft white untreated wood block; provided to each cage throughout the study (except during pairing) and replaced when necessary.

Diet:
SDS VRF1 Certified pelleted diet.
Route of administration:
oral: gavage
Vehicle:
propylene glycol
Remarks:
PEG 300
Details on exposure:
Three groups of 20 females received Macrolex Gelb G at doses of 250, 500 or 1000 mg/kg/day by oral gavage administration, from Day 6 to 19 after mating. A similarly constituted Control group received the vehicle, PEG 300 at the same volume dose as the treated groups. Animals were killed on Day 20 after mating for reproductive assessment and fetal examination.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Stability and homogeneity:
The stability of a homogenous suspension of the test item at a concentration of 20 to 200 mg/ml in the vehicle has been demonstrated over a period of up to eight days at refrigerated (+2 to 8C) and four hours at ambient temperature (+15 to 25ºC).

Achieved concentration:
Samples of each formulation prepared for administration on Day 6 and 19 after mating were analyzed for achieved concentration of the test item. Concentrations of the formulations were confirmed.
Details on mating procedure:
Male/female ratio:
1:1 with identified stock males.

Daily checks for evidence of mating:
Ejected copulation plugs in cage tray and vaginal smears were checked for the presence of sperm.

Day 0 of gestation:
When positive evidence of mating was detected

A colony of stud males was maintained specifically for the purpose of mating; these animals were not part of the study and were maintained as stock animals.
Duration of treatment / exposure:
Gestational day 6 to gestational day 19 (GD6 - GD19)
Frequency of treatment:
daily
Duration of test:
Necropsy on GD 20
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
Concurrent control
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Remarks:
low dose
Dose / conc.:
500 mg/kg bw/day (actual dose received)
Remarks:
mid dose
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
Remarks:
high dose
No. of animals per sex per dose:
20
Control animals:
yes, concurrent vehicle
Details on study design:
The study was designed to meet the requirements of the following guidelines: Current EU, OECD 414 and EPA (OPPTS 870.3700) Guidelines.

The purpose of this study was an assessment of the influence of Macrolex Gelb G (a colorant for plastics) on embryo-fetal survival and development when administered during the organogenesis and fetal growth phases of pregnancy in the Han Wistar rat.

Three groups of 20 females received Macrolex Gelb G at doses of 250, 500 or 1000 mg/kg/day by oral gavage administration, from Day 6 to 19 after mating. A similarly constituted Control group received the vehicle, PEG 300 at the same volume dose as the treated groups. Animals were killed on Day 20 after mating for reproductive assessment and fetal examination.

Clinical observations, body weight and food consumption were recorded. Adult females were examined macroscopically at necropsy on Day 20 after mating and the gravid uterus weight recorded. All fetuses were examined macroscopically at necropsy and subsequently by detailed internal visceral examination or skeletal examination.
Maternal examinations:
Clinical observations, body weight and food consumption were recorded. Adult females were examined macroscopically at necropsy on Day 20 after mating and the gravid uterus weight recorded.
Ovaries and uterine content:
Uterus:
Gravid uterine weight (including cervix and ovaries).

For each ovary/uterine horn:
Number of: Corpora lutea; Implantation sites; Resorption sites (classified as early or late); Fetuses (live and dead).

Apparently empty uterine horns:
The number of uterine implantation sites were checked after staining with ammonium sulphide
Fetal examinations:
All fetuses were examined macroscopically at necropsy and subsequently by detailed internal visceral examination or skeletal examination.

Examination of nominally 50% of fetuses in each litter: Sexed internally and eviscerated.

Fixation:
Fetuses eviscerated were fixed in Industrial Methylated Spirit (IMS).
Remaining fetuses were fixed whole in Bouin’s fluid.

Processing:
Bouin’s fixed fetuses were subject to free-hand serial sectioning.
IMS fixed fetuses were processed and stained with Alizarin Red.

Fetal Pathology Examination
Bouin’s fixed fetuses:
Serial sections were examined for visceral abnormalities.

