2-ethylhexyl acetate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Additional information

There is no fertility study available for 2 -ethylhexyl acetate (2 -EHAc).

However, a weight of evidence approach was performed with a two generation reproduction toxicity study according to OECD guideline 416 with di (2 -ethylhexyl) terephthalate (DEHT, CAS 6422-86-2) and OECD 422/443 studies with 2 -ethylhexanoic acid (CAS 149-57-5) to cover the endpoint’s requirements.

The weight of evidence approach is considered adequate as

- DEHT is metabolised immediately and entirely to 2 -ethylhexanol (2 -EH; hydrolysis product and thus potential metabolite of 2 -EHAc) and terephthalic acid. 2 -EH is thus available in the organism after DEHT application (for further details please see section on toxicokinetics and paragraphs below).

- The highest dose tested in the two generation study with DEHT is in the range of the maximum tolerable dose (MTD) for 2-EH as required by the testing guideline.

For estimating the maximum possible dose of 2-EH in the two generation study with DEHT the following assumptions were made:

- Only 50% absorption of DEHT: In the gavage study by Barber et al. (1994) approximately 65 mg of 100 mg DEHT administered were absorbed (for details please cf. to section on toxicokinetics). Therefore the approach taken is conservative as the maximum height of 2-EH dose reached after DEHT administration is critical for assessing the validity of the study for read-across.

- Complete metabolism of DEHT to 2-EH (1 mole DEHT leads to 2 mole of 2-EH; for details please cf. to section on toxicokinetics).

The tested doses of DEHT correspond to the following maximum doses of 2-EH

-F0 m/f: 10000 ppm = 447-614/595-1349 mg DEHT/kg/d,

corresponding to 149-205/198-450 mg 2-EH/kg/d

-F1 m/f: 10000 ppm = 552-893/697-1549 mg DEHT/kg/d,

corresponding to 184-298/232-516 mg 2-EH/kg/d

- Observed effects (decrease of body weight) are comparable at approximately equivalent 2 -EH doses in between the two generation study performed with DEHT and the 90-day toxicity study in rats using 2-EH as test material (Astill et al., 1996).

- 2-Ethylhexanoic acid (CAS 149-57-5) is a major metabolite of 2-EH (Deisinger et al., 1994; cf. chapter “Toxicokinetics”).

In a two generation reproduction toxicity study according to OECD guideline 416 thirty Crl: CD®(SD) IGS BR rats/sex/group/generation were exposed to di (2-ethylhexyl) terephthalate (DEHT) in the diet at dose concentrations of 0, 3000, 6000, and 10000 ppm. Treatment of parental animals in the F0 generation started at 52 days of age and PND22 for the F1 generation. Animals received the diets for 70 consecutive days prior to mating, through the mating period (maximum of 14 days), during gestation and lactation until their scheduled necropsy (F0/F1 parental animals: 6 -8 days after weaning, F1 pups not selected for further generation and F2 pups at PND21).

In guideline conform intervals cage side and detailed clinical observations, measurements of body weight and food consumption were performed. Various reproductive and developmental indices were assessed (estrous cyclicity, gonadal functions, spermatogenic endpoints (motility, morphology, counts), mating behaviour and performance, conception, gestation and parturition, and fertility in general; total pup number/litter, mean live litter size, gender ratios, postnatal pup survival, developmental landmarks such as balanopreputial separation and vaginal patency). Parturition was allowed naturally as wells as rearing of pups until weaning. On PND4 thirty F1 pups/sex/group were selected to constitute the F1 generation. Gross necropsies were performed on all animals. Histopathological examinations on various organs and tissues were performed on parental animals whereas for pups only organ weights were determined.

In the high dose group deaths of 3 damns in the F1 generation and 7 damns in the F2 generation were attributed to substance treatment, as the deaths occurred 2 to 8 days after weaning - a period in which the damns maintain their body weights while still consuming large amounts of feed and thus resulting in high dose levels in the body. Single deaths in male animals were not treatment related. In high dose female animals of the F0 and F1 generation mean maternal body weights were reduced during gestation and lactation. Food consumption was also reduced in these dose groups during this time of exposure. In high dose group males of the F0 generation transient reductions of mean body weights occurred during various time points of the study. In the F1 generation males of the high and mid dose group showed reduced body weights starting from birth throughout the study. This was also true for females of the F1 in the mid dose group. Food consumption was reduced in males of the F1 generation in the high dose group throughout the study, whereas in the mid dose group this reduction was limited to the first week after weaning. In the high dose group increases in relative liver weights were observed in F0 and F1 females. This effect was not accompanied by any gross or microscopic findings and thus is not accounted for as adverse.

