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The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Based on the results of a chronic feeding study performed with a substance analogue, which included exposure of two generations, the parental, reproduction and developmental NOAEL was found to be 2.0%, which correlates to appr. 1117 mg/kg bw/day for males and for females 1315 mg/kg bw/day. This result is read across to PR63:1.

Link to relevant study records
Reference
Endpoint:
two-generation reproductive toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
The justification to read across the data is attached in Section 13.
Reason / purpose for cross-reference:
read-across source
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Orange coloration of hair, exposed skin, feet, tails, urine and/or faeces was observed for all exposed rats in a dose-related manner. No other changes in general behaviour and appearance considered to be related to the test substance were seen.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Three control rats (2 males (weeks 3 and 12) and 1 female (week 11)), 3 rats dosed at 0.05% (3 females, weeks 1, 9 and 18) and one male dosed at 0.3% (week 18) died during the study. In absence of a dose-relationship, these mortalities were not considered to be related to the test substance.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Changes in body weights were similar for control and treated rats.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food consumption was similar for control and treated rats.
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Description (incidence and severity):
No changes considered to be related to the test substance were seen during the week 15 ophthalmoscopic examination.
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
The urine of rats at the 0.05% dosage level appeared to be slightly darker in color when compared to the urine of control rats. The urine of rats at the 0.3% dosage level generally appared to be yellow-orange in color, and the urine for rats dosed at 2.0% was yellow-dark orange. This effect was a direct
effect of presence of the non-metabolized substance in the urine and considered non-adverse. No other differences were seen in the urinalysis values between control and treated rats.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
not examined
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Description (incidence and severity):
The fertility indices for females and males were 83% and 95% for the two control groups, and 93% for all three test substance groups.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 2 other: %
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects seen at highest dose tested.
Key result
Critical effects observed:
no
Clinical signs:
no effects observed
Description (incidence and severity):
No clinical effects were seen in the F1 rats before weaning. In treated rats, a dose-related colouration was observed of the hair and exposed skin (light-red to red), of urine (dark yellow to orange) and faeces (light-red to red). At the 66-week interim period, a yellow or red material on the anogenital region was noted more frequently for treated rats. The most frequent incidental findings seen at this time for control and treated rats were hair loss, soft stool, red material around the eye, redness and swelling of one or both ears and rales. During the interval 66 to 90 weeks of study, particularly after week 85, the animals began to exhibit several findings at a greater frequency than previously noted; these findings which usually preceded death or moribundity included yellow or red material on the anogenital region, red material around the eyes, excessive lacrimation, rales and labored breathing.
During the interval 91-116 weeks of study, females had rales and accumulation of yellow or red material on the anogenital area slightly more often for treated animals than the controls. The other observations (previously noted) were still evident in similar numbers of treated and control animals. Through 126 weeks of study (95 weeks for the males), masses (abdominal, anogenital, thoracic, inguinal and axillary) were noted. The incidence of masses was simlar for the treated and control groups and was within limits that would be expected for animals of this age and strain.
The observed effects are correlated to chronic exposure and not considered to be related to reproduction or developmental effects of test item exposure.
Mortality / viability:
no mortality observed
Description (incidence and severity):
Survival indices were similar for control and treated pups with all survival indices being at least 98%. Substance-related effects on mortality were not seen up to week 52 and therefore not considered to be a developmental effect, but rather related to chronic exposure.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Changes in body weights of pups were similar for control and treated rats. Substance-related effects on body weight were not seen up to week 52 and therefore not considered to be a developmental effect.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Description (incidence and severity):
No effects were seen in the first 6 months of the F1-generation. Effects at a later timepoint were not considered to be related to exposure to the substance (for details, see section 7.5.1).
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
No changes considered to be related to the test substance were seen in the hematological studies. Although some statistically significant differences were found between the mean values of treated rats when compared to the combined control values, none of these differences was considered biologically significant. Incidental findings noted for a few control and treated rats during the study at single occasions included elevated total leucocyte and reticulocyte counts and/or decreased hemoglobin, hematocrit and erythrocyte values. In absence of a trend (during the study, exposure-related) these findings were considered not adverse. At 20 months of study, one low dose male and one high dose male had markedly to moderately elevated leucocyte counts. Erythrocyte counts, hemoglobin and hematocrit values for a few of the control and treated mice were markedly increased. This effects were found not to be related to test substance exposure.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
No changes considered to be related to the test substance were seen in the biochemical studies. Incidental findings noted for a few control and treated rats included elevations in serum glutamic oxaloacetic- and serum glutamic pyruvic-transaminase activities, alkaline phosphatase, blood urea nitrogen, and/or creatinine.
Urinalysis findings:
no effects observed
Description (incidence and severity):
No effects were observed in the pups. The urine of weaned rats at the 0.05% dosage level appeared to be slightly darker in color when compared to the urine of control rats. The urine of rats at the 0.3% dosage level generally appared to be yellow-orange in color, and the urine for rats dosed at 2.0% was yellow-dark orange. This effect was a direct effect of presence of the non-metabolized substance in the urine and considered non-adverse. No other differences were seen in the urinalysis values between control and treated rats.
Sexual maturation:
no effects observed
Description (incidence and severity):
No effects were noted on the (development of) the sexual organs of the F1-generation.
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
The pups were not examined. At final sacrifice, liver, kidney and heart weights of high dose males were increased relative to body weight compared to control group (+9%, +38% and +23%, for respectively liver, kidneys and heart). Since the effect in liver were ,10%, this was not considered adverse. In females, kidney weights for the high dose group were also increased relative to body weight compared to control group (+16.5%). Since no histopathological effects were seen in kidney and heart, this effect was also considered non-adverse. In mid and high dose females, absolute and relative adrenal weights were increased compared to controls (-30.6% and -9.4% (absolute); -33% and -10.2% (relative)). In absence of a dose-response, this effect on adrenals is not considered to be adverse. For all exposed females, uterine weight was increased (absolute: +119%, +77.7%, 194.6% for groups exposed to respectively 0.05%, 0.3% and 2.0%; relative: +103.8%, +92.3%, 138.5% for groups exposed to respectively 0.05%, 0.3% and 2.0%). It is noted that the standard deviations were high for these effects, no clear dose response was seen and no histopathological effects were noted in the uteri, therefore this observation was considered not adverse.
Gross pathological findings:
no effects observed
Description (incidence and severity):
The pups were not examined. There were no test substance-related macroscopic changes present for animals which died during the study or which were sacrificed at 12 months or terminally. The changes observed were related to spontaneous disease and were agonal or non-specific.
Histopathological findings:
no effects observed
Description (incidence and severity):
The pups were not examined. There was a higher incidence of chronic nephritis, renal tubular epithelial hyperplasia, myocardial fibrosis, reticular tubules and pigment in the spleen, atrophy/degeneration of the testicular tubules and pigment in the spleen for high dose males when compared to controls for animals that died on study from 12 months to termination (higher mortality rate was seen at high doe males compared to other groups). The nature of the lesions found in the high dose males was not specific, but rather representative for aging males of this strain. There was no significant increased incidence of the above lesions in males at terminal sacrifice. No other lesions were found that were attributed to the test substance. The lesions that were present were those of spontaneous disease and they were not unusual for animals of this species and strain.
Other effects:
no effects observed
Description (incidence and severity):
There were no compound related neoplastic lesions. A summary table is included under "Any other information on results incl. tables" of section 7.5.1.
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 2 other: %
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects seen on reproduction up to and including the highest dose tested (2% in feed).
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
no
Conclusions:
Based on the results of a chronic feeding study with D&C Red #6, which included exposure of two generations, the parental, reproduction and developmental NOAEL was found to be 2.0%, which correlates to appr. 1117 mg/kg bw/day for males and for females 1315 mg/kg bw/day. This result is read across to PR63:1.
Executive summary:

A chronic feeding study, covering two generations, was conducted with D&C Red #6. Sixty rats/sex were exposed to 0.05%, 0.3% or 2.0% of the test substance in feed. Two control groups were included. After 60 days, the rats were mated. From the litters, 70 rats/sex/ group were selected. After weaning at 21 days, these rats were exposed to 0.05%, 0.3% or 2.0% of the test substance in feed for a life-time (sacrifice males in week 95 and sacrifice females in week 126). Reproductive parameters were evaluated to determine fertility index, gestation anomalies and effects on parturition and lactation. Indices for live birth and survival to weaning were calculated. During the study, mortality, clinical signs, body weight, eyes and urine were monitored regularly. Hematologial and biochemical evaluations and urinalyses were conducted for 10 rats/ sex/group at 3, 6, 12, 18 and 21 (males) or 24 (females) months of study. Feed intake was monitored for each individual rat. An interim sacrifice and necropsy of 10 rats/sex/group was conducted following 12 months of test substance exposure. After sacrifice, gross necropsy was performed, major organs were weighed and histopathogy was done.

All exposed rats showed direct effects of the test substance: coloured fur, urine and feces. The in utero exposure did not result in adverse effects on body weights of maternal animals or pups, food consumption, ophthalmoscopic examinations, fertility or gestation and lactation indices. For the postweaning part, males at the high dose group showed significant decrease in body weight gain compared to controls, with similar feed intake for exposed and control rats. No changes considered to be related to test substance exposure were observed during ophthalmoscopy. No adverse effects were seen on hematology and biochemistry, no test substance-related changes were present at macroscopy. Histopathology did not reveal adverse effects in exposed animals. There were no test substance related neoplastic lesions in males or females. As the observed adverse effects in males on body weight gain were not expected to influence their ability to reproduce and were considered to be related to chronic exposure instead of in utero exposure, this was not included in the paternal NOAEL. Based on these considerations, the parental, reproduction and developmental NOAEL was found to be 2.0% (corresponding to appr. 1117 mg/kg bw/day for males and for females 1315 mg/kg bw/day). This result is read across to PR63:1.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 117 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The available study was considered to be reliable (guideline study with acceptable restrictions, Klimisch 2).
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