Alizarin Red stained fetuses :
Assessed for skeletal development and abnormalities.
Statistics:
The following data types were analyzed at each timepoint separately:
Body weight, using absolute values and gains over appropriate study periods
Gravid uterine weight and adjusted body weight
Food consumption, over appropriate study periods
Litter size and survival indices
Fetal, placental and litter weight

The following comparisons were performed:
Group 1 vs 2, 3 and 4

The following sequence of statistical tests was used for body weight, gravid uterus weight, food consumption, corpora lutea, implantations, live young, fetal, placental and litter weight data.:

parametric analysis :
Bartlett's test; Williams’ test and Dunnett's test

non-parametric analysis
Bartlett's test; Kruskal-Wallis’ test and Shirley's test

For litter size and survival indices and fetal, placental and litter weight and gravid uterine weight data:
Fisher’s exact tests

Pre/post implantation loss and sex ratio were analyzed by generalized mixed linear model with binomial errors, a logit link function and litter as a random effect (Lipsitz 1991).

For resorptions, each treated group was compared to control by exact Wilcoxon rank sum test

Overall, significant differences between the groups compared were expressed at the 5% (p<0.05) or 1% (p<0.01) level.

Indices:
The following comparisons were performed:
Group 1 vs 2, 3 and 4
Historical control data:
Reported in the report
Clinical signs:
no effects observed
Description (incidence and severity):
There were no adverse clinical signs or adverse signs observed following dose administration that were considered to be related to treatment Macrolex Gelb G.
Mortality:
no mortality observed
Description (incidence):
No mortality observed in any group
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Bodyweight and bodyweight change was not adversely effected by treatment with Macrolex Gelb G, when compared with Controls. (See figure 1and table 1 in the "attached background material" for further information.)
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food consumption was considered unaffected by treatment with Macrolex Gelb G during Days 6-19 of gestation when compared with Controls. (See table 3 in the "attached background material" for further information on food consumption.)
Food efficiency:
no effects observed
Description (incidence and severity):
No effect on body weight or food intake
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):
no effects observed
Description (incidence and severity):
There were no adverse clinical signs or adverse signs observed following dose administration that were considered to be related to treatment Macrolex Gelb G.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Bodyweight and bodyweight change was not adversely effected by treatment with Macrolex Gelb G, when compared with Controls.

Overall group mean bodyweight change (Days 6-19) for females receiving 1000 mg/kg/day was slightly but not statistically significantly reduced when compared with Controls.

Gravid uterine weight was essentially similar across all groups of females, when compared to Controls. (See table 2 in the "attached background material" for further information on uterus weight.)
Gross pathological findings:
no effects observed
Description (incidence and severity):
No abnormality in the appearance or size of any organ and tissue (external and cut surface) was observed. (See table 4 in the "attached background material" for further information on macropathology.)
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Number of abortions:
no effects observed
Description (incidence and severity):
All females were pregnant. The following assessment is based on the 20, 20, 20 and 20 females with live young at termination on Day 20 of gestation in the Control group and at 250, 500 and 1000 mg/kg/day, respectively.
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
For females examined on Day 20 of gestation litter data showed no clear effects of maternal treatment, with mean numbers of implantations, early, late and total resorptions, number of live young and sex ratio and the extent of pre and post-implantation loss, unaffected by treatment.

In all treated groups, the mean numbers of corpora lutea were slightly lower than in Controls (13,6; 12,9; 12,8; 12,2 in control. low, mid and high dosed animals, respectiely), most notably in the females allocated to the 1000 mg/kg/day group; since the number of corpora lutea was established several days before the start of treatment on Day 6 of gestation these differences were due to chance and unrelated to treatment. Although there was no effect of treatment on the levels of pre and post implantation loss, due to the chance differences in the mean numbers of corpora lutea, the mean numbers of implantations and live fetuses in the treated groups were slightly lower than in Controls. (See table 5 in the "attached background material" for further information on litter data.)
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
For females examined on Day 20 of gestation litter data showed no clear effects of maternal treatment, with mean numbers of implantations, early, late and total resorptions, number of live young and sex ratio and the extent of pre and post-implantation loss, unaffected by treatment.

