Registration Dossier

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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

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

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

Toxicity to reproduction:

Based on read-across data, the target chemical is not suspected to be toxic to reproductive performance in rats. NOAEL for reproductive toxicity in male and female rats is considered ≥100 mg/kg bw/day.


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:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Weight of evidence approach based on the available data of read-across chemicals.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Principles of method if other than guideline:
Study 2: Equivalent or similar to OECD TG 421
Study 3: The chemical was tested for reproductive toxicity in two trials. In trial one, the chemical was given to 5 male and 10 female weanling rats per dose level at 0, 1000 and 5000 ppm for 60 days before mating and thereafter until all pups were weaned. In trial two, the chemical was given to 4 males and 8 to 9 female ninety-day-old rats per dose level at 0, 1000 and 5000 ppm for 11 days before mating and thereafter until all pups were weaned.
Species:
rat
Strain:
other: Study 2: Sprague-Dawley. Study 3: Strain not specified.
Sex:
male/female
Details on test animals or test system and environmental conditions:
Study 2: The average body weights of male and female rats at the time of administration were 386 and 239 grams, respectively. The animals were placed individually in stainless steel write mesh cages (temperature 22 +/- 3 degree C; humidity of 55 +/-10%; 12/12 hour light/dark cycle). Nesting material was provided at day 0 of pregnancy. Water and food were available ad lib.
Study 3: No details.
Route of administration:
other: Study 2: oral: gavage; Study 3: oral: feed
Vehicle:
other: Study 2: Aqueous solution (1% methylcellulose). Study 3: Feed
Details on exposure:
Study 3: The chemical was tested for reproductive toxicity in two trials. In trial one, the chemical was given to 5 male and 10 female weanling rats per dose level at 0, 1000 and 5000 ppm for 60 days before mating and thereafter until all pups were weaned. In trial two, the chemical was given to 4 males and 8 to 9 female ninety-day-old rats per dose level at 0, 1000 and 5000 ppm for 11 days before mating and thereafter until all pups were weaned.
Details on mating procedure:
Study 2: No details.

Study 3: Ten weanling female and five male rats were placed on control diet for 60 days, and subsequently mated, one male to two females.
Analytical verification of doses or concentrations:
yes
Remarks:
Study 2: Yes. Study 3: Not specified.
Duration of treatment / exposure:
Study 2: For male rats, the chemical was given two weeks before mating and thereafter for a total of 42 days of dosing. For female rats, the chemical was given two weeks before mating and thereafter until day 4 after delivery, for a total of 42-56 days of dosing.

Study 3: Up to 60 days.
Frequency of treatment:
Study 2: Once Daily
Study 3: Daily by diet
Remarks:
Study 2: 0 (vehicle control), 6, 25 and 100 mg/kg bw/day.
Study 3: 0 (plain diet), 1000 and 5000 ppm.
No. of animals per sex per dose:
Study 2: 12
Study 3: Trial 1: 5 male rats per dose level and 10 female rats per dose level. Trial 2: 4 male rats per dose level and 8-9 female rats per dose level.
Control animals:
yes, concurrent vehicle
yes, plain diet
Parental animals: Observations and examinations:
Study 2: The animals were examined for mortality and clinical signs twice per day. The body weight and food intake of each male rat were measured weekly. For female rats, the body weight and food intake of each animal were measured weekly before mating; on day 1, 7, 14, 20 of gestation; and on day 0 and 4 of lactation. Female rats were examined for oestrous cycle length, number of female rats with successful copulation, paring days until copulation, number of pregnant female rats, fertility index, number of corpora lutea, number of implantation sites, implantation index, number of female rats with parturition, gestation length, gestation index and number of female rats with live pups at day 4.

Study 3: The number of females delivering pups
Oestrous cyclicity (parental animals):
Study 2: Yes
Study 3: Not examined
Sperm parameters (parental animals):
Study 2: Morphological evaluation of the spermatogenesis was performed post-mortem.
Study 3: Not examined
Litter observations:
Study 2: Specific observations for the developmental phase of the study included number of pups born, delivery index, number of pups alive at day 0 of lactation, live birth index, sex ratio, number of pups alive on day 4 of lactation, viability index, and body weight of live pups at day 0 and 4 of lactation.
Study 3: The total number of pups and the size of the litters.
Postmortem examinations (parental animals):
Study 2: All adult male and female rats were sacrificed after treatment for gross pathology, organ weight determinations and histopathology, which included a morphological evaluation of the spermatogenesis in the male rats.
Study 3: Not performed
Postmortem examinations (offspring):
Study 2: All pups were examined externally for malformations and internally for visceral variations/malformations.
Study 3: Not performed
Statistics:
Study 2: Parametric data: For multiple comparisons, Bartlett's variance test, Dunnett's test. Non-parametric data: Kruskal Wallis. Categorical data: Fischer test. Histopathological data: Mann-Whitney.
Study 3: Not specified.
Reproductive indices:
Study 2: Fertility index, implantation index, gestation index, and delivery index.
Study 3: No indices
Offspring viability indices:
Study 2: Live birth index and viability index.
Study 3: No indices
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Study 2: Clinical findings included excessive salivation in male and female rats treated at 100 mg/kg.
Study 3: Not examined
Mortality:
no mortality observed
Description (incidence):
Study 2 and 3: No mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Study 2: Male rats treated at 100 mg/kg showed significantly lower body weights on day 7, 14 and 28 of dosing (mean 8.1% lower) and decreased body weight gain between day 1 and 42 of dosing (by 16.4%) when compared to the control group. Female rats treated at 100 mg/kg showed lower body weights at day 14 and 20 of gestation (mean, 9.5%), markedly decreased body weight gain between day 0 to
20 of gestation (by 22.8%), and lower body weights at day 0 and 4 of lactation (mean, 11.3%) when compared to the control group.

Study 3: The male and female rats in trial one and two were not weighed during the study period. However, based on data from the same study in which male and female rats were treated at the dietary concentrations of 0, 10, 50, 100, 500, 1000, 5000 and 10000 ppm for two years; both male and female rats treated at ≥5000 ppm showed significant growth inhibition compared to the concurrent control groups. This effect was accompanied by reduced food intake and was therefore considered to be due to poor palatability of the feeding material.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Study 2: Deviations in food intake in male rats were minor and occurred sporadically. In female rats, marked decreases in food intake were observed in the group of animals treated at 100 mg/kg on day 0 of lactation (56% lower) and day 3 of lactation (40% lower) when compared to the control group.

