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EC number: 947-527-0 | CAS number: -
A combined oral repeated dose study with screening for reproductive and/ or developmental effects was performed according to OECD/EC guidelines and GLP principles. C12-14 Alkyl ethoxylated glycidylether was administered by daily oral gavage to male and female rats at dose levels of 83, 250 and 750 mg/kg bw/day. Based on the results of this study, the parental NOEL was concluded 250 mg/kg/day (based on lower body weight gain and food consumption, increased liver weights in males, a thickened forestomach in males and hyperplasia in the forestomach in males and females at 750 mg/kg/day). As these fefects were considered to be non-adverse, the NOAEL was found to be 750 mg/kg bw/day, the highest dose tested.
Results Dose Formulation Analyses:
The concentrations analyzed in the formulations of the low , mid and high dose groups were in agreement with target concentrations (i.e. mean accuracies between 96% and 99%). No test item was detected in the Control group formulation. The formulations of the low dose group and the high dose group were homogeneous (i.e. coefficient of variation ≤ 2.0%).
Results dose range finder study:
No mortality occurred. At 1000 mg/kg bw/day, piloerection was present in all animals during Days 2-8. Hunched posture was present in 2-3/3 animals from Days 3-8 and from Days 11-14. Salivation was observed in 3/3 animals on most days during the second week of treatment. On Day 7, lethargy was observed in 2/3 animals. Body weight was reduced in 1/3 animals during Days 1-4, followed by normal body weights and body weight gain. During Days 1-4, absolute and relative food consumption was reduced. At 500 mg/kg bw/day, a hunched posture was observed in 1/3 animals on Days 13 and 14. Piloerection was seen in 3/3 animals on Day 8. Salivation was observed in 3/3 animals on most days during the second week of treatment. Normal body weights and body weight gain was measured, food consumption was considered within normal range.
At necropsy, no abnormalities were noted at 500 mg/kg bw/day. Kidney weights were within normal range, but relative liver weights were increased with approximately 16% compared with the historical control range. At 1000 mg/kg bw/day, in 1/3 animals the stomach was grown together with the liver and the liver was grown together with the diaphragm. No effects were seen on kidney weights, relative liver weights were increased with approximately 39% compared with the historical control range.
C12-14 Alkyl ethoxylated glycidylether has been evaluated in a combined 28-day repeated dose toxicity with reproduction/developmental toxicity screening in rats. The animals were dosed for 29-32 days (males) and average 54 days (females, range 50-67 days and 40-43 days in case non-pregnant or total litter loss).
The applied dose levels of 0, 83, 250, 750 mg/kg/day were based on results of a 14-day range finder involving two groups of 3 female rats at 500 and 1000 mg/kg/day. Effects at 1000 mg involved: hunched posture and lethargy; BW reduction in one animal; reduction absolute and relative food consumption; effects on stomach in one animal at macroscopic examination; increase relative liver weights by 39%.
The following parameters and end points were evaluated in this study: mortality/moribundity, clinical signs, functional observations, body weight and food consumption, estrous cycle determination, clinical pathology, measurement of thyroid hormone T4 (F0-males), gross necropsy findings, organ weights and histopathologic examinations. In addition, the following reproduction/developmental parameters were determined: mating and fertility indices, precoital time, number of implantation sites, gestation index and duration, parturition, maternal care, sex ratio and early postnatal pup development (mortality, clinical signs, body weights, sex, anogenital distance, areola/nipple retention and macroscopy, measurement of thyroid hormone T4 (PND 14-16 pups)).
Formulation analyses confirmed that formulations of test item in water were prepared accurately and homogenously.
The observed decrease in body weight gain in males at 750 mg/kg/day on Day 8, was considered non adverse as body weights were normal and the body weight gain recovered to normal levels in the following weeks. The decrease in body weight gain may have been related to the decreased food consumption levels found during the first week of treatment in males at 750 mg/kg/day.
For females, (relative) food consumption levels were decreased during the premating, post coitum and/or lactation period at 750 mg/kg/day. Though not statistically significant, body weight gains were lower at the end of post coitum and lactation period at 750 mg/kg/day. These findings were likely the result of the decreased litter sizes at 750 mg/kg/day and were considered secondary to developmental and reproductive toxicity.
Liver weights were increased in males and at the observed magnitude of the effect (relative increase of 27% at 750 mg/kg/day) and in absence of correlating microscopic findings, this was considered non adverse.
A test item-related thickened forestomach was observed in males treated at 750 mg/kg/day. The microscopic correlate for this finding was hyperplasia in the forestomach. Hyperplasia in the forestomach was observed in both males and females at 750 mg/kg/day. Based on the low severity (minimal to slight) and the absence of any inflammatory response, the hyperplasia in the forestomach was considered not adverse. This forestomach lesion was considered to be a local response and most likely due to the minor irritating properties of the test item.
Parental toxicity: NOEL = 250 mg/kg bw/day. The main observed effects involve:
1. consistent effects that suggest local irritation:
- Dose related salivation, starting at 250 mg/kg bw
- Consistent slightly lower food intake and BW-gain at 750 mg/kg.
- forestomach effects in 4/5 males and 3/5 females at 750 mg/kg.
2. increase liver weight at least in males, suggesting liver induction involving change of epoxide into diols that are readily further metabolized, as first pass metabolism after uptake. These effects are consistent with adverse effects observed after only 14 days treatment in RF.
These effects were however not considered adverse, resulting to a NOAEL of 750 mg/kg bw/day.
(Dosing dissolved in water, 5 mL/kg bw)
The following observed effects in the repeated dose study suggest local irritation in the gastro-intestinal tract starting from 50 g/L (250 mg/kg bw):
- Dose related salivation, starting at 50 g/L (250 mg/kg bw).
- Consistent slightly lower food intake and BW-gain at 150 g/L (750 mg/kg).
- forestomach effects in 4/5 males and 3/5 females at 150 g/L (750 mg/kg).
The slight increase liver weight at 750 mg/kg bw at least in males, suggesting liver induction involving change of epoxide into diols that are readily further metabolized, as first pass metabolism after uptake. These effects are consistent with adverse effects observed after only 14 days treatment in RF where a clear increase was observed at 1000 mg/kg bw.
These effects were however not considered adverse, resulting to a NOAEL of 750 mg/kg bw/day.
Manufacture and use are highly controlled. Its use is limited to industrial application as intermediate in chemical production where its classification as skin sensitiser will provide for sufficient protection measures to prevent exposure. Furthermore, systemic toxicity via oral route has shown to be low, and as dermal uptake can be expected to be limited, as consequence, effects will be characterised by local irritation rather than by systemic toxicity following dermal uptake.The skin is therefore not a preferred route for testing to evaluate systemic toxicity following repeated dose.
Likelihood of exposures via inhalation is low considering thevapour pressure of ≤ 0.070 Pa at 25°C. Its use is highly controlled, limited to industrial chemical manufacturing and does not involve the forming of aerosols, particles or droplets of an inhalable size. Emission rates to air were measured to be 28 µg/day. So, exposure to humans via the inhalation route will be unlikely to occur.
With NOAEL of 750 mg/kg bw from a sub-acute repeated dose toxicity study no classification for STOT-RE is indicated.
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