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EC number: 204-464-7
CAS number: 121-32-4
Two studies have been selected as key study, a 90 day study and an OECD 421 study.
In the 13-week study (Huntingdon et al. , 1992) performed on rats, the NOAEL is 1000 mg/kg bw/day based on spleen weight which is higher than control group (relative) related with histopathological changes.
In the OECD 421 study performed by gavage in 2017 (Charles River, 2017), transient but adverse clinical signs were observed in male and female rats at the dose level of 1000 mg/kg/day. A NOAEL of 500 mg/kg/day was therefore identified for these effects.
In a subchronic
toxicity study (Hooks, 1992), ethylvanillin was administered to CD(SD)
BR rats (males and females, 20 per sex per dose), in diet at dose levels
of 0; 500; 1000; 2000 mg/kg/day for 13 weeks. Yellow discolouration of
some or all of the fur of rats treated with 500 mg/kg/day, 1000
mg/kg/day, or 2000 mg/kg/day, were not considered to be of toxicological
For males and females,
inferior bodyweight gain was recorded in the 2000 mg/kg/day group. For
males receiving 500 or 1000 mg/kg/day, the mean bodyweight gain was
inferior to that of controls during the first 4 weeks and the cumulative
mean food intake by all the male treated groups was stastistically lower
than that of controls. The food intake by females receiving 500 or 1000
mg/kg/day was considered to be similar to that of controls throughout
the study. The decrease of bodyweight gain is observed in the fourth
first weeks, related with a decrease in food consumption. This variation
is due to the unpathability of the substance, and was not considered to
related with toxicological property of the substance.
investigations showed slightly higher than control values for
glutamic-pyruvic transaminase, alkaline phosphatase, cholesterol and
total plasma protein at the high dosage level, only occasionally
involving the intermediate dosage level. These differences from control
may be related to treatment in view of the histopathological changes in
liver. The remaining differences from the control were considered
unlikely to be of toxicological importance.
observations done on the increase of liver weight (relative), it appears
to be not correlated with hepathological changes, because these effects
were observed in the control group too, that would be due to the strain
of rat used in this study. Therefore the increase of the liver weight is
not considered as adverse effect.
The NOAEL is 1000
mg/kg bw/day based on spleen weight which is higher than control group
(relative) related with histopathological changes.
Table: Summary of salient mean body weight changes of males (mean
values, in grams – percentage of difference with the control between
The test item, 3-ethoxy-4-hydroxybenzaldehyde (Ethylvanillin), was administered by daily oral gavage to male and female Wistar Han rats at dose levels of 250, 500 and 1000 mg/kg/day. A control group of 10 rats/sex was given the vehicle (Propylene glycol). Males were treated for 31 days, i.e. 2 weeks prior to mating, during mating, and up to termination. Females were treated during 2 weeks prior to mating, during mating, during post-coitum, and up to the day before necropsy (i.e. on day 13 of lactation for females delivered, on day 26 of gestation for female with total litter resorption and on day 1 of lactation for
female with total litter death). The following observations and examinations were performed: mortality / morbidity, clinical signs, body weight, food consumption, estrous cycle determination, clinical pathology,
measurement of thyroid hormone T4, macroscopy at termination, organ weights and histopathology on a selection of tissues.
All analyzed samples for formulations prepared at nominal concentrations of 50, 100 and 200 mg/mL were in agreement with acceptance criteria and no test item was present in the vehicle sample.
Furthermore, the test item prepared as a suspension in the vehicle was homogenous. There was no test item-related mortality in any group. Transient test item-related clinical signs in 5/10 females given 1000 mg/kg/day during the pre-mating period consisted of decreased activity and/or abnormal breathing associated or not with partly closed eye(s), piloerection, cold body and/or recumbency. A transient decreased activity was observed also for 4/10 males at this dose level. The mean body weight gain was lower than in controls in both males and females during the pre-mating period in the 1000 mg/kg/day group.
Some females in all treated groups lost weight. The final mean body weight of males and females in the high dose group was not, however, overtly affected (-1 % for males on Day 29 and -5 % for females on Day 15). There were no test item-related body weight changes thereafter nor adverse changes in body weight gain at 250 and 500 mg/kg/day. Consistent with effects on body weight gains, there was a slightly lower food consumption in the 1000 mg/kg/day female group than in other groups.
In conclusion, 3-ethoxy-4-hydroxybenzaldehyde (Ethylvanillin) given by oral gavage in male and female Wistar Han rats at dose levels of 250, 500 and 1000 mg/kg/day revealed transient parental toxicity (considered as adverse) at 1000 mg/kg/day. Based on these results, a parental No Observed Adverse Effect Level (NOAEL) of 500 mg/kg was derived.
Several studies were available by oral route (feed and gavage), but only 2 of them were chosen as key study (Huntingdon, 1992 and Charles River, 2017). These 2 studies have the reliability 1 according to Klimish score.
In a subchronic toxicity study (Huntingdon, 1992), Ethylvanillin was administered to CD(SD) BR rats (males and females, 20 per sex per dose), in diet at dose levels of 0 to 2000 mg/kg bw per day for 13 weeks. The NOAEL is 1000 mg/kg bw/day based on spleen weight which is higher than control group (relative) related with histopathological changes. In a subacute toxicity study (Dose-range finding) (Huntingdon, 1992) (selected as 'supporting study'), ethylvanillin was administered to CD(SD) rats (males and females, 10 per sex per dose), in diet at dose levels of 0 to 2000 mg/kg bw/day for 2 weeks. The NOAEL is 1000 mg/kg bw/day based on bodyweight gain.
The OECD 421 study performed on rats in 2017 (Charles River, 2017) was also selected as a key study. Such study is not really designed to assess repeated toxicity. However in this study transient but adverse clinical signs were observed in male and female rats at the dose level of 1000 mg/kg/day. Therefore, based on this study a NOAEL of 500 mg/kg/day was identified in rats. Since this NOAEL is lower than the NOAEL identified in the 90 day study, the OECD 421 study was retained, in a conservative approach, for the derivation of the DNELs.
In the different studies available, ethylvanillin did not show adverse systemic effects up to 500 mg/kg/day, and should not be classified for repeated toxicity or STOT repeated exposure, according to CLP 1272/2008 criteria.
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