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Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Study duration:
subchronic
Species:
rat
Quality of whole database:
A single two generation study is available. The study was performed in line with GLP and accepted standardised guidelines with a high standard of reporting. The study was assigned a reliability score of 1 in accordance with the criteria for assessing data quality as outlined in Klimisch (1997) and considered suitable for assessment as an accurate reflection of the test material.
Additional information

The reproductive toxicity of the test material was determined in accordance with standardised guidelines OECD 416, EPA OPP 83-4 and EPA OPPTS 870.3800. During the study rats were dosed test material in diet at 0, 500, 1000, 8000 and 12000 ppm. After 10 weeks of exposure, the animals (P) were cohabited 1:1 within each dose group for up to 21 days. Gestation and delivery were allowed to occur naturally. Litters (F1) were culled to four males and four females on day 4 post partum. After weaning of the last litter, selected F1 young (30 animals per sex and dose) were continuously exposed to test material for 10 weeks after which time animals of the same group were cohabited 1:1 for up to 21 days. Gestation and delivery were allowed to occur naturally. Resulting F2 litters were necropsied after weaning. Clinical observations, bodyweights, food consumption, mating, gestation and delivery parameters, estrous cycle stages and sperm characteristics, pup survival, pup developmental landmarks, pup sexual maturation (F1), necropsy examinations of adults and pups and histopathological observations in sex and target organs of mating were recorded.

Under the conditions of the study, dietary administration of test material to rats through two generations produced effects on bodyweight and bodyweight gain, food consumption, organ weights and liver histopathology at dietary concentrations of 8000 and 12000 ppm. The findings were by and large consistent and indicative of generalised toxic properties of the test material. Reduced bodyweight and bodyweight gain were apparent in adult males and females in the 8000 and 12000 ppm dose groups in both generations. Adult males were affected throughout the study period. Adult females were affected to a somewhat lesser extent, primarily during the premating phases, but also during gestation and lactation; the effects were only minimally apparent in 8000 ppm females. Food consumption was also reduced among 8000 and 12000 ppm males throughout the study, and to a lesser extent in 12000 ppm females. Most organ weight changes considered to be effects of retarded growth/reduced feeding were also seen in the adult animals in these two dose groups.

The liver was identified as the target organ, based on findings of increased liver weights which correlated with minimal hepatocellular hypertrophy on adult males and females at the two highest feeding levels in both generations.

In pups, reduced bodyweight and bodyweight gain were seen at 8000 and 12000 ppm from the second lactation week onwards in both generations, and subsequent effects on organ weights were also observed.

The NOAEL was defined as 1000 ppm in both males and females which is approximately equal to 48-137 mg/kg/day for males and 60-199 mg/kg/day for females. The grand mean test material intake at this dose levels was 83.4 mg/kg/day.

There were no effects of dietary administration of the test material on any of the reproductive parameters assessed in this study.

The available data are considered to be complete and the result determined, NOAEL (test material toxicity) 83.4 mg/kg bw, was taken forward for risk assessment.

 


Short description of key information:
Oral: NOAEL (test material toxicity) = 83.4 mg/kg/day, two generation reproduction toxicity (male/female), OECD 416, EPA OPP 83-4, EPA OPPTS 870.3800, Gillis & Doubovetzky 2000

Justification for selection of Effect on fertility via oral route:
Only one two generation study is available.

Effects on developmental toxicity

Description of key information
Teratogenicity (rat)  - NOAEL (maternal, fetal toxicity) 30 mg/kg bw - OECD 414, EPA OPP 83-3 - Doubovetzky 1999
Teratogenicity (rabbit) - NOAEL (maternal toxicity) 100 mg/kg bw; NOAEL (fetal toxicity) 250 mg/kg bw - OECD 414, EPA OPP 83-3 - Doubovetzky 1998
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Study duration:
subacute
Species:
other: rat and rabbit
Quality of whole database:
A preliminary range finding study and two prenatal developmental toxicity studies are available. The range finding study was performed in line with GLP and sound scientific principles and was assigned a accepted reliability score of 2 in accordance with the criteria for assessing data quality as outlined in Klimisch (1997). The two developmental toxicity studies were performed to GLP and followed accepted standardised guidelines with a high level of reporting and, as such, were assigned a reliability score of 1 in accordance with the criteria for assessing data quality as outlined in Klimisch (1997). The overall quality of the database is high and the available data are considered suitable for assessment as an accurate reflection of the test material. Under the conditions of the two studies the test material was not embryotoxic, foetotoxic, or teratogenic in rats or rabbits. A slight reduction in foetal weight and increased incidences of a few skeletal variations were considered related to delayed development and secondary to maternal toxicity and based on these observations, the maternal and foetal NOAELs were defined as 30 mg/kg.
Additional information

A GLP compliant range finding study was conducted to provide a basis for dose selection for a subsequent developmental toxicology study. During the study, groups of eight female rats were dosed on days 6 to 15 post coitum, by gavage, with 0, 100, 300 and 1000 mg/kg bw doses of test material in a 0.5% sodium carboxymethylcellulose at a volume of 10 mL/kg body weight. On day 21 post coitum animals were sacrificed and submitted to gross necropsy. The uteri were dissected and contents examined. Live foetuses were weighed, sexed and inspected for external abnormalities.

