Calcium 4-chloro-2-(5-hydroxy-3-methyl-1-(3-sulfonatophenyl)pyrazol-4-ylazo)-5-methylbenzenesulfonate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

In a one- to two-generation reproduction toxicity study in Sprague Dawley SD rats (including sperm analysis) no evidence of an effect of the test item was found, therefore the study was completed with the F1 generation. On the basis of these results the NOAEL (No Observed Adverse Effect Level) for parental F0 males and females is 1000 mg/kg/day. In addition, since no effect of treatment at any dose level, on foetal or pup development was observed the F1 NOAEL is 1000 mg/kg/day.

Link to relevant study records

Reference

Reference 1

Endpoint:

one-generation reproductive toxicity

Remarks:

based on generations indicated in Effect levels

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

well performed GLP and OECD guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]

Deviations:

yes

Remarks:

attributed to the partial combination of OECD 415 and 416 and as far as exceeding the requirements of OECD 415

Qualifier:

according to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

Deviations:

yes

Remarks:

attributed to the partial combination of OECD 415 and 416 and as related to the finalisation of the study without the use of a second generation

Principles of method if other than guideline:

Treatment of F1 pups started the day after the selection of pups. The treatment continued for approximately 4 weeks. During this period all available data were collected and examined. Since no evidence of an effect of the test item was found, the study was completed with the F1 generation.

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Italy S.r.l., San Pietro al Natisone (UD)
- Age at study initiation: (P ) Males: 5 wks; Females: 8-9 wks at receipt
- Weight at study initiation: (P) Males: 134.1-159.3 g; Females: 200.6- 229.4 g at receipt
- Housing: In a limited access rodent facility. At arrival, the animals were housed up to 5 of one sex to a cage, after allocation, during the pre-pairing period, the animals were housed 4 of one sex to a cage, during the mating period, the rats were housed one male to one female, males were re-caged after mating as they were before mating, after mating, the females were transferred to individual breeding cages.

- Diet (e.g. ad libitum): laboratory rodent diet (4RF21, Mucedola S.r.l., Via G. Galilei 4, 20019 Settimo Milanese (MI), Italy) ad libitum
- Water (e.g. ad libitum): Drinking water ad libitum
- Acclimation period: approximately 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 55 ± 15
- Air changes (per hr): 15 to 20
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

other: carboxymethylcellulose 1% in water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:

A weighed amount of PV-Echtgelb HGR was suspended in the vehicle (carboxymethylcellulose 1% in water) and brought to the final volume appropriate for each concentration. The formulations were prepared daily.

VEHICLE
- Concentration in vehicle: range of 5-100 mg/ml
- Amount of vehicle (if gavage): dose volume of 10 ml/kg body weight

Details on mating procedure:

- M/F ratio per cage: monogamous (one male to one female)
- Proof of pregnancy: presence of sperm in the vaginal smear and/or by the presence of a copulation plug, was considered Day 0 of gestation (or Day 0 post coitum).
- After successful mating each pregnant female was caged (how): after mating, the females were transferred to individual breeding cages

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Prior to commencement of treatment, analysis was performed to confirm that the proposed formulation procedure was acceptable. Data of the test item stability were obtained in this study in the concentration range of 5-100 mg/ml. The formulations prepared at the required concentration resulted stable 24 hours at room temperature. Samples of the formulations prepared during the first and the last week of treatment were analysed to check the homogeneity and concentration.

Duration of treatment / exposure:

The test item was administered orally by gavage at a dose volume of 10 ml/kg body weight. Control animals received the vehicle alone at the same dose volume.


Treatment (F0 generation)

Males
Males were treated for at least 10 weeks prior to pairing and thereafter through the day prior to sacrifice.
Dose volumes were calculated according to individual body weights on the first day of treatment and adjusted according to individual body weights at weekly intervals thereafter.