In all treated groups, the mean numbers of corpora lutea were slightly lower than in Controls, most notably in the females allocated to the 1000 mg/kg/day group; since the number of corpora lutea was established several days before the start of treatment on Day 6 of gestation these differences were due to chance and unrelated to treatment. Although there was no effect of treatment on the levels of pre and post implantation loss, due to the chance differences in the mean numbers of corpora lutea, the mean numbers of implantations and live fetuses in the treated groups were slightly lower than in Controls.
Early or late resorptions:
no effects observed
Description (incidence and severity):
For females examined on Day 20 of gestation litter data showed no clear effects of maternal treatment, with mean numbers of implantations, early, late and total resorptions, number of live young and sex ratio and the extent of pre and post-implantation loss, unaffected by treatment. (See table 5 in the "attached background material" for further information on litter data.)
Dead fetuses:
no effects observed
Description (incidence and severity):
For females examined on Day 20 of gestation litter data showed no clear effects of maternal treatment, with mean numbers of implantations, early, late and total resorptions, number of live young and sex ratio and the extent of pre and post-implantation loss, unaffected by treatment.
Changes in pregnancy duration:
not examined
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
All females were pregnant. The following assessment is based on the 20, 20, 20 and 20 females with live young at termination on Day 20 of gestation in the Control group and at 250, 500 and 1000 mg/kg/day, respectively.
Other effects:
no effects observed
Key result
Dose descriptor:
NOAEC
Effect level:
> 1 000 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Basis for effect level:
other: No effect observed at the limit dose
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Placental, litter and fetal weights were considered to be unaffected by treatment with Macrolex Gelb G when compared with Controls. Mean fetal weights in the 1000 mg/kg/day group were slightly but statistically significantly higher than in Controls; this may reflect the slightly lower mean litter size in this group. (See table 6 in the "attached background material" for further information on placental, litter and fetal weights.)
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): For females examined on Day 20 of gestation litter data showed no clear effects of maternal treatment, with mean numbers of implantations, early, late and total resorptions, number of live young and sex ratio and the extent of pre and post-implantation loss, unaffected by treatment. (See table 6 in the "attached background material" for further information on placental, litter and fetal weights.)
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
For females examined on Day 20 of gestation litter data showed no clear effects of maternal treatment, with mean numbers of implantations, early, late and total resorptions, number of live young and sex ratio and the extent of pre and post-implantation loss, unaffected by treatment.

In all treated groups, the mean numbers of corpora lutea were slightly lower than in Controls, most notably in the females allocated to the 1000 mg/kg/day group; since the number of corpora lutea was established several days before the start of treatment on Day 6 of gestation these differences were due to chance and unrelated to treatment. Although there was no effect of treatment on the levels of pre and post implantation loss, due to the chance differences in the mean numbers of corpora lutea, the mean numbers of implantations and live fetuses in the treated groups were slightly lower than in Controls.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
For females examined on Day 20 of gestation litter data showed no clear effects of maternal treatment, with mean numbers of implantations, early, late and total resorptions, number of live young and sex ratio and the extent of pre and post-implantation loss, unaffected by treatment.
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
For females examined on Day 20 of gestation litter data showed no clear effects of maternal treatment, with mean numbers of implantations, early, late and total resorptions, number of live young and sex ratio and the extent of pre and post-implantation loss, unaffected by treatment. (See table 6 in the "attached background material" for further information on placental, litter and fetal weights.)
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
The incidence of major and minor abnormalities and skeletal variants showed no relationship to treatment. (See table 7 in the "attached background material" for further information on external observations.)
Skeletal malformations:
no effects observed
Description (incidence and severity):
The incidence of major and minor abnormalities and skeletal variants showed no relationship to treatment. (See table 8 in the "attached background material" for further information on skeletal observations.)
Visceral malformations:
no effects observed
Description (incidence and severity):
The incidence of major and minor abnormalities and skeletal variants showed no relationship to treatment. (See table 9 in the "attached background material" for further information on visceral observations.)
Other effects:
no effects observed
Key result
Dose descriptor:
NOAEC
Effect level:
> 1 000 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: No effect at the limit dose
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no

The following audited tables and figures taken from the draft study report are attached under "attached background material" :

FIGURES

Figure 1 Body weight - group mean values (g) during gestation

TABLES

Table 1 Body weight and body weight change - group mean values (g) during gestation

Table 2 Gravid uterine weight, adjusted body weight and adjusted body weight change - group mean values (g) on Day 20 of gestation

Table 3 Food consumption - group mean values (g/animal/day) during gestation

Table 4 Macropathology - group distribution of finding

Table 5 Litter data - group mean values on Day 20 of gestation

Table 6 Placental, litter and fetal weights - group mean values (g) on Day 20 of gestation

Table 7 Fetal examinations - major abnormality findings - group incidences

Table 8 Fetal examinations - minor skeletal abnormality and variants findings - group incidences

Table 9 Fetal examinations - minor visceral abnormality and necropsy findings - group incidences

