Registration Dossier

Diss Factsheets

Toxicological information

Endpoint summary

Currently viewing:

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

Rats were exposed to 2-ethylhexanoic acid in a one generation study. EHA induced increased epididymal weights, but no histological changes were observed. A dose-dependent delay in fertility was observed, and the mean litter size in high-dose females was significantly reduced. The parental NOAEL was 300 mg/kg bw/day; this effect occurred in the presence of maternal toxicity.

Link to relevant study records
Reference
Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Remarks:
based on generations indicated in Effect levels
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Read Across to an analogue based on structural similarity. An analogue justification is attached to section 13 of the dataset.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across: supporting information
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
A 9-12% decrease in bodyweight was observed from gestation day 7 onwards in females of the high-dose group, which disappeared during lactation.
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Liquid consumption by pregnant females was slightly reduced at the high dose.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
In two of five dams of the mid- and high-dose group, a slight dilatation of the lumen in uterus and epithelial hyperplasia in vagina were observed.
Reproductive function: sperm measures:
effects observed, treatment-related
Description (incidence and severity):
Sperm quality was slightly, but not uniformly dose-dependent, affected. The total number of spermatozoa in the cauda epididymis was 14% lower at the high dose level, but not statistically reduced. The proportion of motile spermatozoa had decreased by 37% at the low dose and by 22% at the high dose. The share of nonmotile spermatozoa was highest in the low-dose group. The number of animals with morphologically abnormal spermatozoa was increased, however not statistically significant, at the two highest dose levels. The most common abnormalities were agglutinations and abnormal heads of spermatozoa. The latter was observed in 13% and 21% of the animals of the mid- and high-dose groups, respectively.
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
A dose-dependent delay in fertility was observed. All non-pregnant animals belonged to the 2-EHA-treated groups. Six males at the high dose and three males at the mid dose copulated occasionally with females in diestrus while all control and the lowest dose group males copulated in estrus.
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Delay in fertility
Critical effects observed:
not specified
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
The frequency of lethargy, hematomas, and abnormally thin hair was higher at the two highest dose levels. Kinky tail showed a dose-dependent increase, and the frequency of abnormal legs (e.g. severe flabby legs) was higher in the 2-EHA-treated animals. The latter animals were cannabalized by the dams soon after birth.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weights were similar at birth, but decreased transiently at the high dose during lactation.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
One male pup of the high dose had a mass in the left testis and the left epididymis was missing.
Other effects:
effects observed, treatment-related
Description (incidence and severity):
PHYSICAL DEVELOPMENT
Exposure to 2-EHA delayed physical development of the pups. Ears raised later in mid- and high-dose groups, and eye opening, eruption of teeth, and hair growth occurred significantly later at the high dose level. The development of the grip and cliff avoidance reflexes were delayed, more clearly in males than females.

LITTER SIZE
Average litter size was reduced by 16% at the high dose. Postnatal deaths tended to be more common in the 2-EHA-treated groups, but this was not statistically significant.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: lower litter size, lower body weights and delayed physical development
Reproductive effects observed:
not specified
Conclusions:
In summary, 2-ethylhexanoic acid increased time to mating, inhibited implantation, and tended to decrease fertility in Wistar rats at 600 mg/kg. At this same dose level 2-EHA decreased pup weights during lactation and at and above 300 mg/kg delayed postnatal development of pups as noted in the reflex and physical parameters evaluated.
Executive summary:

Reproductive toxicity of 2-ethylhexanoic acid (2-EHA) was studied in Wistar rats. The animals (24 animals per sex per group) were given 2-EHA as a sodium salt in drinking water at

daily doses of 100, 300, or 600 mg/kg. Control animals received plain water. Male rats were exposed to 2-EHA for 10 weeks and females for 2 weeks prior to mating, both sexes during the mating period and females during the entire gestation and lactation period. 2-EHA caused a slight but dose-dependent decrease in fertility, time to mating increased at 300 and 600 mg/kg and even total infertility ensued. 2-EHA slightly decreased sperm quality in males. The spermatozoa were significantly less motile at 100 and 600 mg/kg and abnormal sperm occurred more frequently at the two highest dose levels. The average litter size was reduced by 16% in the dose group receiving 600 mg/kg. The birth weights of the pups were unaffected but the body weight gain was transiently slower during lactation at 600 mg/kg. Several pups appeared abnormal (kinky tail, lethargic, slightly paralyzed legs) and the physical development assessed by several landmarks (opening of eyes, eruption of teeth, hair growth) and reflexes (grip reflex, cliff avoidance) was delayed at 300 and 600 mg/kg. In another experiment, a single dose of 600 mg/kg 2-EHA was given to pregnant females by gavage on Gestational Day 4, 5, 6, or 7 and the number of implantations were counted on Gestational Day 10. Administration on Day 6 decreased the number of implantations and caused resorptions. In conclusion, 2-ethylhexanoic acid caused impaired fertility in Wistar rats and delayed postnatal development of pups. The reduced fertility might result from disturbed implantation in uterus and the retarded development of pups from teratogenicity and pre- and postnatal toxic effects of 2-EHA.