Females
Females were treated at least 2 weeks prior to pairing, during mating, gestation and post partum periods until the day before sacrifice (on post partum Day 21 or shortly after). Dose volumes were calculated according to individual body weights on the first day of treatment and adjusted according to individual body weights at weekly intervals up to positive identification of mating and then according to body weight on Days 0, 7, 14 and 20 post coitum and on Days 1, 4, 7 and 14 post partum.

Treatment (F1 generation)

Pups of F1 generation were treated for approximately 4 weeks after weaning and then sacrificed without necropsy.

Frequency of treatment:

daily in the course of specified treatment periods

Details on study schedule:

Treatment P0 generation
Males were treated for at least 10 weeks prior to pairing and thereafter through the day prior to sacrifice.
Females were treated at least 2 weeks prior to pairing, during mating, gestation and post partum periods until the day before sacrifice (on post partum Day 21 or shortly after)

Selection of F1 pups
One male and one female pup from each litter were selected on Day 21 post partum for the production of F2 generation and allocated to groups. All aspects of the random selection procedure were documented. The 24 litters selected were those weaned as close as possible to the median weaning date for the study or group. The nominal age of all selected pups was based on the median weaning date as nominal age 21 days.

Treatment F1 generation
Animals were treated, starting from the day after selection (day 22 of age) for approximately 4 weeks.

Dose / conc.:

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

Remarks:

Doses / Concentrations:
0 mg/kg/day (in terms of test item as supplied)
Basis:
nominal conc.
Control Group

Dose / conc.:

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

Remarks:

Doses / Concentrations:
50 mg/kg/day (in terms of test item as supplied)
Basis:
nominal conc.
Low Dose Group

Dose / conc.:

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

Remarks:

Doses / Concentrations:
200 mg/kg/day (in terms of test item as supplied)
Basis:
nominal conc.
Medium Dose Group

Dose / conc.:

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

Remarks:

Doses / Concentrations:
1000 mg/kg/day (in terms of test item as supplied)
Basis:
nominal conc.
High Dose Group

No. of animals per sex per dose:

24 (parental generation, P0)

Control animals:

yes, concurrent vehicle

Details on study design:

Euthanasia F0
One group 4 female sacrificed for humane reasons (no. 46350147) and those that had completed the scheduled test period were killed with carbon dioxide. Dams with total litter loss were sacrificed the day of occurrence or shortly after.

Euthanasia Pubs
Pups sacrificed for humane reasons were killed by intrascapular injection of "Tanax" (before Day 21 post partum) or by carbon dioxide (from Day 21 post partum). Pups selected for necropsy at weaning were killed by carbon dioxide. Culled pups were sacrificed on Day 4 post partum by intrascapular injection of "Tanax" and no necropsy was performed. All animals, including those found dead, were subjected to necropsy.

Euthanasia F1
The study terminated with the sacrifice of all animals a few days after the last bleeding procedures. The animals were euthanised with carbon dioxide.

Positive control:

none

Parental animals: Observations and examinations:

In vivo observations (F0 generation)

- Mortality: twice daily or once daily at weekends and public holidays
- Pre- and post-dose observations: daily, prior to dosing, soon after dosing and 1 (and 2) hour(s) after dosing
- Clinical signs: Once before treatment commenced and at weekly intervals each animal was given a more detailed examination
- Body weight: Males were weighed weekly from the first day of treatment to termination. Females were weighed weekly from the first day of treatment until positive identification of mating. After mating, the females were weighed on Days 0, 7, 14 and 20 post coitum. Dams were weighed on Days 1, 4, 7, 14 and 21 post partum.
- Food consumption: Food consumption was recorded weekly from allocation to pairing. For the females, during the post coitum period food consumption was measured on Days 7, 14 and 20 post coitum starting from Day 0 post coitum. During the post partum period, food consumption was measured on Days 4, 7, 14 and 21 starting from Day 1 post partum.
- Mating: Mating was monogamous (one male to one female). Vaginal smears were taken, during pairing up to the day of positive identification of mating. The day successful mating was detected, as judged by the presence of sperm in the vaginal smear and/or by the presence of a copulation plug, was considered Day 0 of gestation
- Blood collection: Blood samples (approximately 0.8 ml) were collected from the tail vein of the first 5 high dose and 5 control surviving male rats on days 10 and 61 of dosing 4 hours after dosing. For females, blood samples were collected from the tail vein of the first 5 high dose and 5 control rats 4 hours after dosing on Day 5 of dosing and during pregnancy (Day 15 post coitum) from selected animals.
- Parturition check and duration of gestation: A parturition check was performed from Day 20 post coitum. Gestation periods were taken as the time between the day of successful mating and the commencement of birth. The day offspring was first detected was considered Day 0 post partum.