In the high and mid dose group mean F1 and F2 male and female offspring weights were reduced on PND14 to 21. In the high dose group also reduced pup weights were observed at earlier time points (PND 1 and 7). In the high dose group in both sexes of F1 and F2 pups increased relative brain weights were found. In males of both generations decreased relative spleen weights were also observed. In female animals of the F2 generation reduced relative spleen and thymus weights were noted. In the mid dose group increased relative brain weights were found in females of the F1 generation.

Taken together these results indicate that a NOAEL for parental toxicity can be established at 3000 ppm (133 to 516 mg DEHT/kg x d). Substance treatment had no adverse toxicological effect on any of the measured reproductive parameters for the F0 and F1 generations. Therefore, the no-observed-adverse-effect level (NOAEL) for reproductive toxicity was considered to be 10000 ppm (F0 m/f: 447 -614/595/1349; F1 m/f: 552 -893/697-1549 mg DEHT/kg x d). The NOAEL for developmental toxicity was considered to be 3000 ppm (Faber et al., 2007).

 

As a dose-range finder for an OECD 443 study with 2 -ethylhexanoic acid, an oral repeated dose toxicity study and reproduction/developmental toxicity screening test based on OECD 422 was performed at concentrations of 0, 1538, 4615 and 15385 mg/kg diet (TNO, 2015). In addition, satellite groups were incorporated into this study which were sacrificed after mating on gestation day 20 to compare the analytical results with the results observed in the animals sacrificed on PN day 4 to 7 in order to gain knowledge regarding the possible mechanisms of toxicity.

No mortalities occurred and no treatment-related clinical signs were observed during the study. During a major part of the study the body weight and food consumption of the male and female animals of the high-dose group were decreased (up to 10% decreased body weight in females at the end of gestation). Haematology conducted on PN days 4-7 showed lower values for mean corpuscular volume, mean corpuscular haemoglobin concentration and reticulocytes in the high-dose group compared to controls. Total white blood cells, monocytes and the absolute number of neutrophils were higher than in controls in females of the high-dose group. Clinical chemistry conducted on PN days 4-7 showed lower total protein concentration and albumin concentration than in controls in females of the high-dose group while the albumin/globulin ratio was higher. Clinical chemistry conducted on day 30 showed an increase in bile acids in high-dose males. The relative weight of the liver was increased in the high dose group in both sexes. The absolute and relative weights of the thymus were lower in high dose females than in controls. The relative weight of the kidney was increased in high-dose males. Microscopic examination showed an increased incidence of proteinaceous droplets in the kidney renal tubuli of high dose males. The incidence of extramedullary hematopoiesis in the spleen was reduced in high-dose females.

No effect was observed on fertility and reproductive performance of the male and female animals. No effects were observed on the incidences of liveborn and stillborn pups and fetuses, viability indices of pups and fetuses, sex-ratio’s and pup- and fetal observations. The weight of the pups of the high-dose group was decreased on PN day 4 (14%). At Caesarian section performed on GD 20, no effects were observed on fetal weight and on the weight of the placenta. No effects on zinc concentrations were observed in male animals whereas the mean zinc concentration in female animals of the high-dose group was higher in liver (F0-generation females sacrificed at Caesarian section) and kidneys (all F0-generation females and pups) than in the control group. Except for a higher concentration of metallothionein-1 in liver of male animals of the high-dose group as compared to controls, no effects were observed on the concentrations of metallothionein-1 (MT-1) and metallothionein-2 (MT-2) in kidneys and livers of male animals. With the exception of the concentration of MT-1 in kidneys of female animals of the high-dose group which was not affected, MT-1 and MT-2 concentrations in kidneys and livers of female animals of the high-dose group was higher than in the corresponding organs of the females of the control group.

In conclusion, there were no effects of 2 -ethylhexanoic acid on fertility and reproductive performance at any dose level. Based on lower pup weights as observed in the high-dose group, the NOAEL for developmental toxicity was placed at the mid-dose concentration of 4615 mg/kg diet (corresponding to at least 248 mg/kg bw/d for male and 308 mg/kg bw/d for female animals). Based on the effects on body weights, food consumption, organ weights, haematology and clinical chemistry, zinc- and metallothionein concentrations in animals of the high dose group, the NOAEL for parental effects was placed at the mid-dose concentration of 4615 mg/kg diet (corresponding to at least 248 mg/kg bw/d for males and 308 mg/kg bw/d for female animals).