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Stannous chloride and 2-ethylhexanoic acid [hydrolysis products of tin bis(2 -ethylhexanoate)] have been tested in 90 day toxicity studies in rats and mice and there were no effects noted on reproductive organs. 

Reproductive and developmental toxicity studies are not available for tin bis(2 -ethylhexanoate). Tin bis(2-ethylhexanoate) has not been evaluated for potential adverse effects in OECD 422 screening studies. But a one generation reproductive toxicity study is available. Rats were exposed to 2-ethylhexanoic acid in a one generation study, via drinking water,at 0, 100, 300, or 600 mg/kg bw/day. No mortality was observed. The relative epididymal weights in high-dose males were significantly increased, but no histologic changes were noted. A slight, but not statistically significant, increase in the number of abnormal sperm was reported in the two highest dose groups; however, the incidence per animal was not provided. A dose dependent delay in fertility was observed,and the mean litter size in high-dose females was significantly reduced. The mean pup weights in the high-dose group were significantly lower on postnatal day 7 and 14.

Development of the eyes, teeth and hair appeared to be slightly later in the pups from the high-dose groups; the significance of this finding is unclear since no data were presented on the length of gestation in treated and control dams. The high-dose of 600 mg/kg bw/day significantly reduced overall water consumption and body weights in female animals. The NOEL for reproductive effects in parental animals was 300 mg/kg-bw/day; this effect occurred in the presence of maternal toxicity. The NOEL for F1 offspring was 100 mg/kg-bw/day.

Effects on developmental toxicity

Description of key information

Data are considered to be fulfilled by studies on the hydrolysis products of tin bis(2-ethylhexanoate), tin(II) and EHA:

 

In a reliable prenatal development study (Pennanen, 1992) in Wistar rats 100, 300 and 600 mg/kg of EHA was administered via drinking water to pregnant dams from gestational days 6 to 19. On gestational day 20, the fetuses were examined for external, visceral, and skeletal malformations and variations. Skeletal malformations (clubfoot, absence of fibula, polydactyly) were observed in all treatment groups, with the incidence increasing in a dose-dependent way. Also visceral malformations were noted at all dose levels, however, severity and incidence was less pronounced than the skeletal effects. At the highest dose tested (600 mg/kg), a 5 to 8% decrease in the mean fetal body weight both in males and females was noted in presence of a near-term body weight decrease of dams of 11 %. Due to the skeletal malformations at 100 mg/kg, a NOAEL could not be established. Benchmark dose analysis provided a lower confidence limit (BMDL) of 35 mg/kg, based on total skeletal malformations per litter.

 

In a supporting prenatal development study (Hendrickx, 1993), slight fetotoxicity (reduced ossification and increased incidence of skeletal variations) was noted in the offspring of rats exposed to gavage doses of EHA in oil of 250 mg/kg/d and above (NOEL = 100 mg/kg/d) and also in the offspring of rats exposed to EHA in the drinking water at an equivalent doses of 300 mg/kg/d and above (NOEL= 100 mg/kg/d).

 