Study 3: The male and female rats in trial one and two were not observed for food intake. However, based on data from the same study in which male and female rats were treated at the dietary concentrations of 0, 10, 50, 100, 500, 1000, 5000 and 10000 ppm for two years; reduced food intake was evident at 5000 ppm. This effect was attributed to poor palatability of the feeding material.
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:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Study 2: Males: Slight hepatocellular hypertrophy at 100 mg/kg, a dose-dependent increase of hyaline droplets in the proximal tubular epithelium at ≥25 mg/kg and an increased tendency of tubule basophilia (indicative of renal toxicity) at 100 mg/kg. Microscopic examination of the male reproductive organs showed no treatment-related effects. Females: Slight hepatocellular hypertrophy at 100 mg/kg. Microscopic examination of the female reproductive organs showed no treatment-related effects.

Study 3: Not examined.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
Study 2: No effects observed.
Study 3: Not examined.
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
Study 2: No effects observed.
Study 3: Not examined.
Reproductive function: sperm measures:
effects observed, non-treatment-related
Description (incidence and severity):
Study 2: The results from the spermatogenesis cycle test showed no significant effects attributed to the test chemical.
Study 3: Not examined.
Reproductive performance:
no effects observed
Description (incidence and severity):
Study 2: There were no significant effects on oestrous cycle length, number of female rats with successful copulation, paring days until copulation, number of pregnant female rats, fertility index, number of corpora lutea, number of implantation sites, implantation index, number of female rats with parturition,gestation length, gestation index, or the number of female rats with live pups at day 4.

Study 3: No significant effects were reported on the number of females delivering, the total number of pups, or the size of the litters.
Dose descriptor:
NOAEL
Effect level:
>= 25 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
organ weights and organ / body weight ratios
histopathology: non-neoplastic
histopathology: neoplastic
reproductive function (oestrous cycle)
reproductive function (sperm measures)
reproductive performance
Remarks on result:
other:
Remarks:
Study 2
Dose descriptor:
LOAEL
Effect level:
<= 100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
body weight and weight gain
food consumption and compound intake
Remarks on result:
other:
Remarks:
Study 2
Dose descriptor:
NOAEL
Effect level:
>= 100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
mortality
body weight and weight gain
food consumption and compound intake
reproductive performance
Remarks on result:
other:
Remarks:
Study 3
Clinical signs:
not examined
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
Study 2: The results from the developmental phase of the study showed a marked decrease in the number of live pups at day 0 and 4 of lactation at 100 mg/kg compared to the control group. This effect was accompanied by a marked decrease in the viability index at 100 mg/kg (mean viability, 28.0%) compared to the control group (mean viability, 97.5%).
Study 3: Not examined.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Study 2: The mean body weights of live pups were also significantly lower on day 0 and 4 of lactation at 100
mg/kg compared to the control group.
Study 3: Not examined.
Food consumption and compound intake (if feeding study):
not examined
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
Sexual maturation:
not examined
Anogenital distance (AGD):
not examined
Nipple retention in male pups:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
Study 2: Gross examination revealed a low incidence of malformations at 0 mg/kg (0.6%) and 6 mg/kg (0.6%). No gross malformations were observed at 25 or 100 mg/kg. No visceral malformations were observed at any dose level. The incidences of visceral variants, which included persistent left umbilical artery and dilatation of renal pelvis, did not differ significantly between the groups.
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 25 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
mortality
body weight and weight gain
other: gross and visceral malformations/variations.
Remarks on result:
other: Study 2
Dose descriptor:
LOAEL
Generation:
F1
Effect level:
<= 100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
mortality
body weight and weight gain
Remarks on result:
other:
Remarks:
Study 2
Reproductive effects observed:
no
Conclusions:
Based on read-across data, the target chemical is not suspected to be toxic to reproductive performance in rats. NOAEL for reproductive toxicity in male and female rats is considered ≥100 mg/kg bw/day.
Executive summary:

Data for read-across chemicals were evaluated to determine if the target chemical can be suspected, or not be suspected, to be toxic to reproduction in humans.

Study 2:

The chemical was given by oral gavage to 12 rats per sex per dose level at 0, 6, 25 and 100 mg/kg bw/day. For male rats, the chemical was given two weeks before mating and thereafter for a total of 42 days of dosing. For female rats, the chemical was given two weeks before mating and thereafter until day 4 after delivery, for a total of 42-56 days of dosing. Dose levels were selected based on the results from a dose range-finding study in which male and female rats were treated by oral gavage at 0, 50, 100, 200 and 400 mg/kg bw/day for a total of 14 days. The animals were examined for mortality and clinical signs twice per day. The body weight and food intake of each male rat were measured weekly. For female rats, the body weight and food intake of each animal were measured weekly before mating; on day 1, 7, 14, 20 of gestation; and on day 0 and 4 of lactation. Female rats were examined for oestrous cycle length, number of female rats with successful copulation, paring days until copulation, number of pregnant female rats, fertility index, number of corpora lutea, number of implantation sites, implantation index, number of female rats with parturition, gestation length, gestation index and number of female rats with live pups at day 4. Specific observations for the developmental phase of the study included number of pups born, delivery index, number of pups alive at day 0 of lactation, live birth index, sex ratio, number of pups alive on day 4 of lactation, viability index, and body weight of live pups at day 0 and 4 of lactation. All adult male and female rats were sacrificed after treatment for gross pathology, organ weight determinations and histopathology, which included a morphological evaluation of the spermatogenesis in the male rats. All pups were examined externally for malformations and internally for visceral variations/malformations. No mortality was observed during the dosing period. Clinical findings included excessive salivation in male and female rats treated at 100 mg/kg. Male rats treated at 100 mg/kg showed significantly lower body weights on day 7, 14 and 28 of dosing (mean 8.1% lower) and decreased body weight gain between day 1 and 42 of dosing (by 16.4%) when compared to the control group. Female rats treated at 100 mg/kg showed lower body weights at day 14 and 20 of gestation (mean, 9.5%), markedly decreased body weight gain between day 0 to 20 of gestation (by 22.8%), and lower body weights at day 0 and 4 of lactation (mean, 11.3%) when compared to the control group. Deviations in food intake in male rats were minor and occurred sporadically. In female rats, marked decreases in food intake were observed in the group of animals treated at 100 mg/kg on day 0 of lactation (56% lower) and day 3 of lactation (40% lower) when compared to the control group. There were no significant effects on oestrous cycle length, number of female rats with successful copulation, paring days until copulation, number of pregnant female rats, fertility index, number of corpora lutea, number of implantation sites, implantation index, number of female rats with parturition, gestation length, gestation index, or the number of female rats with live pups at day 4. At necropsy, male rats showed increased liver weights at ≥25 mg/kg, increased spleen weights at 100 mg/kg, decreased epididymides weights at 100 mg/kg and increased kidney weights at 100 mg/kg relative to the control data. These effects were accompanied by slight hepatocellular hypertrophy at 100 mg/kg, a dose-dependent increase of hyaline droplets in the proximal tubular epithelium at ≥25 mg/kg and an increased tendency of tubule basophilia (indicative of renal toxicity) at 100 mg/kg. Microscopic examination of the male reproductive organs showed no treatment-related effects. Furthermore, the results from the spermatogenesis cycle test showed no significant effects attributed to the test chemical. Female rats showed decreased thymus weights at ≥25 mg/kg, increased relative liver weights at ≥25 mg/kg and increased relative kidney weight at 100 mg/kg relative to the control data. These effects were accompanied by slight hepatocellular hypertrophy at 100 mg/kg. Microscopic examination of the female reproductive organs showed no treatment-related effects. The results from the developmental phase of the study showed a marked decrease in the number of live pups at day 0 and 4 of lactation at 100 mg/kg compared to the control group. This effect was accompanied by a marked decrease in the viability index at 100 mg/kg (mean viability, 28.0%) compared to the control group (mean viability, 97.5%). The mean body weights of live pups were also significantly lower on day 0 and 4 of lactation at 100 mg/kg compared to the control group. Gross examination revealed a low incidence of malformations at 0 mg/kg (0.6%) and 6 mg/kg (0.6%). No gross malformations were observed at 25 or 100 mg/kg. No visceral malformations were observed at any dose level. The incidences of visceral variants, which included persistent left umbilical artery and dilatation of renal pelvis, did not differ significantly between the groups. NOAEL for systemic toxicity in male and female rats was found at ≥25 mg/kg bw/day. NOAEL for toxicity to reproduction in both male and female rats was found at ≥100 mg/kg bw/day.The observed effects on development at 100 mg/kg bw/day were not considered to be solely non-specific, secondary to maternal toxicity.

Study 3:

The chemical was tested for reproductive toxicity in two trials. In trial one, the chemical was given to 5 male and 10 female weanling rats per dose level at 0, 1000 and 5000 ppm for 60 days before mating and thereafter until all pups were weaned. In trial two, the chemical was given to 4 males and 8 to 9 female ninety-day-old rats per dose level at 0, 1000 and 5000 ppm for 11 days before mating and thereafter until all pups were weaned. The male and female rats in trial one and two were not weighed during the study period. However, based on data from the same study in which male and female rats were treated at the dietary concentrations of 0, 10, 50, 100, 500, 1000, 5000 and 10000 ppm for two years; both male and female rats treated at ≥5000 ppm showed significant growth inhibition compared to the concurrent control groups. This effect was accompanied by reduced food intake and was therefore considered to be due to poor palatability of the feeding material. In the reproductive phases of trial one and two, no significant effects were reported on the number of females delivering, the total number of pups, or the size of the litters. NOAEL for reproductive toxicity in male and female rats was found at 5000 ppm (equivalent to approx 250 mg/kg bw/day). The study was limited in scope and lacked modern endpoint-parameters for systemic and reproductive toxicity.

Based on read-across data, the target chemical is not suspected to be toxic to reproductive performance in rats.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Data is from Klimisch 2 source.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Reproductive Toxicity Study:

Data for read-across chemicals were evaluated to determine if the target chemical can be suspected, or not be suspected, to be toxic to reproduction in humans.

Study 2:

The chemical was given by oral gavage to 12 rats per sex per dose level at 0, 6, 25 and 100 mg/kg bw/day. For male rats, the chemical was given two weeks before mating and thereafter for a total of 42 days of dosing. For female rats, the chemical was given two weeks before mating and thereafter until day 4 after delivery, for a total of 42-56 days of dosing. Dose levels were selected based on the results from a dose range-finding study in which male and female rats were treated by oral gavage at 0, 50, 100, 200 and 400 mg/kg bw/day for a total of 14 days. The animals were examined for mortality and clinical signs twice per day. The body weight and food intake of each male rat were measured weekly. For female rats, the body weight and food intake of each animal were measured weekly before mating; on day 1, 7, 14, 20 of gestation; and on day 0 and 4 of lactation. Female rats were examined for oestrous cycle length, number of female rats with successful copulation, paring days until copulation, number of pregnant female rats, fertility index, number of corpora lutea, number of implantation sites, implantation index, number of female rats with parturition, gestation length, gestation index and number of female rats with live pups at day 4. Specific observations for the developmental phase of the study included number of pups born, delivery index, number of pups alive at day 0 of lactation, live birth index, sex ratio, number of pups alive on day 4 of lactation, viability index, and body weight of live pups at day 0 and 4 of lactation. All adult male and female rats were sacrificed after treatment for gross pathology, organ weight determinations and histopathology, which included a morphological evaluation of the spermatogenesis in the male rats. All pups were examined externally for malformations and internally for visceral variations/malformations. No mortality was observed during the dosing period. Clinical findings included excessive salivation in male and female rats treated at 100 mg/kg. Male rats treated at 100 mg/kg showed significantly lower body weights on day 7, 14 and 28 of dosing (mean 8.1% lower) and decreased body weight gain between day 1 and 42 of dosing (by 16.4%) when compared to the control group. Female rats treated at 100 mg/kg showed lower body weights at day 14 and 20 of gestation (mean, 9.5%), markedly decreased body weight gain between day 0 to 20 of gestation (by 22.8%), and lower body weights at day 0 and 4 of lactation (mean, 11.3%) when compared to the control group. Deviations in food intake in male rats were minor and occurred sporadically. In female rats, marked decreases in food intake were observed in the group of animals treated at 100 mg/kg on day 0 of lactation (56% lower) and day 3 of lactation (40% lower) when compared to the control group. There were no significant effects on oestrous cycle length, number of female rats with successful copulation, paring days until copulation, number of pregnant female rats, fertility index, number of corpora lutea, number of implantation sites, implantation index, number of female rats with parturition, gestation length, gestation index, or the number of female rats with live pups at day 4. At necropsy, male rats showed increased liver weights at ≥25 mg/kg, increased spleen weights at 100 mg/kg, decreased epididymides weights at 100 mg/kg and increased kidney weights at 100 mg/kg relative to the control data. These effects were accompanied by slight hepatocellular hypertrophy at 100 mg/kg, a dose-dependent increase of hyaline droplets in the proximal tubular epithelium at ≥25 mg/kg and an increased tendency of tubule basophilia (indicative of renal toxicity) at 100 mg/kg. Microscopic examination of the male reproductive organs showed no treatment-related effects. Furthermore, the results from the spermatogenesis cycle test showed no significant effects attributed to the test chemical. Female rats showed decreased thymus weights at ≥25 mg/kg, increased relative liver weights at ≥25 mg/kg and increased relative kidney weight at 100 mg/kg relative to the control data. These effects were accompanied by slight hepatocellular hypertrophy at 100 mg/kg. Microscopic examination of the female reproductive organs showed no treatment-related effects. The results from the developmental phase of the study showed a marked decrease in the number of live pups at day 0 and 4 of lactation at 100 mg/kg compared to the control group. This effect was accompanied by a marked decrease in the viability index at 100 mg/kg (mean viability, 28.0%) compared to the control group (mean viability, 97.5%). The mean body weights of live pups were also significantly lower on day 0 and 4 of lactation at 100 mg/kg compared to the control group. Gross examination revealed a low incidence of malformations at 0 mg/kg (0.6%) and 6 mg/kg (0.6%). No gross malformations were observed at 25 or 100 mg/kg. No visceral malformations were observed at any dose level. The incidences of visceral variants, which included persistent left umbilical artery and dilatation of renal pelvis, did not differ significantly between the groups. NOAEL for systemic toxicity in male and female rats was found at ≥25 mg/kg bw/day. NOAEL for toxicity to reproduction in both male and female rats was found at ≥100 mg/kg bw/day.The observed effects on development at 100 mg/kg bw/day were not considered to be solely non-specific, secondary to maternal toxicity.

Study 3:

The chemical was tested for reproductive toxicity in two trials. In trial one, the chemical was given to 5 male and 10 female weanling rats per dose level at 0, 1000 and 5000 ppm for 60 days before mating and thereafter until all pups were weaned. In trial two, the chemical was given to 4 males and 8 to 9 female ninety-day-old rats per dose level at 0, 1000 and 5000 ppm for 11 days before mating and thereafter until all pups were weaned. The male and female rats in trial one and two were not weighed during the study period. However, based on data from the same study in which male and female rats were treated at the dietary concentrations of 0, 10, 50, 100, 500, 1000, 5000 and 10000 ppm for two years; both male and female rats treated at ≥5000 ppm showed significant growth inhibition compared to the concurrent control groups. This effect was accompanied by reduced food intake and was therefore considered to be due to poor palatability of the feeding material. In the reproductive phases of trial one and two, no significant effects were reported on the number of females delivering, the total number of pups, or the size of the litters. NOAEL for reproductive toxicity in male and female rats was found at 5000 ppm (equivalent to approx 250 mg/kg bw/day). The study was limited in scope and lacked modern endpoint-parameters for systemic and reproductive toxicity.

Based on read-across data, the target chemical is not suspected to be toxic to reproductive performance in rats. NOAEL for reproductive toxicity in male and female rats is considered ≥100 mg/kg bw/day.

Effects on developmental toxicity

Description of key information

Developmental toxicity

Based on read-across data, the target chemical is suspected to be toxic to development in humans. NOAEL for systemic and developmental toxicity is considered at 25 mg/kg bw/day in pregnant rats by conservative approach.

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data for the target chemical is summarized based on the data from various test chemicals.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Principles of method if other than guideline:
Study 2 was equivalent or similar OECD 421. Study 3 was an OECD 414 study with acceptable deviations.
Species:
rat
Strain:
Sprague-Dawley
Remarks:
Study 2 and 3: Sprague-Dawley
Details on test animals or test system and environmental conditions:
Study 2: Nesting material was provided at day 0 of pregnancy. Water and food were available ad lib.
Study 3: Rats were obtained from Charles River Breeding Laboratories. Females were sexually matured and 50-90 dyas of age at initiation of mating. Males were used only for mating. Animals were housed individually except during mating in stainless steel cages with wire mesh floors. Food and water were available ad lib. Temperature and relative humidity were maintained within specified limits to the maximum extent possible. 12 hour light/dark cycles were used.
Route of administration:
oral: gavage
Vehicle:
other: Study 2:Aqueous solution (1% methylcellulose). Study 3: corn oil
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Study 2: No details
Study 3: Analyses of homogeneity, stability and recovery samples for the dosing solutions all fell within a range of +/- 10% of the nominal concentration. Actual analytical results for all samples collected were no less than 99.2% nor greater than 106%.
Details on mating procedure:
Study 2: No details
Study 3: Females selected for mating were placed with male rats nightly in a 1:1 ratio. Vaginal smears were taken early in the morning and females were considered to have mated when sperm and/or a vaginal plug was observed. Day on which evidence of mating was observed was defined as Day 0 of gestation.
Duration of treatment / exposure:
Study 2: For male rats, the chemical was given two weeks before mating and thereafter for a total of 42 days of dosing. For female rats, the chemical was given two weeks before mating and thereafter until day 4 after delivery, for a total of 42-56 days of dosing.
Study 3: Gestation day 6 to 15.
Frequency of treatment:
Study 2 and 3: Once per day
Duration of test:
Study 3: The pregnant rats were sacrificed at Day 20 of gestation.
Remarks:
0 (vehicle), 6, 25 and 100 mg/kg bw/day (Study 2)
Remarks:
0 (vehicle), 50, 200 and 500 mg/kg bw/day (Study 3)
No. of animals per sex per dose:
Study 2: 12
Study 3: 24 mated female rats per dose level.
Control animals:
yes, concurrent vehicle
Maternal examinations:
Study 2: For female rats, the body weight and food intake of each animal were measured weekly before mating; on day 1, 7, 14, 20 of gestation; and on day 0 and 4 of lactation. Female rats were examined for oestrous cycle length, number of female rats with successful copulation, paring days until copulation, number of pregnant female rats, number of female rats with parturition, gestation length,and number of female rats with live pups at day 4. All female rats were sacrificed after treatment for gross pathology, organ weight determinations and histopathology.