The reproductive toxicity of 2-ethylhexanoic acid was investigated in an extended one generation reproductive toxicity study according to OECD 443 (TNO, 2016). The objective of this study was to provide data on the possible effects on reproductive performance of male and female Wistar rats and on the development of pups consequent to daily oral administration of various concentrations (0, 1231, 3845 and 12308 mg/kg diet) of the test item during a premating period of 2 weeks and during mating and gestation. During the lactation period, the concentration in the diets was halved. At weaning, pups were distributed to different cohorts and exposed to the same dose levels as their parents during growth into adulthood. The first cohort was assessed for reproductive performance, the second cohort focused on neurodevelopmental endpoints and the third cohort was examined for developmental immune toxicity. Based on equivocal results of the F0-generation of this study, a second mating of the animals of cohort 1B was triggered. Therefore, the animals of cohort 1B were used for breeding of a second generation.

During the F0-generation, two male animals of the high-dose were untimely sacrificed in a moribund condition. During the F1-generation, one female animal of the low-dose group of Cohort 1A and one male animal of the cyclosporine A positive control group of Cohort 3 were found dead. The macro- and micro-observations in these animals were not considered to be related to treatment. Furthermore, no treatment-related clinical signs were observed during the study. Body weight and food consumption of male and to a lesser extend of female animals of the high-dose group were slightly, but statistically significantly decreased in major parts of the F0- generation and F1-generation. During the second part of the lactation periods of the F0-generation and the F1-generation of Cohort 1B (most probably the pups start to eat) and in the first weeks of the F1-generation of each Cohort (food consumption is relatively high in young animals) the food consumption was relatively high. Consequently, test item intake during these period was higher than anticipated and reached a maximum value of 183, 669 and 1842 mg/kg body weight/day for the low- (F1- generation female animals of Cohort 2A and Cohort 3) and mid- (F1-generation male animals of Cohort 3) and high-dose (F1-generation male animals of Cohort 2A) groups, respectively. The statistically significant slight increases in both the absolute and relative weights of the liver and kidneys of males and females of both generations were considered to be related to treatment. Microscopic examination revealed a treatment-related effect in the kidneys of high-dose male animals of the F0-generation and of the male animals of Cohort 1A of the F1-generation. In the F0-generation, minimal to moderate accumulation of proteinaceous droplets in the tubuli was observed. In the male animals of the high-dose group of Cohort 1A, an increase in both the incidence and the severity of proteinaceous accumulation was observed in the tubuli. Similarly, an increase in both the incidence and the severity of basophilic tubuli formation was observed in the high-dose group in comparison to the control group.

Regarding fertility and reproductive performance parameters, no treatment-related effects were observed on estrus cycle in animals of the F0-generation and in animals of Cohort 1A of the F1-generation. Furthermore, no treatment-related effects were observed on fertility and reproductive performance of male and female animals of the F0-generation and of Cohort 1B of the F1-generation and no effects were observed on epididymal and testicular sperm parameters in animals of the F0-generation and of Cohort 1A of the F1-generation. No effects were observed on TSH and T4 analysis in animals of the F0-generation and of Cohort 1A of the F1-generation.

Regarding general and sexual developmental parameters, no treatment-related effects were observed on the incidences of liveborn and stillborn pups, pup viability indices, sex-ratio’s, pup weights and clinical and macroscopic observations in F1- generation pups and Cohort 1B F2-generation pups. No effects were observed on nipple retention in male F1-generation pups. No effects were observed on sexual maturation parameters (preputial separation and vaginal opening) in F1-generation pups and no effects were observed on organ weights of F1-generation pups. Furthermore, no treatment-related effects were observed on the development of the follicles from primordial small follicles into corpora lutea. The statistically significant effects on anogenital distance after correction for pup weights as observed in F1-generation male pups on postnatal day 4 were considered fortuitous findings that were not related to treatment. The anogenital distance in the male pups was higher than in control male pups whereas in case of endocrine related activity a decrease would be expected. Furthermore, no effects were observed on anogenital distance on postnatal days 0 and 4 in F2-generation pups.

