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EC number: 293-878-1 | CAS number: 91648-19-0
The subacute toxicity of Cocamidopropyl hydroxysultaine was tested in an OECD 422 compliant study following daily oral administration (by gavage) to male and female rats from before mating, during mating and, for the females, throughout gestation until day 5 post‑partum (p.p.) inclusive.
Three groups of ten male and ten female Sprague-Dawley rats received the test item, Cocamidopropyl hydroxysultaine, as a 36.2% aqueous solution, daily, by oral administration (gavage), over the administration period, at dose‑levels of 30, 100 or 300 mg/kg/day.An additional group of 10 males and 10 females received the vehicle control, drinking water, under the same experimental conditions. The dosing volume was 5 mL/kg/day.
Animals were checked daily for clinical signs, mortality, and detailed clinical observations were conducted weekly. Body weights and food consumption were recorded weekly until mating and then at designated intervals throughout gestation and lactation. A Functional Observation Battery including touch response, forelimb grip strength, pupillary reflex, visual stimulus response, auditory startle reflex, tail pinch response, righting reflex, landing foot splay, rectal temperature and motor activity was performed on five males and females per group at the end of the study. Prior to sacrifice, blood samples were also taken from these animals for analysis of hematology and blood biochemistry parameters.
The males were sacrificed after completion of the mating period and dams were sacrificed on day 6 p.p.. Body weights and selected organs weights were recorded and a complete macroscopicpost-mortemexamination performed, with particular attention paid to the reproductive organs. A microscopic examination was also conducted on selected organs from the first five animals in the control groups and the high-dose groups. Microscopic examination was conducted on all macroscopic lesions from all groups.
Based upon the microscopic results of the high-dose group, stomach, forestomach, kidneys, lungs and trachea of the first five animals of the low- and intermediate-dose groups were also examined. Pups, including those found dead before study termination, were also submitted for a macroscopic post-mortem examination.
The test item concentrations in the administered dose formulations analyzed in weeks 1, 3, 5 and 7 remained within an acceptable range of -7.0% to +4.5% when compared to the nominal values, except for group 3 analyzed in week 5 found at -16.0% and groups 3 and 4 analyzed in week 7 found respectively at -11.7% and -12.3%. When compared with the nominal values (±10%), these variations were of small amplitude and therefore to considered to have no impact on the integrity of the study. Cocamidopropyl hydroxysultaine was not detected in control samples.
With regards to repeated-dose toxicity parameters, the following observations were made:
There were no unscheduled deaths in control, 30 and 100 mg/kg/day groups.
In the 300 mg/kg/day group, one male was found dead on study day 34. At macroscopic post‑mortem examination, there were enlargment of lungs (with presence of red discoloration) and white discoloration and irregular surface of the wall of stomach. At microscopic examination, the cause of death was moderate subacute bronchioalveolar inflammation, most likely secondary to aspiration of the test item after regurgitation at dosing. This mortality was not considered incidental but attributed to the test item.
At 300 mg/kg/day, loud breathing was recorded during the period of days 17 to19 in one male, during all the pregnancy period in one female and at the end of the lactation period in another one. This clinical sign was considered to be related to the treatment with the test item and of toxicological significance. Ptyalism, frequently observed in most animals given 300 mg/kg/day, was considered to be related to the test item but of minor toxicological importance.
Functional Observation Battery
There were no findings considered to have obvious biological or toxicological significance.
There were no relevant differences in rearing in treated group animals when compared with control animals.
There was a trend towards a decrease in the number of horizontal movements in females. However, in the absence of associated clinical signs, in the absence of effects in males and taking into account variability across groups, a treatment-related effect was excluded.
Body weight and body weight change
In males, there were no effects on mean body weight or mean body weight gain.
In females, there was a dose-related decrease in mean body weight gain (-37% at 300 mg/kg/day vs. controls, p< 0.05) during the premating period and decreases in mean body weight during the pregnancy and lactation periods (-7%vs.controls on day 0p.c., p<0.05and -8% on day 5 p.p., p< 0.05, at 300 mg/kg/day) which was associated with a non-statistically significant decrease in mean body weight gain (‑29%vs. controls at 300 mg/kg/day) during the lactation period (days 1-5p.p.). All these finding were considered to be treatment-related.
There were no effects on mean food consumption during the premating, mating, gestation or lactation period.
There were no effects on the hematological parameters.
A few isolated findings were considered to be of non toxicological significance.
There were no organ weight or macroscopic changes attributed to the test item.
The test item administration at the highest dose-level induced microscopic changes in the stomach, lungs, trachea and kidneys.In the forestomach, squamous cell hyperplasia was most likely due to irritant properties of the test item. Pulmonary bronchioalveolar inflammation and tracheal epithelial alteration were thought to be related to aspiration of compound after regurgitation at dosing. In the kidneys, there were minimal to slight degeneration/hypertrophy of the tubular epithelium, principally in males, and minimal tubular vacuolation in some females.
At 100 mg/kg/day, there was only minimal epithelial alteration in the trachea from a single male, which was not considered as adverse in view of its low incidence and magnitude. There were no microscopic findings in the stomach, forestomach, kidneys or lungs.
In conclusion, based on the experimental conditions of this study, the No Observed Adverse Effect Level (NOAEL) for parental toxicity was considered to be 100 mg/kg/day based on microscopic findings in the forestomach, lungs, trachea and kidneys of animals given 300 mg/kg/day.
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