Study 3: The animals were observed twice per day for signs of toxicity and mortality. Detialed physical examinations were performed on Days 0, 6, 10, 12, 15 and 20 of gestation. Body weights were recored on Days 0, 6, 10, 12, 15 and 20 of gestation. Day 20 body weights were presented as actual and corrected (the actual Day 20 body weight minus the weight of the gravid uterus). Food intake was recorded for the following intervals during gestation: 0-6, 6-10, 10-15 and 15-20. Each mated female rat was given a complete postmortem examination.
Ovaries and uterine content:
Study 2: Number of corpora lutea and number of implantation sites were recorded.
Study 3: The intact uterus was removed from the abdominal cavity, weighed and the number and location of the following were recorded for each uterine horn: live fetuses, dead fetuses, late resorptions, early resorptions, implantation sites. The ovaries were dissected and evaluated for the presence and number of corpora lutera. When no uterine implants were visible, the uterus was stained with ammonium sulfide. When no foci were visible after staining, the female was considered non-pregnant.
Fetal examinations:
Study 2: Specific observations for the developmental phase of the study included number of pups born, delivery index, number of pups alive at day 0 of lactation, live birth index, sex ratio, number of pups alive on day 4 of lactation, viability index, and body weight of live pups at day 0 and 4 of lactation. All pups were examined externally for malformations and internally for visceral variations/malformations.

Study 3: All fetuses were examined grossly for external malformations/variations. Each fetus was then weighed and sexed. One-half of the fetuses in each litter were evaluated for visceral malformations/variations. The remaining fetuses in each litter were examined for skeletal malformations/variations.
Statistics:
Study 2: No details
Study 3: The following statistical methods were used in the study: Bartlett's test, one way ANOVA, Dunnett's test, Kruskal-Wallis test, Dunn's summed rank test, standard regression techniques (trend analysis of parametric data), Jonckheere's test (trend analysis of non-parametric data), standard chi-square analysis, 2x2 Fisher Exact test, and Armitage's test for linear trend.
Indices:
Study 2:
Dams: Fertility index, implantation index and gestation index.
Offspring: Live birth index and viability index.

Study 3:
No indices
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Study 2: Excessive salivation at 100 mg/kg.
Study 3: Excessive salivation, staining of the skin/fur in the anogenital area and alopecia were all seen with increased incidences at ≥200 mg/kg
Mortality:
mortality observed, treatment-related
Description (incidence):
Study 2: No mortality observed
Study 3: No mortality was observed at 0 or 50 mg/kg. One female died at 200 mg/kg due to gavage error. At 500 mg/kg, two deaths were observed without evidence of gavage error.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Study 2: Female rats treated at 100 mg/kg showed lower body weights at day 14 and 20 of gestation (mean, 9.5%), markedly decreased body weight gain between day 0 to 20 of gestation (by 22.8%), and lower body weights at day 0 and 4 of lactation (mean, 11.3%) when compared to the control group.

Study 3: The group of female rats treated at 500 mg/kg showed a slight but statistically secured decrease in mean body weight at gestations day 15 compared to the control group. Mean body weight gains during the treatment period were significantly lower at 200 mg/kg (-19.8%) and at 500 mg/kg (-44.2%) when compared to the control group. Likewise, mean weight gains from gestation day 6 to 20 using the corrected day 20 body weights were significantly lower at 200 mg/kg (-21.1%) and at 500 mg/kg (-36.4%) compared to the control group.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Study 2: In female rats, marked decreases in food intake were observed in the group of animals treated at 100 mg/kg on day 0 of lactation (56% lower) and day 3 of lactation (40% lower) when compared to the control group.

Study 3: Reduced food intake was observed at ≥200 mg/kg.
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:
effects observed, treatment-related
Description (incidence and severity):
Study 2: Female rats showed decreased thymus weights at ≥25 mg/kg, increased relative liver weights at ≥25 mg/kg and increased relative kidney weight at 100 mg/kg relative to the control data. These effects were accompanied by slight hepatocellular hypertrophy at 100 mg/kg.

Study 3: Not examined
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Study 2: Not specified

Study 3: Hair loss was evident in a number of animals in different anatomical sites with increased incidence at 500 mg/kg. Other postmortem findings observed grossly occured sporadically and were not considered to be related to the test material.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Females: Slight hepatocellular hypertrophy at 100 mg/kg. Microscopic examination of the female reproductive organs showed no treatment-related effects.
Histopathological findings: neoplastic:
no effects observed
Number of abortions:
no effects observed
Description (incidence and severity):
Study 2 and 3: No abortions observed
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
Study 2: No treatment-related effects on the number of implantation sites were observed. Implantation index (i.e. the number of implantation sites divided by the number of corpora lutea) was also unaffected by treatment.

Study 3: The mean number of uterine implantations per pregnant female rat was unaffected by treatment. The mean pre-implantation loss index and mean resorption/implantation ratio were also unaffected by treatment.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
Study 2: Not specified

Study 3: The incidence of females witlh resorptions among their uterine implants was unaffected by treatment.
Early or late resorptions:
no effects observed
Description (incidence and severity):
Study 2: Not specified

Study 3: The mean number of resorptions per pregnant female rat were unaffected by treatment.
Dead fetuses:
no effects observed
Description (incidence and severity):
Study 2: Not specified

Study 3: The mean number of viable fetuses per pregnant rat was unaffected by treatment.
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Study 2: No treatment-related effects on gestation length were observed.

Study 3: Not examined
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
Study 2: No treatment-related effects on the number of pregnant female rats were observed.