Regarding neuro(developmental) parameters (cf. IUCLID chapter 7.9), Functional observation battery (FOB) and spontaneous motor activity analysis did not reveal any effect of the test item in animals of Cohort 2A of the F1-generation. The results of the auditory startle response did not indicate any neurotoxic potential of the test item in animals of Cohort 2A. No treatment-related adverse effects were observed on brain weight, brain length and brain width measurements in animals of Cohort 2A and Cohort 2B, respectively. No treatment-related differences were observed in thicknesses of 10 major regions of the brain regions as measured in male and female animals of the control and high-dose group. Macroscopic observation at sacrifice of animals of Cohort 2A and Cohort 2B did not reveal any treatment-related abnormalities. Microscopic observations of brains and neuronal tissues of animals of Cohort 2A and brains of animals of Cohort 2B revealed no treatment-related abnormalities.

Regarding immune(developmental) parameters (cf. IUCLID chapter 7.9), no effect was observed on the composition of the splenic lymphocyte subpopulation in animals of Cohort 1A of the F1-generation. In contrast to the positive control cyclosporine A, the test item had no effect on the KLHspecific IgM antibody levels in animals of Cohort 3 of the F1-generation.

In conclusion, the NOAEL for fertility and reproductive performance of F0- and F1-generation animals, general and sexual developmental parameters, (developmental) neurotoxicity and immune toxicity parameters was the highest dose tested (12308 mg/kg diet).

Based on the effects on body weights, food consumption, kidney and liver weights and kidney pathology in animals of the high-dose group, the NOAEL for parental effects was the mid-dose concentration of 3845 mg/kg diet.

Furthermore two non guideline in vitro and in vivo studies applying 2-EH are available.

- When 2-EH was administered to cells of mouse Leydig tumour cell line, MA-10, in concentrations up to 1 mM for at least 24 hours the test material did not reveal any cytotoxic effects nor did 2-EH reduce steroidogenic potential of the cells (no reduction of progesterone production or gene expression of key steroidogenic enzymes; Piche et al., 2012, cf. IUCLID section 7.9.3).

- The effects of 2-EH (and also of DEHP, MEHP, and 3 metabolites of MEHP; all test substances were administered at 2.7 mmol/kg bw/day for 5 consecutive days) were examined in vivo and in vitro by Sjöberg et al., 1986. No testicular damage was seen in rats that were dosed with 2-EH, i. e. the number of degenerated cells in the seminiferous tubules was not increased, whereas this was the case with MEHP. This was supported by the observation that MEHP in the range 1–200 µM increased significantly the detachment of germ cells in primary rat testicular cell cultures. 2-EH had no effect at 200µM. It was concluded that MEHP, but not 2-EH was responsible for testicular damage observed after dosing DEHP (cf. IUCLID section 7.9.3).

Taken the results of the two generation study with DEHT and the reproductive toxicity studies (OECD 422/443) with 2-ethylhexanoic acid together with studies for 2-EH which demonstrate the lack of toxicity to reproduction, i. e.

- no adverse effect on any gestational parameter in prenatal developmental studies with various routes of exposure (NTP 1991- oral; Tyl et al, 1992 –dermal; Nelson et al., 1989 –inhalation; cf. IUCLID section 7.8.2),

- no effect on testes and ovaries of rats and mice in 90-d oral gavage studies (Astill et al., 1996; cf. IUCLID section 7.5.1),

- no anti-androgenic activity in vitro (Piche et al., 2012), or

- no degeneration of testes (in vivo) and sertoli cells (in vivo and in vitro), Sjöberg et al., 1986

the overall evidence is given that 2 -EH and thus 2 -EHAc is not triggering adverse effects on reproduction.

In 2014, 2 -EH was evaluated as CoRAP substance by the Member State Competent Authority of Poland. Conclusion: "Based on these data it is concluded that 2 -EH is not affecting fertility and sexual function and it does not warrant classification to this hazard category."

Short description of key information:
There is no reproductive toxicity study available for 2-EHAc.
Taken the results of a two generation study with DEHT (precursor of 2-ethylhexanol) and the studies (OECD 422/443) conducted with 2-ethylhexanoic acid (metabolite of 2-EH) together with various studies for 2-EH which demonstrate the lack of toxicity to reproduction (e. g no adverse effect on any gestational parameter in prenatal developmental studies, no effect on testes and ovaries of rats and mice in 90-d oral gavage studies, no anti-androgenic activity in vitro or degeneration of testes (in vivo) and sertoli cells (in vivo and in vitro)) it can be reasonably concluded that 2-EH and thus also 2-EHAc is not affecting fertility or sexual function.