Oestrous cyclicity (parental animals):

- Vaginal smears: Vaginal smears were taken daily in the morning starting 2 weeks before pairing and during the mating period until a positive identification of mating was made (see section 5.2.7). The vaginal smear data were examined to determine the following:
a) anomalies of the oestrous cycle
b) the pre-coital interval (i.e., the number of nights paired prior to the detection of mating).

Sperm parameters (parental animals):

During the macroscopic examination one cauda of the epididymis was taken from each male from all groups for sperm count and evaluation of viability and motility. In addition, sperm was classified as normal (both head and midpiece/tail appeared normal) or abnormal (fusion, isolated heads, misshapen head and/or tails).

During the necropsy procedure one testis was taken from each male from the control and high dose group for enumeration of testicular sperm heads. The testis was decapsulated, weighed and homogenised. After homogenisation an aliquot of the cell suspension was loaded onto an haemocytometer and resistant sperm heads were counted under light microscope.

Litter observations:

Litter Observations

The total litter size (live and dead) was counted, sexed and examined for abnormalities as soon as possible after parturition (Day 0/1 post partum). All live pups were individually identified within the litter by toe amputation.

All pups were weighed on Days 1, 4, 7, 14 and 21 post partum. Pup sex was confirmed on Day 21 post partum.

All litters were examined daily for dead or abnormal young and all pups found dead or sacrificed for humane reasons were necropsied, with the exception of those excessively cannibalised or autolysed.

In vivo observations F1 generation

Mortality: Throughout the study, twice a day. At weekends and Public Holidays onvce a day.
Pre- and post-dose observations: Examination of individual animals for signs of reaction to treatment was carried out daily, prior to dosing, soon after dosing and 1 (and 2) hours after dosing.
Clinical signs: After weaning, at weekly intervals each animal was given a more detailed examination.
Body weight: weekly from nominal day 28 to termination
Food consumption: weekly from nominal day 28 until termination
Vaginal opening: The onset of vaginal opening was monitored from day 28 of age until 100% occurrence
Preputial separation: The cleavage of the balonopreputial gland was checked from day 35 of age until 100% occurrence
Motor activity: During weeks 5, 6 and 7 (protocol deviation), nominal age, the general activity of the animals within each cage was monitored electronically overnight using the optical beam technique.
Water-filled Y-maze: During week 5, nominal, a water-filled Y-maze was used to assess learning ability of the offspring. Maintained improvement in swimming time was considered as an indication of learning.
Blood, urine and faeces collection: During the last day of treatment of pups, blood samples (0.6 ml) were collected from the tail vein of the first 8 males and 8 females of the high dose group at 1, 3, 6, 24 and 48 hours after dosing (4 rats per sampling time; 2 or 3 blood samples from each animal) and urine and faeces were collected at 48 hours post-dose from the first 4 males and 4 females of the high dose group.

Postmortem examinations (parental animals):

NECROPSY

The clinical history of the animal was studied and a detailed post mortem examination was conducted (including examination of the external surface and orifices). Changes were noted.

Females
All dams that gave birth were sacrificed on Day 21 post partum and examined externally and internally for abnormalities. The uterus of each female which gave birth was inspected for implantation sites and the number of sites was recorded. All apparently non pregnant females were killed after 25 days post coitum.
Uteri of females without litters were immersed in a 10-20% solution of ammonium sulphide to reveal evidence of implantation.

Males
Almost all males (protocol deviation) were killed after the females gave birth.