Stannous chloride and EHA [hydrolysis products of tin bis(2-ethylhexanoate)] have been tested in 90-day toxicity studies in rats and mice and there were no effects noted on reproductive organs. Further, stannous chloride has been evaluated for potential adverse developmental effects in studies in four species (US FDA 71 -33). No adverse effects on development were found at doses up to and including 50 mg/kg/d during gestation in these studies.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Read Across to an analogue based on structural similarity. An analogue justification is attached to section 13 of the dataset.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across: supporting information
Clinical signs:
no effects observed
Description (incidence and severity):
The doses of 2-EHA employed did not cause visible maternal toxicity (clinical signs or behavioral changes).
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The body weight of the dams at 600 mg/kg decreased slightly (around 10%) from Day 13 onward. At termination the mean body weight of dams was 11 % (p < 0.001) lower at 600 mg/kg. The weight of the gravid uterus did not differ significantly between groups, but the corrected maternal body weight gain was reduced (53.8%, p < 0.001) at 600 mg/kg compared to controls.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food consumption (g/kg body wt) did not differ significantly between groups.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
At the 600 mg/kg dose level, the consumption of 2-EHA containing drinking water also exhibited some decrease from Day 6 onward, being maximally 20% less than in controls.
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
The weight of the gravid uterus did not differ significantly between groups.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No gross pathological changes were noted upon necropsy in the organs of the dams.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
effects observed, treatment-related
Description (incidence and severity):
The placental weight was slightly reduced (10.2%, p < 0.001) in both 300 and 600 mg/kg dose groups.
Number of abortions:
not specified
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
No statistically significant differences were noted in pre- and postimplantation loss.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
2-EHA did not cause resorptions.
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Description (incidence and severity):
2-EHA affected neither the number of implantations nor that of living fetuses.
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
The pregnancy rate was slightly but, not significantly, decreased in the 300 and 600 mg/kg dose groups as compared to the control group (67 and 67% vs 84%).
Other effects:
no effects observed
Description (incidence and severity):
No statistically significant differences were noted in the number of corpora lutea.
Key result
Remarks on result:
other: Maternal NOEL/NOAEL values were not stated in this study.
Abnormalities:
not specified
Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
The mean fetal body weight/litter showed a marginal decrease in males (5.6%, p < 0.001) and in females (8.6%, p < 0.001) at 600 mg/kg. The mean body weight of female fetuses was slightly decreased (5.7%, p < 0.001) also at 300 mg/kg.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
All fetuses in treated and control groups were alive.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
No statistically significant differences were noted in sex ratio.
External malformations:
not specified
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
Clubfoot was the most severe skeletal malformation. It occurred at all dose levels, more notably at 300 and 600 mg/kg. Other skeletal malformations included abnormal cartilage in ankle (acampsia, strongly cartilagenous ankle, no flexure of the tarsal joints), absence of fibula, polydactyly, flabby legs (external, slightly paralyzed), scoliosis, lordosis, and extra thoracic ribs. With the exception of polydactyly and extra thoracic ribs, they did not occur spontaneously in control animals. Flabby legs, mild scoliosis, and lordosis occurred even at 100 mg/kg.
Visceral malformations:
effects observed, treatment-related
Description (incidence and severity):
Only a few visceral malformations were found altogether but all cases were in 2-EHA-treated animals. There was one hydronephrosis at the dose level of 600 mg/kg. Kidney hypoplacia and rudimentary adrenal were also observed in the 300 and 100 mg/kg group respectively. A convoluted retina was also observed at the dose level of 600 mg/kg.
Other effects:
effects observed, treatment-related
Description (incidence and severity):
The incidence of several skeletal variations was increased in 2-EHA-treated animals, including the 100 mg/kg dose group. The frequency was highest at 600 mg/kg. The reduced ulna and lumbar ossification as well as the cases of twisted hind legs are in concordance with the more drastic malformations in feet.
Among visceral variations, curved or dilated ureter, congestion in the kidney cortex and displacement of the kidney occurred only in 2-EHA groups but pelvic dilatation was common in all animals. The incidence of slightly dilated brain ventricles was increased in the dose groups of 300 and 600 mg/kg. The frequency was higher in females than that in males (9 and 4 at 300 mg/kg, 15 and 9 at 600 mg/kg). The degree of dilatation of brain ventricles is known to reflect the developmental stage of the conceptus and the data fit well with the observation that the body weights of fetuses were slightly retarded at 600 mg/kg and in female fetuses also at 300 mg/kg.
Key result
Dose descriptor:
LOAEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
skeletal malformations
Key result
Abnormalities:
effects observed, treatment-related
Localisation:
skeletal: skull
skeletal: forelimb
skeletal: sternum
skeletal: rib
skeletal: vertebra
skeletal: pelvic girdle
skeletal: hindlimb
visceral/soft tissue: hepatobiliary
visceral/soft tissue: urinary
visceral/soft tissue: eye
other: Dilation of brain ventricles
Description (incidence and severity):
2-EHA affected particularly skeletal development of the fetuses. The spectrum of changes ranged from skeletal variants to clubfoot, including a few cases of retarded lumbar and ulna ossification. Clubfoot does not occur spontaneously in rats and it must be regarded as a definitive indicator of teratogenicity. Most of the skeletal variations occurred also in control animals but with a lower frequency. In the present study variations already increased at doses which did not cause visible maternal toxicity. The skeletal variations are known to reflect to some extent delays in the stage of normal development. Meanwhile, 2-EHA did not markedly affect development of visceral tissues. There was only one case of hydronephrosis at the highest dose level and other minor changes were scattered without dose dependence. All cases, however, occurred in 2-EHA-treated animals.
Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
100 mg/kg bw/day (nominal)
Treatment related:
yes
Relation to maternal toxicity:
developmental effects in the absence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
not specified