Description of key information

Based on the results of a chronic feeding study with a substance analogue, which included exposure of two generations, the parental, reproduction and developmental NOAEL was found to be 2.0%, which correlates to appr. 1117 mg/kg bw/day for males and for females 1315 mg/kg bw/day. This reasult is read across to PR63:1.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
The justification to read across the data is attached in Section 13.
Reason / purpose for cross-reference:
read-across source
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Orange coloration of hair, exposed skin, feet, tails, urine and/or faeces was observed for all exposed rats in a dose-related manner. No other changes in general behaviour and appearance considered to be related to the test substance were seen.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Three control rats (2 males (weeks 3 and 12) and 1 female (week 11)), 3 rats dosed at 0.05% (3 females, weeks 1, 9 and 18) and one male dosed at 0.3% (week 18) died during the study. In absence of a dose-relationship, these mortalities were not considered to be related to the test substance.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Changes in body weights were similar for control and treated rats.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food consumption was similar for control and treated rats.
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
The urine of rats at the 0.05% dosage level appeared to be slightly darker in color when compared to the urine of control rats. The urine of rats at the 0.3% dosage level generally appared to be yelloworange in color, and the urine for rats dosed at 2.0% was yellow-dark orange. This effect was a direct effect of presence of the non-metabolized substance in the urine and considered non-adverse. No other differences were seen in the urinalysis values between control and treated rats.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not specified
Number of abortions:
not specified
Description (incidence and severity):
The fertility indices for females and males were 83% and 95% for the two control groups, and 93% for all three test substance groups.
Pre- and post-implantation loss:
not specified
Total litter losses by resorption:
not specified
Early or late resorptions:
not specified
Dead fetuses:
not examined
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
>= 2 other: %
Based on:
test mat.
Basis for effect level:
other: No adverse effects seen at highest dose tested.
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
No clinical effects were seen in the F1 rats before weaning. Changes in body weights of pups were similar for control and treated rats.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
Survival indices were similar for control and treated pups with all survival indices being at least 98%.
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
Survival indices were similar for control and treated pups with all survival indices being at least 98%.
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
not specified
Key result
Dose descriptor:
NOAEL
Effect level:
>= 2 other: %
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects seen at highest dose tested.
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Conclusions:
Based on the results of a chronic feeding study performed with D&C Red #6, which included exposure of two generations, the parental, reproduction and developmental NOAEL was found to be 2.0%, which correlates to appr. 1117 mg/kg bw/day for males and for females 1315 mg/kg bw/day. This result is read across to PR63:1.
Executive summary:

A chronic feeding study, covering two generations, was conducted with D&C Red #6. Sixty rats/sex were exposed to 0.05%, 0.3% or 2.0% of the test substance in feed. Two control groups were included. After 60 days, the rats were mated. From the litters, 70 rats/sex/ group were selected. After weaning at 21 days, these rats were exposed to 0.05%, 0.3% or 2.0% of the test substance in feed for a life-time (sacrifice males in week 95 and sacrifice females in week 126). Reproductive parameters were evaluated to determine fertility index, gestation anomalies and effects on parturition and lactation. Indices for live birth and survival to weaning were calculated. During the study, mortality, clinical signs, body weight, eyes and urine were monitored regularly. Hematologial and biochemical evaluations and urinalyses were conducted for 10 rats/ sex/group at 3, 6, 12, 18 and 21 (males) or 24 (females) months of study. Feed intake was monitored for each individual rat. An interim sacrifice and necropsy of 10 rats/sex/group was conducted following 12 months of test substance exposure. After sacrifice, gross necropsy was performed, major organs were weighed and histopathogy was done.

All exposed rats showed direct effects of the test substance: coloured fur, urine and feces. The in utero exposure did not result in adverse effects on body weights of maternal animals or pups, food consumption, ophthalmoscopic examinations, fertility or gestation and lactation indices. For the postweaning part, males at the high dose group showed significant decrease in body weight gain compared to controls, with similar feed intake for exposed and control rats. No changes considered to be related to test substance exposure were observed during ophthalmoscopy. No adverse effects were seen on hematology and biochemistry, no test substance-related changes were present at macroscopy. Histopathology did not reveal adverse effects in exposed animals. There were no test substance related neoplastic lesions in males or females. As the observed adverse effects in males on body weight gain were not expected to influence their ability to reproduce and were considered to be related to chronic exposure instead of in utero exposure, this was not included in the paternal NOAEL. Based on these considerations, the parental, reproduction and developmental NOAEL was found to be 2.0% (corresponding to appr. 1117 mg/kg bw/day for males and for females 1315 mg/kg bw/day). This result is read across to PR63:1.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 117 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The available study was considered to be reliable (guideline study with acceptable restrictions, Klimisch 2).
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on the available data, PR63:1 is not classified for effects on reproduction and development according to Regulation (EC) 1272/2008.

Additional information