Organ weights
From all animals completing the scheduled test period, the organs were dissected free of fat and weighed.

Tissues fixed and preserved
Samples of all the tissues listed were fixed and preserved in 10% buffered formol saline (except testes and epididymides which were fixed in Bouin's solution and all preserved in 70% ethyl alcohol).

HISTOPATHOLOGY

After dehydration and embedding in paraffin wax, sections of the tissues were cut at 5 micrometre thickness and stained with haematoxylin and eosin.
The examination was as detailed below:
a) Tissues specified from 10 randomly selected high dose and control animals of parental generation killed at term.
b) Tissues specified from all animals killed or dying during the treatment period.
c) All abnormalities in all groups of parental animals.
d) Abnormalities, from at least one/pup/sex/litter sacrificed at term.
Since no differences were observed in the reproductive organ weights of males and females and in the sperm analysis of the treated groups (including daily sperm production of the control and high dose groups), histopathological examination required by the study protocol was not performed on the few animals which failed to mate.

Postmortem examinations (offspring):

All pups found dead or humanely killed and three pups/sex/litter randomly selected for necropsy at weaning, were necropsied, with the exception of those that were excessively cannibalised or autolysed, and examined for the following:
a) external and internal abnormalities
b) sex confirmation by gonadal inspection
All pups from the 5 females (animal nos. 19, 57, 73, 77, 159) were necropsied on Day 21 post partum, since these pups were not selected for subsequent generation.
In addition, for one pup/sex/litter randomly selected for necropsy at weaning the following
organs were weighed:
Brain
Spleen
Thymus
Abnormalities preserved, of at least one pup/sex/litter, were examined

Statistics:

For the body weights, body weight gain, food consumption, organ weights and Y-maze test the significance of the differences amongst group means was assessed by analysis of variance. Differences between each treated group and the control group were assessed by Dunnett’s test using a pooled error variance. The homogeneity of the data was assessed by Bartlett’s Test before Dunnett’s Test was performed. If the data were found to be inhomogeneous, a modified t test (Cochran and Cox) was applied.

The mean values, standard deviations and statistical analysis were calculated from actual values in the computer without rounding off.

The non-parametric Kruskal-Wallis analysis of variance was used for litter data, sex ratios, sperm analysis, daily sperm production, implantation, pre-weaning development and prebirth loss data. Intergroup differences between the control and treated groups were assessed by the non-parametric version of the Williams test using the SAS system program.

The criterion for statistical significance was p<0.05.

Statistical analysis of histopathological findings was carried out by means of the nonparametric Kolmogorov-Smirnov test.

Reproductive indices:

Females

Pre-birth loss = ((no. of visible implantations - total litter size at birth) / (no. of visible implantations)) x 100

Pup loss at birth = ((Total litter size - live litter size) / (Total litter size)) x 100

Cumulative pup loss through Day 4 post partum = ((Total litter size at birth - live litter size at Day 4, before culling) / (Total litter size at birth)) x 100

Cumulative pup loss through Day 21 post partum = ((Live litter size at Day 4, after culling - live litter size at Days 7, 14, 21) / (Live litter size at Day 4 after culling)) x 100

Sex ratios were calculated at birth, Day 4 post partum and Day 21 post partum and were presented as the percentage of males per litter.

Lactation index for females = ((no. of pups surviving at 21 days (weaned)) / (no. of pups retained at Day 4)) x 100


Males and Females

Copulatory Index (%) (males and females) = ((no. of animals mated) / (no. of animals paired)) x 100

Fertility Index (%) (males) = ((no. of males which induced pregnancy) / (no. of males paired)) x 100

Fertility Index (%) (females) = ((no. of pregnant females) / (no. of females paired)) x 100

Copulatory Interval = Mean number of days between pairing and mating

Clinical signs:

no effects observed

Description (incidence and severity):

except yellow coloration of the faeces that was considered to be related to the excretion of the yellow colored test item with the faeces

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

except one female from group 4 that was killed for humane reasons on day 9 of the premating phase and that showd effects suggesting a possible misdosing

Other effects:

not examined

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Description (incidence and severity):

except a statistically significant increase in the percentage of sperm mobility was noted in group 4

Reproductive performance:

no effects observed

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 signs of toxicity up to 1000 mg/kg bw, which was the highest dose tested

Clinical signs:

no effects observed

Description (incidence and severity):

No relevant differences between the control and the treated groups were noted.