2-EHA affected development of the embryos/fetuses at all dose levels. The number of affected fetuses (having skeletal or visceral malformation) increased in a dose-dependent manner (p < 0.001) being 4.9, 8.9, and 15.3% per litter in 2-EHA groups vs 2.4% in the control group.

Conclusions:
The results indicate that 2-EHA is teratogenic, i.e., increases malformations in Wistar rats at doses which are apparently not maternally toxic, embryotoxic, nor frankly fetotoxic. There was a dose-dependent increase in the frequency of skeletal malformations starting at a dose level of 100 mg/kg. The dose 300 mg/kg was slightly fetotoxic in females as indicated by the reduced body weight in female fetuses. The 600 mg/kg dose was slightly fetotoxic in both sexes and maternally toxic as judged by the reduction of the body weights of the fetuses and dams. With regard to teratogenicity, the lowest-observed-adverse-effect-level (LOAEL) was 100 mg/kg and the NOAEL (no-observed-adverse-effect level) was lower than the lowest dose administered.
Executive summary:

The developmental toxicity of 2-ethylhexanoic acid (2-EHA), a wood preservative and a mammalian metabolite of di-(2-ethylhexyl) phthalate was examined in Wistar rats (20-21 pregnant females/dose). Mated animals were exposed to 2-EHA in their drinking water at doses of 100, 300, or 600 mg/kg/day on Days 6-19 of gestation. Control animals received vehicle water. The

fetuses were examined (on Gestational Day 20) for external, visceral, and skeletal malformations and variations.

2-EHA was marginally toxic to the dams at 600 mg/kg, but not at lower doses, since the mean near term body weight was reduced by 11%. This dose level was also slightly fetotoxic as indicated by a 5 to 8% decrease in the mean fetal body weight both in males and females. No treatment-related effects were observed in the number of implantations or live fetuses. At doses of 100 mg/kg and above, 2-EHA caused skeletal malformations (clubfoot, absence of fibula, polydactyly), while the development of visceral tissues was less affected. The number of affected fetuses increased in a dose-dependent way (4.9,8.9, and 15.3% of treated offspring at 100, 300, and 600 mg/kg/day, respectively, vs 2.4% control). See attachment Pennanen 1992 - Table 2 and Table 3.

These results indicate that 2-EHA is teratogenic in rats already at doses which are not yet maternally toxic. The skeleton appears to be the main target of 2-EHA in developing rats. With regard to teratogenicity, the lowest-observed-adverse-effect-level (LOAEL) was 100 mg/kg and the NOAEL (no-observed-adverse-effect level) was lower than the lowest dose administered.

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Read Across to an analogue based on structural similarity. An analogue justification is attached to section 13 of the dataset.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across: supporting information
Vehicle:
corn oil
Mortality:
mortality observed, treatment-related
Description (incidence):
One doe each died at 125.0 and 250.0 mg/kg/day.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The only significant change among groups for maternal weight change was a significant decrease for gd 18-29 (the post-treatment period) at 250.0 mg/kg/day.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Food consumption was significantly reduced only at 250.0 mg/kg/day for gd 25-26, 27-28, 28-29 and gd 18-29 (post-treatment period).
Number of abortions:
effects observed, treatment-related
Description (incidence and severity):
One doe aborted at 125.0 mg/kg/day.
Details on maternal toxic effects:
Details on maternal toxic effects:
One animal died in the high-dose group and another one died at the mid-dose level. One doe aborted in the mid-dose group. Body weight was decreased in the high-dose group on GD 18-29. Hypoactivity, ataxia, audible respiration, gasping and coughing was noticed in the high-dose group, though not statistically significant. Food consumption was reduced during the post-exposure period in the high-dose group.
Key result
Dose descriptor:
NOEL
Effect level:
25 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
body weight and weight gain
food consumption and compound intake
mortality
Key result
Abnormalities:
effects observed, treatment-related
Localisation:
other: One doe aborted at 125.0 mg/kg/day.
Description (incidence and severity):
One doe aborted at 125.0 mg/kg/day.
Key result
Dose descriptor:
NOEL
Effect level:
> 250 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No fetotoxicity observed in this study.
Developmental effects observed:
not specified
Conclusions:
Administration of 2-ethylhexanoic acid by gavage to timed-pregnant New Zealand white rabbits during organogenesis at 0.0, 25.0, 125.0 or 250.0 mg/kg/day resulted in maternal toxicity at 125.0 and 250.0 mg/kg/day (mortality at 125.0 and 250.0 mg/kg/day, abortion at 125.0 mg/kg/day, and reduced weight gain and clinical signs of toxicity at 250.0 mg/kg/day). No developmental toxicity was observed at any doses employed. The "no observable effect level" (NOEL) for maternal toxicity was 25.0 mg/kq/day and the NOEL for developmental toxicity was at least 250.0 mg/kg/day. There was no treatment-related increased incidence of malformations at any dosage employed.
Executive summary:

Timed-pregnant New Zealand white rabbits were exposed to 2-ethylhexanoic acid by gavage on gestational days (gd) 6 through 18 at doses of 0.0, 25.0, 125.0 or 250.0 mg/kg/day in certified corn oil, 15 mated females per group. The dose volume employed was 2.0 ml/kg based on the body weight of each female on gd 6. Clinical observations were taken daily (twice daily during dosing) and maternal body weights were taken on a11 study females on gd 0, 6, 12, 15, 18, and 29. Maternal food consumption was measured daily, gd 0-29. At scheduled sacrifice on gd 29, the does were evaluated for body weight, liver and gravid uterine weight, number of corpora lutea and number and status of implantation sites (i.e., resorptions, dead fetuses, live fetuses). Sections of maternal liver were retained in fixative for possible subsequent microscopic examination. All live fetuses were dissected from the uterus, counted, weighed, and examined for eternal malformations (including cleft palate), and variations. All live fetuses in each litter were also examined for visceral malformations and variations by the method of Staples (1974) and sexed internally. Approximately one-half of the live fetuses in each litter were then decapitated and the heads fixed in Bouin's solution and examined for soft tissue craniofacial malformations according to the techniques of Wilson (1965, 1973) and van Julsingha and Bennett (1977). All fetuses in each litter (50% intact and 50% decapitated) were eviscerated, fixed in alcohol, stained with alizarin red S and examined for skeletal malformations and variations.

One doe each died at 125.0 and 250.0 mg/kg/day and one doe aborted at 125.0 mg/kg/day. No females delivered early. Two does were removed from study, one each at 125.0 and 250.0 mg/kg/day, due to dosing error. Pregnancy rate was equivalent across all groups. All pregnant females had one or more live fetuses at scheduled sacrifice.

Maternal toxicity was also indicated by significant reduced weight gain for gd 18-29 (post-treatment period) at 250.0 mg/kg/day. Treatment-related clinical signs were observed only at 250.0 mg/kg/day. Food consumption was reduced at 250.0 mg/kg/day in the post-treatment period. At the gd 29 sacrifice, there were no effects of treatment on maternal body weight (absolute or corrected), gravid uterine weight, or on absolute or relative liver weight. Gestational parameters, including ovarian corpora lutea of pregnancy, implantations per litter (viable, nonviable and total), sex ratio, and fetal body weights per litter were unaffected by treatment.

There was no significant increase in the incidence of malformations (individual, external, visceral, skeletal or total) in any treated group relative to controls. There were no treatment-related differences among groups for individual or pooled external, visceral, skeletal or total variations.

Administration of 2-ethylhexanoic acid by gavage to New Zealand white rabbits during organogenesis resulted in evidence of maternal toxicity at 125.0 and 250.0 mg/kg/day. No embryotoxicity, fetotoxicity, or teratogenicity was observed at any dosage employed. The “no observable effect level” (NOEL) for maternal toxicity was 25.0 mg/kg/day and the NOEL for developmental toxicity was at least 250.0 mg/kg/day.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
100 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

2 -Ethylhexanoic acid has been tested in 90 day toxicity studies in rats and mice, and there were no effects noted on reproductive organs.

Skeletal and visceral malformations were noted in the offspring of rats exposed to gavage doses of EHA in drinking water of 100 mg/kg/d and above (LOAEL = 100 mg/kg/d). Based on this effect on development, a classification as toxic to reproduction Category 2 (repr. 2) is applied. This classification is already a harmonised classification, as it is derived from the harmonised classification of the hydrolysis product 2-ethyl hexanoic acid.

Additional information