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EC number: 947-954-2 | CAS number: -
The following related microscopic findings were detected.
2 (60 mg/kg bw/day)
3 (125 mg/kg bw/day)
4 (250 mg/kg bw/day)
Squamous cell hyperplasia:
Erosion: Mean severity
There were no treatment-related effects on mating performance.
No treatment-related effects on fertility were detected for treated animals when compared to controls.
Two control females and one female treated with 60 mg/kg bw/day did not achieve pregnancy following evidence of mating. No histopathological correlates were evident in either the male or female reproductive organs however, the male partner treated with 60 mg/kg bw/day revealed a moderate multifocal squamous hyperplasia and hyperkeratosis with slight multifocal submucosal inflammation in forestomach. These findings are considered to possibly be the cause of unsuccessful mating. In the absence of any similar infertility effects detected at 250 mg/kg bw/day the intergroup differences were considered not to be related to test item toxicity.
No treatment-related effects were detected in the length of gestation for treated females when compared to controls. All animals showed gestation lengths of 22½ to 24 days.
In total eight females from control, nine females from the 60 mg/kg bw/day dose group and ten females from the 125 and 250 mg/kg bw/day dose group gave birth to a live litter and successfully reared young to Day 5 age. The following assessment of litter response is based on all litters reared to termination on Day 5 of lactation/age.
Offspring Litter Size and Viability
No toxicologically significant effects were detected.
No significant differences were detected for corpora lutea, implantation counts, litter size or litter viability for treated animals when compared to controls. Statistical analysis of the data did not reveal any significant intergroup differences.
There were no intergroup differences in sex ratio (percentage male offspring) for litters from treated groups compared to controls. Statistical analysis of the data did not reveal any significant intergroup differences.
Offspring Growth and Development
There were no significant differences in litter, offspring weights or surface righting reflex. Statistical analysis of the data did not reveal any significant intergroup differences.
No obvious clinical signs of toxicity were detected for offspring from treated females when compared to controls. The incidental clinical signs detected throughout the control and treated groups, consisting of small size, offspring found dead or missing, no milk in stomach, cold, weak, pale, no tail and physical injury were considered to be low incidence findings observed in offspring in studies of this type, and were unrelated to test item toxicity.
The study was designed to investigate the systemic toxicity and potential adverse effects of the test item on reproduction (including offspring development) and are compatible with the requirements of the OECD TG 422.
This study was also designed to be compatible with the 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 twice daily by gavage to three groups, each of ten male and ten female Wistar Han™:RccHan™:WIST strain rats, for up to eight weeks (including a two week maturation phase, pairing, gestation and early lactation for females), at dose levels of 0, 60, 125 and 250 mg/kg bw/day. A control group of ten males and ten females was dosed with vehicle alone (Arachis oil BP).
Clinical signs, behavioural assessments, body weight change, food and water consumption were monitored during the study.
Pairing of 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 5 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 surface righting reflex.
Extensive functional observations were performed on five selected males from each dose group after the completion of the mating phase, and for five selected parental females from each dose group on Day 4 post-partum. Haematology and blood chemistry were evaluated prior to termination on five selected males and females from each dose group.
Adult males were terminated on Day 43, followed by the termination of all females and offspring on Day 5 post-partum. All animals were subjected to a gross necropsy examination and histopathological evaluation of selected tissues was performed.
Mortality: There were no unscheduled deaths.
Episodes of increased salivation were evident in animals of either sex treated with 250 mg/kg bw/day and in males treated with 125 mg/kg bw/day during the treatment period. An isolated incident of noisy respiration was also evident in one female treated with 250 mg/kg bw/day on Day 6. No such effects were detected in females treated with 125 mg/kg bw/day or animals of either sex treated with 60 mg/kg bw/day. Such effects on salivation are likely due to the palatability of the test substance which is a known skin irritant.
There were no toxicologically significant changes in the behavioural parameters measured.
Functional Performance Tests.
There were no toxicologically significant changes in functional performance.
Sensory Reactivity Assessments.
There were no treatment-related changes in sensory reactivity.
Males treated with 250 mg/kg bw/day showed a reduction in body weight gain during Weeks 1, 2 and during the final week of treatment. No such effects were detected in females treated with 250 mg/kg bw/day or animals of either sex treated with 125 or 60 mg/kg bw/day.
Males treated with 250 mg/kg bw/day showed a slight reduction in overall food consumption when compared to controls. No such effects were detected in females treated with 250 mg/kg bw/day or in animals of either sex treated with 125 or 60 mg/kg bw/day.
No toxicologically significant effect on water consumption was detected.
Mating and Fertility: There were no treatment-related effects on mating or conception rates for treated animals.
There were no treatment-related differences in gestation lengths. The distribution for treated females was comparable to controls.
Offspring Litter Size and Viability: Of the litters born, litter size at birth and subsequently on Day 1 and 4 post-partum were comparable to controls. There were no significant intergroup differences in sex ratio.
Offspring Growth and Development.
Offspring bodyweight gain and litter weights at birth and subsequently on Day 1 and 4 post-partum were comparable to controls.
No clinically observable signs of toxicity were detected for offspring from all treatment groups.
Haematology: There were no toxicologically significant effects detected in the haematological parameters examined.
Blood Chemistry: There were no toxicologically significant effects detected in the blood chemical parameters measured.
Necropsy: Sloughing on the non-glandular and/or glandular regions of the stomach were evident in a number of animals treated with 250 and 125 mg/kg bw/day and in one male treated with 60 mg/kg bw/day. No such effects were detected in females treated with 60 mg/kg bw/day.
No toxicologically significant effects were detected in the organ weights measured.
Stomach: Focal to multifocal squamous hyperplasia with hyperkeratosis, submucosal inflammation, and sometimes erosion in the forestomach were noted in a dose-related manner in treated animals of all dose groups. The minimally increased incidence of mucosal glandular dilation in the glandular stomach of females from intermediate and high dose groups were considered secondary to the locally irritant effects in the forestomach.
The oral administration of Reaction mass of bis(2-ethylhexyl) hydrogen phosphate and 2-ethylhexyl dihydrogen phosphate to rats by gavage, at dose levels of 0, 60, 125 and 250 mg/kg bw/day, resulted in some effects in animals of either sex from all treatment groups, none of which were considered to be due to adverse systemic toxicity. The histopathological changes seen in the forestomach may be a result of local irritation of the test item rather than a true effect of systemic toxicity. The NOAEL for systemic toxicity was therefore determined to be 250 mg/kg bw/day. Additionally, no treatment related effects were detected in any of the reproductive parameters examined and therefore the NOEL for reproductive/developmental toxicity was greater than 250 mg/kg bw/day.
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