Mortality / viability:

no mortality observed

Description (incidence and severity):

No significant differences in total and live litter size at birth. Litter and mean pup weight comparable on Day 1 and 4 post partum. On Days 7, 14 and 21 number of live pups, litter weight and mean pup weight comparable.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

except a statistically significant increase in body weight was recorded in the mid-dose group of F1 female generation at the end of treatment.

Sexual maturation:

no effects observed

Description (incidence and severity):

Vaginal opening / Preputial separation

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

except the spleen weight was statistically significantly higher in group 4 females compared to the control group.

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

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 signs of toxicity up to 1000 mg/kg bw, which was the highest dose tested

Reproductive effects observed:

not specified

Y-Maze test of F1 pups: Y-Maze test across several sessions (four trials in total) showed learning ability in all groups of both sexes. The mean time required for successful trial was comparable between the groups during the test.

Motor activity of F1 pups: The overnight cage activity to assess spontaneous motor activity did not show any differences between the control and the treated groups in either sex.

The lactation index was also similar in all treated groups in comparison with controls.

No differences were observed on sex ratio during the post partum period.

Conclusions:

On the basis of these results the NOAEL (No Observed Adverse Effect Level) for parental F0 males and females is 1000 mg/kg/day. In addition, since no effect of treatment at any dose level, on foetal or pup development was observed the F1 NOAEL is 1000 mg/kg/day.

Executive summary:

The potential toxic effect of Pigment Yellow 191 was investigated in male and female Sprague Dawley rats before and during mating, throughout gestation and weaning periods. The development and behaviour of the offspring was also evaluated. The treatment groups and dose levels for F0 and F1 generations were as follows:

Group	Treatment (mg/kg/day) in terms of test item as supplied	Number of animals/sex
1 (control)	0	24
2	50	24
3	200	24
4	1000	24

The males of parental generation were dosed daily for 10 consecutive weeks before pairing, during pairing and thereafter until termination. The females of parental generation were dosed daily for 2 consecutive weeks before and during pairing, throughout gestation and up to termination (Day 21 post partum). Pups of F1 generation were treated for approximately 4 weeks after weaning and then sacrificed without necropsy.

Data of the in vivo phase included mortality, body weight, food consumption, clinical signs pre- and post-dose observations, observation of the cage tray and reproductive parameters (litter data, sex ratio and gestation length). All animals of F0 generation were subjected to a post mortem examination.

P0 parental generation

Fate of females

A total of 10 females were proved not pregnant at necropsy: 2 animals in the control group, 4 in the low dose group, 1 in the mid-dose group and 3 in the high dose group. Two animals had unilateral implantation: one in the control group and one in the mid-dose group. Two control animals had total litter loss on Day 1 and Day 2 post partum. One animal in the control group had total resorption and one in the mid-dose group had unilateral total resorption. One high dose animal was sacrificed for humane reasons on day 9 of treatment. The number of females with live pups on post partum day 21 was: 19 in the control group, 20 in the low and high dose groups and 22 in the mid-dose group.

Clinical signs, pre- and post-dose observations and cage tray observations

No relevant clinical signs and signs of reaction to treatment were observed during the study. Slight to marked yellow coloration of faeces was recorded on the cage tray during treatment accordingly to the dosages administered.

Body weight and body weight gain

Body weight of males and females was unaffected by treatment during the whole treatment period.

Food consumption

No difference in food consumption was observed between the control and treated animals of both sexes during the whole treatment period.

Reproductive parameters

Oestrus cycle, copulation plug, copulatory interval, copulatory index and fertility index were unaffected by treatment.