Under the conditions of the study, the group which received 1000 mg/kg test material displayed a slight effect on maternal parameters (pushing head through bedding). At this dose level, one animal delivered early and had one live and four dead foetuses. There was no indication of teratogenesis during this range finding study.

 

In a GLP compliant study conducted in line with standardised guidelines OECD 414 and EPA OPP 83-3, the effect of the test material on developmental toxicity was determined in the rat. Rats were administered the test material daily, by oral (gavage), at 0, 30, 300 and 1000 mg/kg bw from day 6 to day 15 post coitum. The animals were checked daily for clinical signs and mortality and body weight and food consumption were measured daily. Maternal animals were sacrificed on day 21 post coitum and subjected to gross necropsy. The uteri were dissected and contents examined. Foetuses were weighed, sexed and inspected for external, visceral and skeletal abnormalities. During the study there were no premature mortalities.

In the high dose group, maternal toxicity was evidenced by an 11% decrease in food consumption over the period of dosing and a 21% decrease of carcass weight minus day 6 weight. Slight but statistically significant reduction in foetal weight and increased incidences of a few skeletal variations were considered to be the consequence of a delay in foetal development and therefore secondary to maternal toxicity.

In the mid-dose group a significant 6% reduction in food consumption over the period of treatment was also observed and the carcass weight minus day 6 weight was reduced by 17%. Lower fetal weights and increased incidences of incomplete ossification of posterior digit phalanges were also recorded.

In the low dose group no treatment-related findings were observed.

Under the conditions of the study the test material was not embryotoxic, foetotoxic, or teratogenic in rats. A slight reduction in foetal weight and increased incidences of a few skeletal variations were considered related to delayed development and secondary to maternal toxicity at 300 and 1000 mg/kg and based on these observations, the maternal and foetal NOAELs were defined as 30 mg/kg.

 

In a GLP compliant study conducted in line with standardised guidelines OECD 414 and EPA OPP 83-3, the effect of the test material on developmental toxicity was determined in the rabbit. Rabbits were administered the test material daily, by oral (gavage), at 0, 50, 100, 250 and 500 mg/kg bw from day 7 to day 19 post coitum. The animals were checked daily for clinical signs and mortality and body weight and food consumption were measured daily. Maternal animals were sacrificed on day 29 post coitum and subjected to gross necropsy. The uteri were dissected and contents examined. Foetuses were weighed and inspected for external, visceral and skeletal abnormalities.

At 500 mg/kg nineteen of twenty animals died or were sacrificed for ethical reasons. Feed consumption was reduced and there was a large average body weight loss during the treatment period. At clinical observation or at necropsy, there was, in general, evidence of haemorrhages.

At 250 mg/kg one animal was found dead and one was sacrificed prematurely, but mean feed consumption and overall body weight gain during treatment period were not affected by treatment.

At 100 and 50 mg/kg there were no treatment-related effects.

Reproduction and caesarean section data were obtained from animals treated at 0, 50, 100 and 250 mg/kg only. In these groups preimplantation losses, number of implantation sites, and postimplantation losses were not affected by treatment. Foetal examinations of these groups were similar across all groups. Two malformations were seen (one generalised oedema and one encephalocele). A number of anomalies or variations were also reported in these treatment groups, however, none of these findings were considered to be treatment-related.

Under the conditions of the study maternal toxicity was seen at 500 mg/kg and 250 mg/kg as evidenced by 19 of 20 and 2 of 20 deaths/premature sacrifice, respectively. The maternal NOAEL was 100 mg/kg and the fetal NOAEL was 250 mg/kg. There was no indication of embryotoxic, foetotoxic or teratogenic potential.

The available data are considered to be complete and the result determined, NOAEL (maternal and foetal toxicity) 30 mg/kg bw, was taken forward for risk assessment. 


Justification for selection of Effect on developmental toxicity: via oral route:
Both studies presented as part of a weight of evidence were performed in line with current OECD guidelines, in line with good laboratory practices, reported to a high level of quality. The studies were performed on the preferred rodent and non-rodent species as detailed by the appropriate guideline. In both studies, effects were only noted in the presence of maternal toxicity (reduced feed consumption)

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Part 3.7, Regulation 1272/2008, the test material does not require classification for reproductive toxicity. There was no indication of reproductive toxicity or of embryotoxic, foetotoxic or teratogenic potential of the test material in any of the studies available for assessment of reproductive and developmental toxicity. All of the effects reported in the available studies were not observed in the absence of parental toxicity.

In accordance with criteria for classification as defined by Directive 2001/59/EC, Annex VI, Point 4.2.3, the test material does not require classification for toxicity to reproduction.

Additional information

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