Conclusions:
Oral administration of Macrolex Gelb G to Han Wistar rats during Days 6 to 19 of gestation at a dose of 250, 500 or 1000 mg/kg/day was well tolerated and did not result in any signs of adverse toxicity or any adverse effects on embryo fetal survival, growth and development.
Dose levels of 0, 250, 500 and 1000 mg/kg/day were well tolerated with no clinical signs and no adverse effect upon body weight or food consumption. There was no clear effect of maternal treatment upon numbers of implantations, early, late and total resorptions, number of live young and sex ratio and the extent of pre and post-implantation loss. Placental, litter and fetal weights were also all considered to be unaffected by treatment.
Executive summary:

Maternal clinical condition, bodyweight, food consumption and macroscopic evaluation were not adversely affected by treatment with Macrolex Gelb G up to 1000 mg/kg/day when compared with Control animals. Embryo fetal survival, growth and development were unaffected by treatment with Macrolex Gelb G up to 1000 mg/kg/day.

Conclusion:

It was concluded from this study that the dosage of 1000 mg/kg/day was the maternal no observed-adverse-effect-level (NOAEL) and 1000 mg/kg/day was the no-observed-effect-level (NOEL) for embryo-fetal survival and development.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
A developmental toxicity study conducted according to OECD TG 414 and GLP is 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
Additional information

A developmental toxicity study conducted according to OECD TG 414 and GLP is available. The purpose of this study was an assessment of the influence of Macrolex Gelb G on embryo-fetal survival and development when administered during the organogenesis and fetal growth phases of pregnancy in the Han Wistar rat.

Three groups of 20 females received Macrolex Gelb G at doses of 250, 500 or 1000 mg/kg/day by oral gavage administration, from Day 6 to 19 after mating. A similarly constituted Control group received the vehicle, PEG 300 at the same volume dose as the treated groups. Animals were killed on Day 20 after mating for reproductive assessment and fetal examination.

Clinical observations, body weight and food consumption were recorded. Adult females were examined macroscopically at necropsy on Day 20 after mating and the gravid uterus weight recorded. All fetuses were examined macroscopically at necropsy and subsequently by detailed internal visceral examination or skeletal examination.

Results

Maternal clinical condition, bodyweight, food consumption and macroscopic evaluation were not adversely affected by treatment with Macrolex Gelb G up to 1000 mg/kg/day when compared with Control animals.

Embryo fetal survival, growth and development were unaffected by treatment with Macrolex Gelb G up to 1000 mg/kg/day.

Conclusion

It was concluded from this study that the dosage of 1000 mg/kg/day was the maternal no observed-adverse-effect-level (NOAEL) and 1000 mg/kg/day was the no-observed-effect-level (NOEL) for embryo-fetal survival and development.

In addition, the physic-chemical parameter, the toxicokinetic assumption, and the experimental data including the developmental toxicity study according to OECD TG 414, oral and dermal acute data and oral sub-acute toxicity data indicate that the compound is not significantly absorbed and not toxic. No maternal or fetal toxicity was observed in the developmental toxicity study up to the highest dose tested (limit dose 1000 mg/kg/day). In an acute oral toxicity study no deaths, no clinical signs and no gross pathological findings were reported after dosing of 5 male and 5 female rats with 5000 mg/kg. In an acute dermal study 5 male and 5 female rats received a single dose of 2000 mg/kg of the test item applied semiocclusively for 24 hours. Rats tolerated the dose without toxicologically relevant clinical signs, mortalities, toxicological effects on body weight development and gross pathological findings. Oral administration of 3-hydroxy-2-(3-hydroxy-2-quinolyl)-1H-inden-1-one to Wistar rats at doses of 100, 300 and 1000 mg/kg/day for 28 days resulted in no changes of toxicological relevance. The orange discoloration of the feces noted in all treated groups represents a typical finding in gavage studies with colored substances or dyestuffs. Although the slight increase in the incidence of dark yellow urine implies that a minimal absorption cannot be excluded, no discoloration was noted in any organ and there were no correlating macroscopical or microscopical findings. Based on the results of this study, the no-observed-effect-level (NOEL) and no-observed-adverse-effect-level (NOAEL) were considered to be 1000 mg/kg body weight/day of 3-hydroxy-2-(3-hydroxy-2-quinolyl)-1H-inden-1-one, the highest dose tested.

Justification for classification or non-classification

No maternal or fetal toxicity was observed in the developmental toxicity study up to the highest dose tested (limit dose 1000 mg/kg/day).