Effects on developmental toxicity

Description of key information

There is no developmental toxicity study available for 2-EHAc.
The hydrolysis product 2-EH revealed no signs of maternal or developmental toxicity in mice treated with 191 mg/kg bw/d (oral); the NOAEL was 191 mg/kg bw/day.
In a gavage study in rats developmental toxicity as well as teratogenic effects were observed at the highest dose group tested (1300 mg 2-EH/kg bw/d), but only in the presence of severe maternal toxicity.
No maternal or developmental toxicity or teratogenicity was seen after inhalation exposure of rats at 850 mg 2-EH/m³ within gestation days 0-19 for 7 hrs/day.
Following dermal application during gestational days 6-15, local skin irritation was seen at 850 mg 2-EH/kg bw/day; slight maternal toxicity at 2520 mg/kg bw/d but no developmental toxicity or teratogenicity was seen up to the highest dose tested (2520 mg/kg bw/d).
The results of animals studies provide evidence of an adverse effect of 2-EH on development at very high doses  causing strong toxic effects in dams including mortality. Thus, the observed effects can be considered as a secondary non-specific consequence of other toxic effects. If 2-EH was administered at doses that are not toxic or are only slightly toxic to maternal animals, no developmental toxicity warranting classification was observed.

Additional information

There is no developmental toxicity study with 2 -EHAc available. Reliable data were available for the structural analogon and potential metabolite, 2-ethylhexanol (2 -EH).

Oral:

2-EH was examined in a mouse developmental toxicity feeding study equivalent to OECD TG 414 and under GLP conditions. Timed pregnant female CD-1 Swiss mice (28 animals/group) received 2-EH in the diet at nominal concentrations of 0, 0.009, 0.03, and 0.09% during gestation days 0-17.Food intake and hence dose levels were higher than expected. Average intakes were 0, 17, 59, and 191 mg/kg bw/day, respectively. No dams died, delivered early or were removed from study. One control litter was fully resorbed; all other pregnant animals had live litters at scheduled necropsy.

Maternal body weights, weight gains (absolute or corrected for gravid uterine weight), gravid uterine weight and liver weight (absolute or relative to body weight) were unaffected. Food consumption was significantly increased for GD 0-3 at 0.09% and unaffected for all other time points evaluated.

There were no effects observed on any of the gestational parameters.The number of corpora lutea, uterine implantation sites (live, dead, resorbed), pre- and postimplantation loss, sex ratio and live fetal body weight per litter (all fetuses or separately by sex) were all equivalent across all groups. There were also no treatment-related changes in the incidence of individual, external, visceral, skeletal or total malformations or variations.

In conclusion, there were no maternal or developmental toxic effects of 2-EH dietary exposure throughout gestation at any concentration tested, in contrast to the qualitatively similar maternal and developmental toxicity previously reported for DEHP (Tyl et al., 1988; not presented here, cf. respective substance dossier) and MEHP (NTP, 1990; not presented here, cf. respective substance dossier) at approximately equimolar doses administered under comparable experimental conditions. The present study therefore indicates that 2-EH plays essentially no role in the expression of DEHP-induced maternal and developmental toxicity. The NOAEL for maternal toxicity and for developmental toxicity and teratogenicity was therefore 191 mg/kg bw/day, the highest dose level tested. This study was conducted equivalent to OECD TG 414 and under GLP conditions, and it is considered to be valid without restriction (Tyl et al., 1991 corresponds to IUCLID study record NTP, 1991).

The developmental toxicity of 2 -EH was furthermore investigated in an oral gavage study according to OECD TG 414. The study addressed all the endpoints required in the OECD TG 414 and was conducted under GLP, but used lower animal numbers (due to the fact that the study purpose was a comparative screening for several alcohols; only 10 instead of 20 pregnant females). This invalidates the study to some extent, but it provides weight of evidence for the developmental toxicity endpoint. Animals were treated on GD 6 to 15 via gavage at concentrations of 130, 650, and 1300 mg/kg bw/d. Controls were either treated with water only or with vehicle (i. e. 0.005% Cremophor EL).

Distinct maternal toxicity was observed at the high dose level including mortality (6/10 animals). Therefore the NOAEL is 650 mg/kg/d for this endpoint under the conditions of this study.

Significant signs of embryo-/fetotoxicity were noted in dams showing distinct maternal toxicity at 1300 mg/kg/d. The observed slightly decreased mean fetal bw in mid dose group was within the range of historical controls. Since the original statistical evaluation of the study was assessed to be invalid, a reevaluation was performed by using Wilcoxon test (based on litter data). Within this statistical reevaluation the statistical significance of skeletal variations at mid dose was not confirmed. The incidence of skeletal retardations was also significantly increased at mid dose, however, skeletal retardations of control goups also exceeded the historical control values. In agreement with current expert opinion and Regulation (EC) No 1272/2008, skeletal retardations can be considered as transient non-adverse effects.Teratogenicity was noted in fetuses from the high dose dams only. Under the conditions of this study, the NOAEL for maternal tox. and developmental tox./teratogenicity was 650 mg/kg/d (BASF AG, 1997).