Study 3: Pregnancy rates were 91.7, 100, 91.7 and 100% at 0, 50, 200 and 500 mg/kg bw/day, thus no treatment-related effect was observed.
Other effects:
no effects observed
Description (incidence and severity):
Study 2: There were no significant effects on oestrous cycle length, number of female rats with successful copulation, paring days until copulation, fertility index, number of corpora lutea, number of female rats with parturition, gestation index, or delivery index.

Study 3: The mean number of corpora lutea per pregnant female rat was unaffected by treatment.
Dose descriptor:
LOAEL
Effect level:
<= 100 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
clinical signs
food consumption and compound intake
Remarks on result:
other:
Remarks:
Study 2
Dose descriptor:
NOAEL
Effect level:
>= 25 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
changes in pregnancy duration
clinical signs
effects on pregnancy duration
food consumption and compound intake
histopathology: neoplastic
histopathology: non-neoplastic
mortality
number of abortions
organ weights and organ / body weight ratios
pre and post implantation loss
Remarks on result:
other:
Remarks:
Study 2
Dose descriptor:
LOAEL
Effect level:
<= 200 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
clinical signs
food consumption and compound intake
gross pathology
Remarks on result:
other:
Remarks:
Study 3
Dose descriptor:
NOAEL
Effect level:
>= 50 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
changes in number of pregnant
clinical signs
dead fetuses
early or late resorptions
food consumption and compound intake
gross pathology
maternal abnormalities
mortality
number of abortions
pre and post implantation loss
total litter losses by resorption
other: mean number of corpora lutea per pregnant female rat
Remarks on result:
other:
Remarks:
Study 3. NOAEL for all endpoints
Dose descriptor:
NOAEL
Effect level:
>= 500 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
changes in number of pregnant
dead fetuses
early or late resorptions
maternal abnormalities
number of abortions
pre and post implantation loss
total litter losses by resorption
other: mean number of corpora lutea per pergnant female rat
Remarks on result:
other:
Remarks:
Study 3. NOAEL for maternal developmental toxicity
Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Study 2: The mean body weights of live pups were significantly lower on day 0 and 4 of lactation at 100 mg/kg compared to the control group. The results were as follows:
For male pups at day 0: Mean weight 6.0 g at 100 mg/kg vs. mean weight 7.0 at 0 mg/kg.
For male pups at day 4: Mean weight 7.5 g at 100 mg/kg vs. mean weight 10.8 at 0 mg/kg.
For female pups at day 0: mean weight 5.7 g at 100 mg/kg vs mean weight 6.8 g at 0 mg/kg.
For female pups at day 4: mean weight 7.8 g at 100 mg/kg vs. mean weight 11.1 g at 0 mg/kg.

Study 3: No treatment-related effects observed.
Reduction in number of live offspring:
effects observed, treatment-related
Description (incidence and severity):
Study 2: The results from the developmental phase of the study showed a marked decrease in the number of live pups at day 0 and 4 of lactation at 100 mg/kg (mean, 7.6 pups at day 0 and mean, 3.1 pups at day 4) compared to the control group (mean, 14.5 pups at day 0 and mean, 14.1 pups at day 4).

Study 3: The mean number of viable fetuses per pregnant rat was unaffected by treatment.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
Study 2 and 3: No treatment-related effects observed.
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
Study 2: The mean number of pups born were 14.7, 14.0, 15.0 and 12.5 at 0, 6, 25 and 100 mg/kg, respectively. No statistically significant differences were observed.

Study 3: The mean numbers of fetuses per litter were 14.4, 14.7, 14.9 and 15.0 at 0, 50, 200 and 500 mg/kg bw/day, respectively.No statistically significant differences were observed.
Changes in postnatal survival:
effects observed, treatment-related
Description (incidence and severity):
Study 2: The viability index was significantly lower at 100 mg/kg (mean, 28.0%) compared to the control group (mean, 97.5%).

Study 3: Not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Study 2: Gross examination revealed a low incidence of malformations at 0 mg/kg (0.6%) and 6 mg/kg (0.6%). No gross malformations were observed at 25 or 100 mg/kg.

Study 3: There were no dose-dependent effects on the incidences of gross malformations or variations.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Study 2: Not examined

Study 3: There were no dose-dependent effects on the incidences of skeletal malformations or variations.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Study 2: No visceral malformations were observed at any dose level. The incidences of visceral variants, which included persistent left umbilical artery and dilatation of renal pelvis, did not differ significantly between the groups.

Study 3: There were no dose-dependent effects on the incidences of visceral malformations or variations.
Details on embryotoxic / teratogenic effects:
Study 3: The test material was concluded to be non-embryotoxic, non-fetotoxic and non-teratogenic in the rat.
Dose descriptor:
LOAEL
Effect level:
<= 100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
fetal/pup body weight changes
changes in postnatal survival
Remarks on result:
other:
Remarks:
Study 2
Dose descriptor:
NOAEL
Effect level:
>= 25 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
fetal/pup body weight changes
changes in litter size and weights
changes in postnatal survival
external malformations
visceral malformations
Remarks on result:
other:
Remarks:
Study 2
Dose descriptor:
NOAEL
Effect level:
>= 500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
fetal/pup body weight changes
changes in litter size and weights
external malformations
skeletal malformations
visceral malformations
Remarks on result:
other:
Remarks:
Study 3
Developmental effects observed:
yes
Lowest effective dose / conc.:
100 mg/kg bw/day (nominal)
Treatment related:
yes
Relation to maternal toxicity:
developmental effects occurring together with maternal toxicity effects, but not as a secondary non-specific consequence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
yes
Conclusions:
Based on read-across data, NOAEL for systemic and developmental toxicity for the target chemical is considered at 25 mg/kg bw/day in rats by conservative approach.
Executive summary:

Data for read-across chemicals were evaluated to determine if the target chemical can be suspected, or not be suspected, to be toxic to development in humans. The results of the studies are summarised below.

