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EC number: 947-129-7 | CAS number: -
The oral administration of X-19574- for Amines, C16-18 and C18-unsatd. alkyl, O,O-di-Bu phosphorothioates (CASRN 97808-07-6) to rats for a period of up to eight weeks (including two weeks pre-pairing, gestation and early lactation for females) at dose levels of up to 75 mg/kg bw/day, resulted in treatment-related effects in animals of either sex treated with 75 and 25 mg/kg bw/day.
Clinical signs were detected in animals of either sex treated with 75 mg/kg bw/day and in males treated with 25 mg/kg bw/day. Episodes of increased salivation and noisy respiration were evident during the study. The physical condition of males treated with 75 mg/kg bw/day was also affected with reductions in body weight development generally being observed throughout the study. Subsequently a reduction in overall body weight gain was evident in these males and reductions in food consumption and food conversion efficiency was also evident throughout the treatment period. A slight reduction in overall body weight gain was evident in males treated with 25 mg/kg bw/day. During the treatment-free period, recovery was evident in males that were previously given 75 mg/kg bw/day. Observations of this nature are often reported when a test item formulation is unpalatable or irritant and can be associated with gastric irritancy rather than attributable to true systemic toxicity. This was supported microscopically in males treated with 75 mg/kg bw/day, where mild hyperplasia of the non-glandular region of the stomach was evident. This change in the rodent-specific non-glandular region is generally considered not to be significant to man as the corresponding anatomical area is not present and given the low severity and lack of other significant pathological changes (eg. inflammation) this finding was considered to be an adaptive and non-adverse change within this study.
Microscopic examination of the mesenteric lymph nodes revealed accumulation of foamy macrophages at a minimal to moderate severity in animals of either sex treated with 75 and 25 mg/kg bw/day. Following the two week treatment free period this finding was evident in all animals that were previously treated with 75 mg/kg bw/day, at a minimal or mild severity. This change is likely to have occurred in response to the oral administration of the test item, possibly representing accumulation of material as part of the process of clearance of the test item or its metabolites. The reduction in severity of the change in the recovery animals indicated reversibility although recovery was incomplete after the treatment free period. At the severities seen and the indication of reversibility together with the absence of necrosis in the lymph node, there is no evidence of functional impact, therefore, within the confines of this study, it is considered most likely to be a non-adverse effect.
Although there were some statistically significant differences in treated animals from controls for the hematological, blood chemical and organ weights measured, these differences were seen in the absence of any associated histopathological correlates and were considered not to be of toxicological significance.
Mating performance and fertility was unaffected by treatment and there were no treatment-related effects detected in the offspring parameters observed.
The study was designed to investigate the systemic toxicity and potential adverse effects of the test item on reproduction (including offspring development), to evaluate some endocrine disruptor relevant endpoints and is designed to be compatible with the requirements of the OECD Guidelines for Testing of Chemicals No. 422 “Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test” (adopted 28 July 2015).
This study was also designed to be compatible with Commission Regulation (EC) No 440/2008 of 30 May 2008 laying down test methods pursuant to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH).
The test item was administered by gavage to three groups, each of twelve male and twelve female Wistar Han™:RccHan™:WIST strain rats, forapproximately 6 weeks (males) and up to eight weeks (females)(including a two week pre-pairing phase, pairing, gestation and early lactation for females), at dose levels of 10, 25 and 75 mg/kg bw/day. A control group of twelve males and twelve females was dosed with vehicle alone (Arachis oil BP). Two recovery groups, each of five males and five females, were treated with the high dose (75 mg/kg bw/day) or the vehicle alone for forty-three consecutive days and then maintained without treatment for a further fourteen days.
Clinical signs, behavioral assessments, body weight change and food and water consumption were monitored during the study.
Pairing of non-recovery animals within each dose group was undertaken on a one male: one female basis within each treatment group on Day 15 of the study, with females subsequently being allowed to litter and rear their offspring to Day 13 of lactation.
During the lactation phase, daily clinical observations were performed on all surviving offspring, together with litter size and offspring weights and assessment of ano-genital distance and visible nipple count (male offspring only).
Extensive functional observations were performed on five selected non-recovery males from each dose group after the completion of the pairing phase, and for five selected non-recovery parental females from each dose group on Day 12post partum. Hematology and blood chemistry were evaluated prior to termination on five selected non-recovery males and females from each dose group. Additionally, blood samples were taken at termination from all non-recovery adult animals and from one male and one female offspring per litter (where possible) on Days 4 and 13post partum, for thyroid hormone analysis; samples from all non-recovery adult males and Day 13 offspring were analyzed for Thyroxine (T4).
Vaginal smears were performed for all females from the day after arrival (enabling the exclusion of females not showing appropriate estrous cycling from dosing) and for all non-recovery treated females including controls through pre-pairing, pairing and up to confirmation of mating.
Vaginal smears were also performed in the morning on the day of termination for all non-recovery treated females.
Non-recovery adult males were terminated on Day 44 or 45, followed by the termination of all surviving offspring and non-recovery adult females on Days 13 and 14post partum, respectively. Any non-recovery female which did not produce a pregnancy was terminated around the same time as littering females. All animals were subjected to a gross necropsy examination and histopathological evaluation of selected tissues was performed.
Following forty-three days of treatment, recovery group animals were maintained without treatment for a further fourteen days. Hematological and blood chemistry were evaluated on all recovery group animals at the end of the treatment-free period. These animals were then subjected to a gross necropsy and histopathological examinations of selected tissues was performed. Additionally, blood samples were taken at termination from all recovery adult animals for possible thyroid hormone analysis.