Implantation, pre-birth loss data and gestation length

No differences were observed in the number of implantations, pre-birth loss and/or gestation length between the groups.

Litter data

No statistically significant differences were noted in total and live litter size at birth. The litter and mean pup weights were comparable between the groups on Days 1, 4, 7, 14 and 21 post partum. In addition, the lactation index was similar in all groups.

Number and sex of F1 pups

No differences were observed on sex ratio during the post partum period.

Terminal body weight and organ weights

No differences in terminal body weight and absolute or relative organ weights were noted between the control and the treated groups.

Sperm analysis

A statistically significant increase in the percentage of sperm mobility was noted in group 4 when compared to the control group. No differences were found in sperm concentration between the two groups.

Daily sperm production

Daily sperm production measured by testicular sperm head counts showed no differences in group 4 compared to the control group. The weight of testis was also comparable betweeen the two groups.

Macroscopic observations

Unscheduled death

One female from group 4 was killed for humane reasons on Day 9 of the premating phase. The most relevant abnormalities detected at necropsy were swelling of the spleen, thickness of the thymus, firm consistency and dark coloration of the liver, pale areas in the kidneys, dark/red colour of the lungs, pale coloration of the heart, yellow/creamy material in the thoracic cavity.

Final sacrifice

No macroscopic finding was described, that could be considered correlated with the administration of the test item.

Histopathological examination

Unscheduled death

Mild to moderate inflammatory reactions were seen involving the thymus, lungs, heart and diaphragm and suggested a possible misdosing. Such lesions were associated with marked atrophy of the thymus, dilatation of the renal cortical tubules and extramedullary haemopoiesis in the spleen.

Final sacrifice

No change was observed in the examined tissues/organs of the terminal kill male and female animals of the parental generation, which could be considered treatment-related. The findings reported were considered to be expression of spontaneous pathology, commonly seen in this species under our experimental conditions.

No toxicological significance was attributed to the abnormalities detected at necropsy of the selected pups.

F1 generation

Clinical signs, pre and post-dose observations and cage tray observations

No relevant clinical signs and/or signs of reaction to treatment were recorded during the study. Slight to marked yellow coloration of the faeces was recorded in the cage tray during treatment in the treated groups in comparison with controls.

Body weight and body weight gain

A statistically significant increase in body weight was recorded in the mid-dose group of F1 female generation at the end of treatment. No significant changes were noted in body weight gain among groups during the study.

Food consumption

Food consumption was unaffected by treatment.

Pre-weaning clinical signs

No relevant differences between the control and the treated groups were noted.

Organ weights

The mean brain and thymus weights were similar between the groups. The spleen organ weight was statistically significantly higher in group 4 females compared to the control group.

Y-Maze test

Y-Maze test across several sessions (four trials in total) showed learning ability in all groups of both sexes. The mean time required for successful trial was comparable between the groups during the test.

Motor activity

The overnight cage activity to assess spontaneous motor activity did not show any differences between the control and the treated groups for either sexes.

Preputial separation

Male pups examined for preputial separation as a landmark of sexual maturation, did not show differences on the mean day of its occurrence between the control and treated groups.

Vaginal opening

Similarly, female pups examined for vaginal opening as a landmark of sexual maturation, did not show differences on the mean day of its occurrence between the control and treated groups.

Necropsy findings

Necropsy findings in decedent pups, humane killed pups and the pups at weaning were considered incidental. No treatment-related effect was attributed to these findings.

Reference 2

Endpoint:

one-generation reproductive toxicity

Type of information:

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

Adequacy of study:

key study

Reason / purpose for cross-reference:

read-across source

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 signs of toxicity up to 1000 mg/kg bw, which was the highest dose tested

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 signs of toxicity up to 1000 mg/kg bw, which was the highest dose tested

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

Species:

rat

Quality of whole database:

reliable without restrictions - well performed GLP and OECD guideline study

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

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

No classification

No adverse effects on fertility and prenatal devlopment were seen in a study according to OECD 415 (one generation).