Study 2:

The chemical was given by oral gavage to 12 rats per sex per dose level at 0, 6, 25 and 100 mg/kg bw/day. For male rats, the chemical was given two weeks before mating and thereafter for a total of 42 days of dosing. For female rats, the chemical was given two weeks before mating and thereafter until day 4 after delivery, for a total of 42-56 days of dosing. Dose levels were selected based on the results from a dose range-finding study in which male and female rats were treated by oral gavage at 0, 50, 100, 200 and 400 mg/kg bw/day for a total of 14 days. The animals were examined for mortality and clinical signs twice per day. The body weight and food intake of each male rat were measured weekly. For female rats, the body weight and food intake of each animal were measured weekly before mating; on day 1, 7, 14, 20 of gestation; and on day 0 and 4 of lactation. Female rats were examined for oestrous cycle length, number of female rats with successful copulation, paring days until copulation, number of pregnant female rats, fertility index, number of corpora lutea, number of implantation sites, implantation index, number of female rats with parturition, gestation length, gestation index and number of female rats with live pups at day 4. Specific observations for the developmental phase of the study included number of pups born, delivery index, number of pups alive at day 0 of lactation, live birth index, sex ratio, number of pups alive on day 4 of lactation, viability index, and body weight of live pups at day 0 and 4 of lactation. All adult male and female rats were sacrificed after treatment for gross pathology, organ weight determinations and histopathology. All pups were examined externally for malformations and internally for visceral variations/malformations. No mortality was observed during the dosing period. Clinical findings included excessive salivation in male and female rats treated at 100 mg/kg. Male rats treated at 100 mg/kg showed significantly lower body weights on day 7, 14 and 28 of dosing (mean 8.1% lower) and decreased body weight gain between day 1 and 42 of dosing (by 16.4%) when compared to the control group. Female rats treated at 100 mg/kg showed lower body weights at day 14 and 20 of gestation (mean, 9.5%), markedly decreased body weight gain between day 0 to 20 of gestation (by 22.8%), and lower body weights at day 0 and 4 of lactation (mean, 11.3%) when compared to the control group. Deviations in food intake in male rats were minor and occurred sporadically. In female rats, marked decreases in food intake were observed in the group of animals treated at 100 mg/kg on day 0 of lactation (56% lower) and day 3 of lactation (40% lower) when compared to the control group. There were no significant effects on oestrous cycle length, number of female rats with successful copulation, paring days until copulation, number of pregnant female rats, fertility index, number of corpora lutea, number of implantation sites, implantation index, number of female rats with parturition, gestation length, gestation index, or the number of female rats with live pups at day 4. At necropsy, male rats showed increased liver weights at ≥25 mg/kg, increased spleen weights at 100 mg/kg, decreased epididymides weights at 100 mg/kg and increased kidney weights at 100 mg/kg relative to the control data. These effects were accompanied by slight hepatocellular hypertrophy at 100 mg/kg, a dose-dependent increase of hyaline droplets in the proximal tubular epithelium at ≥25 mg/kg and an increased tendency of tubule basophilia (indicative of renal toxicity) at 100 mg/kg. Microscopic examination of the male reproductive organs showed no treatment-related effects. Female rats showed decreased thymus weights at ≥25 mg/kg, increased relative liver weights at ≥25 mg/kg and increased relative kidney weight at 100 mg/kg relative to the control data. These effects were accompanied by slight hepatocellular hypertrophy at 100 mg/kg. Microscopic examination of the female reproductive organs showed no treatment-related effects. The results from the developmental phase of the study showed a marked decrease in the number of live pups at day 0 and 4 of lactation at 100 mg/kg compared to the control group. This effect was accompanied by a marked decrease in the viability index at 100 mg/kg (mean viability, 28.0%) compared to the control group (mean viability, 97.5%). The mean body weights of live pups were also significantly lower on day 0 and 4 of lactation at 100 mg/kg compared to the control group. Gross examination revealed a low incidence of malformations at 0 mg/kg (0.6%) and 6 mg/kg (0.6%). No gross malformations were observed at 25 or 100 mg/kg. No visceral malformations were observed at any dose level. The incidences of visceral variants, which included persistent left umbilical artery and dilatation of renal pelvis, did not differ significantly between the groups. NOAEL for systemic toxicity was found at ≥25 mg/kg bw/day.The observed effects on development at 100 mg/kg (i.e the observed effects on number of live offsprings, the viability index, and the weight of the pups) were not considered to be solely non-specific, secondary to maternal toxicity.

Study 3:

The test material was given to 24 mated female rats per dose level by oral gavage at 0, 50, 200 and 500 mg/kg bw/day from gestation day 6 to 15. No mortality was observed at 0 or 50 mg/kg. One female died at 200 mg/kg due to gavage error. At 500 mg/kg, two deaths were observed without evidence of gavage error. The group of female rats treated at 500 mg/kg showed a slight but statistically secured decrease in mean body weight at gestations day 15 compared to the control group. Mean body weight gains during the treatment period were significantly lower at 200 mg/kg (-19.8%) and at 500 mg/kg (-44.2%) when compared to the control group. Likewise, mean weight gains from gestation day 6 to 20 using the corrected day 20 body weights were significantly lower at 200 mg/kg (-21.1%) and at 500 mg/kg (-36.4%) compared to the control group. Reduced food intake was observed at ≥200 mg/kg. Excessive salivation, staining of the skin/fur in the anogenital area and alopecia were all seen with increased incidences at ≥200 mg/kg. Pregnancy rates were 91.7, 100, 91.7 and 100% at 0, 50, 200 and 500 mg/kg, respectively. No significant effects were observed on the number of corpora lutea, the number of implantations, the number of viable foetuses, the number of resorptions, the number of pre-implantation losses, or on the resorption/implantation ratio. Mean foetal weight and sex ratio were unaffected by treatment. There were no dose-dependent effects on the incidences of gross, visceral or skeletal malformations/variations. NOAEL for maternal systemic toxicity was established at 50 mg/kg bw/day. No adverse effects on development were reported at doses up to 500 mg/kg bw/day in the study. 

Based on read-across data, the target chemical is suspected to be toxic to development in humans. NOAEL for systemic and developmental toxicity is considered at 25 mg/kg bw/day in pregnant rats by conservative approach.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
25 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Data is from Klimisch 2 source.
Additional information

Data for read-across chemicals were evaluated to determine if the target chemical can be suspected, or not be suspected, to be toxic to development in humans. The results of the studies are summarised below.