There were no treatment-related deaths.
One male treated with 75 mg/kg bw/day was killedin extremison Day 23 due to a physical injury to the foot.
Animals of either sex treated with 75 mg/kg bw/day and to a lesser extent, males treated with 25 mg/kg bw/day showed increased salivation and noisy respiration during the treatment period. No such effects were evident in females treated with 25 mg/kg bw/day or in animals of either sex treated with 10 mg/kg bw/day.
One female treated with 75 mg/kg bw/day had increased salivation during Day 4 of gestation behavioral observations and one male treated with 25 mg/kg bw/day showed noisy respiration during Week 6 behavioral assessments. No such effects were evident in the remaining treated animals of either sex.
Functional Performance Tests
There was no effect of treatment with the test item at any dose level on functional performance in animals of either sex.
Sensory Reactivity Assessments
Sensory reactivity scores across all test item-treated dose groups were similar to controls.
Males treated with 75 mg/kg bw/day showed a reduction in body weight gain throughout the treatment period. Recovery was evident however during the fourteen day treatment free period. A slight reduction in overall body weight gain was also evident in males treated with 25 mg/kg bw/day. No such effects were evident in males treated with 10 mg/kg bw/day.
No adverse effects were evident in treated females during maturation, gestation or lactation.
Males treated with 75 mg/kg bw/day showed a reduction in food consumption and food conversion efficiency throughout the treatment period. Recovery was evident however during the fourteen day treatment free period. No such effects were evident in males treated with 25 or 10 mg/kg bw/day.
Daily visual assessment of water consumption did not reveal any significant intergroup differences.
There was no effect of treatment with the test item at any dose level on the nature of estrous cycle with most females showing regular cycles over the pre-pairing phase of the study. There were also no intergroup differences in the stage of estrus on the day of necropsy.
There was no effect of treatment on mating performance. With the exception of three animals, all remaining animals mated within four days of pairing.
There were no treatment-related effects in conception rates for test item-treated animals in relation to controls.
There were no differences in gestation lengths in animals receiving the test item when compared with controls.
Offspring Litter Size, Sex Ratio and Viability
There was no detrimental effect of treatment with the test item on the mean number of implantations, post-implantation loss, litter size, sex ratio and subsequent offspring survival to Day 13 of age at 10, 25 or 75 mg/kg bw/day.
Offspring Growth and Development
There was no detrimental effect of treatment with the test item indicated by offspring body weight or body weight gain and litter weights, ano-genital distance on Day 1post partum, visible nipple count in male offspring on Day 13post partumor clinical signs up to Day 13 of age at 10, 25 or 75 mg/kg bw/day.
There were no toxicologically significant effects detected in the hematological parameters examined.
There were no toxicologically significant effects detected in the blood chemical parameters examined.
Neither the type, incidence or distribution of macroscopic observations in surviving adult animals or offspring indicated any treatment-related effect up to a dose level of 75 mg/kg bw/day.
No toxicologically significant changes were evident in animals of either sex treated up to a dose level of 75 mg/kg bw/day.
The following treatment-related microscopic abnormalities were detected:
Mesenteric Lymph Node:Foamy macrophage accumulation, minimal to moderate was present in all animals of either sex treated with 75 mg/kg bw/day. It was also present in three males and two females treated with 25 mg/kg bw/day at a minimal level. Following the two week treatment free period this finding was evident in all animals that were previously treated with 75 mg/kg bw/day, at a minimal or mild level. There was however, a minor reduction in severity in both sexes.
Stomach:Mild hyperplasia of the non-glandular region was evident in two males treated with 75 mg/kg bw/day. No such effect was evident in males treated with 25 or 10 mg/kg bw/day and following the two week treatment free period, this finding had completely resolved in males that were previously given 75 mg/kg bw/day.
Thyroid Hormone Analysis
An evaluation of Thyroxine (T4) in adult males and male/female offspring (Day 13 of age) did not identify any treatment-related findings.
The oral administration of X-19574- for Amines, C16-18 and C18-unsatd. alkyl, O,O-di-Bu phosphorothioates (CASRN 97808-07-6) to rats by gavage, at dose levels of 10, 25 and 75 mg/kg bw/day, resulted in reduced body weight gains in males treated with 75 and 25 mg/kg bw/day and microscopic effects detected in the stomach of males treated with 75 mg/kg bw/day and in the mesenteric lymph nodes of animals of either sex treated with 75 and 25 mg/kg bw/day. The ‘No Observed Effect Level’ (NOEL) for systemic toxicity was therefore considered to be 10 mg/kg bw/day.
The microscopic changes evident in the mesenteric lymph nodes were considered likely to represent the accumulation of material as part of the process of clearance of the test item or its metabolites. The reduction in severity of the change in recovery animals in both sexes indicated reversibility and at the severities observed in this study along with the absence of necrosis in the lymph node, it was considered that this finding was non-adverse. The reduced body weight development and microscopic changes evident in the stomach were considered to be the result of an irritant effect of the test item rather than a true systemic effect and as such was considered adaptive and non-adverse. Therefore, a ‘No Observed Adverse Effect Level’ (NOAEL) can be established at 75 mg/kg bw/day for animals of either sex.
The ‘No Observed Effect Level’ (NOEL) for reproductive and developmental toxicity was considered to be 75 mg/kg bw/day.
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