Dermal:

The developmental toxicity of 2-EH following dermal absorption was examined in an OECD TG 414 study with F344 rats that was conducted under GLP. 2-EH was applied to the skin of 25 females at 0, 252, 840, and 2520 mg/kg bw/day under an occlusive dressing during gestational days 6 -15 for 6 hours per day. There were no deaths or severe clinical signs of toxicity. A reduced body weight gain in high-dose rats was noted and local skin irritation in rats at the intermediate and the high dose level. 2-EH had no adverse effect on the maternal gestational parameters, or maternal organ weights, or on the fetal weight, sex ratio, viability, or the incidence of malformations and variations.

Therefore, the NOAEL for maternal systemic toxicity was 840 mg/kg bw/day, based on the effects on body weight gain; the NOAEL for skin irritation was 252 mg/kg bw/day. The NOAEL for developmental toxicity and teratogenicity was 2520 mg/kg bw/day (Tyl et al., 1992).

Inhalation:

No maternal or developmental toxicity was noted in a rat inhalation study that was conducted similar to OECD TG 414; the study is considered valid though less animals (n = 15) than suggested by the test guideline. The rats were exposed during days 0-19 of gestation to 2-EH at 850 mg/m³.There were only minor signs of maternal toxicity, i. e. reduction of feed consumption and body weight gain during gestation. The reproduction parameters were unaffected. There was no indication of developmental toxicity or teratogenicity, as the incidences of resorptions, the number of fetuses per litter, the sex ration, fetal weight, were all comparable to the control group. Moreover, there were no external, skeletal or visceral malformations observed in any group.The inhalationNOAECfor maternal toxicity and developmental toxicity and teratogenicity was therefore 850 mg/m³ (Nelson et al., 1989).

Other oral or inhalation developmental toxicity studies are judged as invalid due to extreme maternal toxicity including mortality, major methodological and/or reporting deficiencies (Hardin et al., 1987; Ritter et al., 1987; NTP, 2007a). These studies are considered invalid and do not contribute to the overall hazard assessment concerning developmental toxicity of 2 -EH. 2 -EH has been selected for CoRAP evaluation in 2014. One of the reasons for selection of 2-EH was health hazard concern. It was noted that developmental effects were observed in the pre-natal developmental toxicity studies, therefore a full evaluation of the available information was required in order to assess whether the observed developmental effects are the result of maternal toxicity. The evaluating Member State Competent Authority of Poland concluded on the endpoint developmental toxicity: "The results of animals studies provide evidence of an adverse effect of 2-EH on development at very high doses causing strong toxic effects in dams, therefore they can be considered as a secondary non-specific consequence of other toxic effects. In case when doses of 2-EH are not toxic or are only slightly toxic to maternal animals no developmental toxicity warranting classification is observed." According to US EPA (US EPA 2006) although some of the developmental toxicity studies showed effects; however these are not of concern due to limitations in the studies. For example, Hardin et al (1987) reported teratogenic effects in the offspring but they occurred at a high dose (1,525 mg/kg/day) and in the presence of severe maternal toxicity; only a single dose level was used in the study. Ritter et al (1987) also reported developmental effects in offspring at a high dose (1,600 mg/kg bw) but they did not report whether or not there were maternal effects so it is difficult to determine the significance of their data. A key oral developmental toxicity study, that conducted by NTP (1991) in mice, concluded that 2-EH did not cause maternal or developmental toxic effects at doses as high as 135 mg/kg/day. A dermal toxicity study conducted in mice and rats showed no developmental toxicity at 3.0 mL/mg/day. An inhalation study performed using rats showed no developmental toxicity at 850 mg/rn³(190 ppm). In summary, US EPA believes that the overall weight of evidence shows that 2-EH is not developmentally toxic.

Justification for classification or non-classification

Based on the results of reliable studies with the structural analogon and potential metabolite of 2 -EHAc, 2-ethylhexanol, there is no indication given for reproductive toxicity and developmental toxicity below maternally toxic doses; therefore, 2 -EHAc has not to be classified according to 67/548/EEC and GHS requirements, respectively.