Study 2:

The chemical was given by oral gavage to 12 rats per sex per dose level at 0, 6, 25 and 100 mg/kg bw/day. For male rats, the chemical was given two weeks before mating and thereafter for a total of 42 days of dosing. For female rats, the chemical was given two weeks before mating and thereafter until day 4 after delivery, for a total of 42-56 days of dosing. Dose levels were selected based on the results from a dose range-finding study in which male and female rats were treated by oral gavage at 0, 50, 100, 200 and 400 mg/kg bw/day for a total of 14 days. The animals were examined for mortality and clinical signs twice per day. The body weight and food intake of each male rat were measured weekly. For female rats, the body weight and food intake of each animal were measured weekly before mating; on day 1, 7, 14, 20 of gestation; and on day 0 and 4 of lactation. Female rats were examined for oestrous cycle length, number of female rats with successful copulation, paring days until copulation, number of pregnant female rats, fertility index, number of corpora lutea, number of implantation sites, implantation index, number of female rats with parturition, gestation length, gestation index and number of female rats with live pups at day 4. Specific observations for the developmental phase of the study included number of pups born, delivery index, number of pups alive at day 0 of lactation, live birth index, sex ratio, number of pups alive on day 4 of lactation, viability index, and body weight of live pups at day 0 and 4 of lactation. All adult male and female rats were sacrificed after treatment for gross pathology, organ weight determinations and histopathology. All pups were examined externally for malformations and internally for visceral variations/malformations. No mortality was observed during the dosing period. Clinical findings included excessive salivation in male and female rats treated at 100 mg/kg. Male rats treated at 100 mg/kg showed significantly lower body weights on day 7, 14 and 28 of dosing (mean 8.1% lower) and decreased body weight gain between day 1 and 42 of dosing (by 16.4%) when compared to the control group. Female rats treated at 100 mg/kg showed lower body weights at day 14 and 20 of gestation (mean, 9.5%), markedly decreased body weight gain between day 0 to 20 of gestation (by 22.8%), and lower body weights at day 0 and 4 of lactation (mean, 11.3%) when compared to the control group. Deviations in food intake in male rats were minor and occurred sporadically. In female rats, marked decreases in food intake were observed in the group of animals treated at 100 mg/kg on day 0 of lactation (56% lower) and day 3 of lactation (40% lower) when compared to the control group. There were no significant effects on oestrous cycle length, number of female rats with successful copulation, paring days until copulation, number of pregnant female rats, fertility index, number of corpora lutea, number of implantation sites, implantation index, number of female rats with parturition, gestation length, gestation index, or the number of female rats with live pups at day 4. At necropsy, male rats showed increased liver weights at ≥25 mg/kg, increased spleen weights at 100 mg/kg, decreased epididymides weights at 100 mg/kg and increased kidney weights at 100 mg/kg relative to the control data. These effects were accompanied by slight hepatocellular hypertrophy at 100 mg/kg, a dose-dependent increase of hyaline droplets in the proximal tubular epithelium at ≥25 mg/kg and an increased tendency of tubule basophilia (indicative of renal toxicity) at 100 mg/kg. Microscopic examination of the male reproductive organs showed no treatment-related effects. Female rats showed decreased thymus weights at ≥25 mg/kg, increased relative liver weights at ≥25 mg/kg and increased relative kidney weight at 100 mg/kg relative to the control data. These effects were accompanied by slight hepatocellular hypertrophy at 100 mg/kg. Microscopic examination of the female reproductive organs showed no treatment-related effects. The results from the developmental phase of the study showed a marked decrease in the number of live pups at day 0 and 4 of lactation at 100 mg/kg compared to the control group. This effect was accompanied by a marked decrease in the viability index at 100 mg/kg (mean viability, 28.0%) compared to the control group (mean viability, 97.5%). The mean body weights of live pups were also significantly lower on day 0 and 4 of lactation at 100 mg/kg compared to the control group. Gross examination revealed a low incidence of malformations at 0 mg/kg (0.6%) and 6 mg/kg (0.6%). No gross malformations were observed at 25 or 100 mg/kg. No visceral malformations were observed at any dose level. The incidences of visceral variants, which included persistent left umbilical artery and dilatation of renal pelvis, did not differ significantly between the groups. NOAEL for systemic toxicity was found at ≥25 mg/kg bw/day.The observed effects on development at 100 mg/kg (i.e the observed effects on number of live offsprings, the viability index, and the weight of the pups) were not considered to be solely non-specific, secondary to maternal toxicity.

Study 3:

The test material was given to 24 mated female rats per dose level by oral gavage at 0, 50, 200 and 500 mg/kg bw/day from gestation day 6 to 15. No mortality was observed at 0 or 50 mg/kg. One female died at 200 mg/kg due to gavage error. At 500 mg/kg, two deaths were observed without evidence of gavage error. The group of female rats treated at 500 mg/kg showed a slight but statistically secured decrease in mean body weight at gestations day 15 compared to the control group. Mean body weight gains during the treatment period were significantly lower at 200 mg/kg (-19.8%) and at 500 mg/kg (-44.2%) when compared to the control group. Likewise, mean weight gains from gestation day 6 to 20 using the corrected day 20 body weights were significantly lower at 200 mg/kg (-21.1%) and at 500 mg/kg (-36.4%) compared to the control group. Reduced food intake was observed at ≥200 mg/kg. Excessive salivation, staining of the skin/fur in the anogenital area and alopecia were all seen with increased incidences at ≥200 mg/kg. Pregnancy rates were 91.7, 100, 91.7 and 100% at 0, 50, 200 and 500 mg/kg, respectively. No significant effects were observed on the number of corpora lutea, the number of implantations, the number of viable foetuses, the number of resorptions, the number of pre-implantation losses, or on the resorption/implantation ratio. Mean foetal weight and sex ratio were unaffected by treatment. There were no dose-dependent effects on the incidences of gross, visceral or skeletal malformations/variations. NOAEL for maternal systemic toxicity was established at 50 mg/kg bw/day. No adverse effects on development were reported at doses up to 500 mg/kg bw/day in the study. 

Based on read-across data, the target chemical is suspected to be toxic to development in humans. NOAEL for systemic and developmental toxicity is considered at 25 mg/kg bw/day in pregnant rats.

Justification for classification or non-classification

Based on read-across data, the target chemical is not suspected to be toxic to reproductive performance in rats. Hence, the test chemical is not likely to be classified for Reproductive toxicity.

Additional information