2-aminobutan-1-ol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Dose descriptor:

NOAEL

213 mg/kg bw/day

Additional information

Fertility

 

The key study for this end point is the oral (diet) OECD 422 study on 2 -aminobutanol (hydrochloride salt). 

In the OECD422 study on 2 -aminobutanol there were no effects on male or female reproductive parameters. In the mid and high dose group there were effects on litter size due to post implantation loss. These effects were considered to be developmental rather than fertility effects and as such are discussed in the developmental summary. The No observed effect level for fertility is therefore the highest dose, 213 mg/kg bw/day.

Read across information:

In the OECD 421 using AMP and the 2 -generation study on 4,4 -Dimethyloxazolidine there were no effects on reproductive organs or fertility parameters.

The absence of any fertility effects in these studies on structurally related substances indicates that 2 -aminobutanol is not toxic to reproduction and as such a 2 -generation study on 2 -aminobutanol is not considered appropriate.

Short description of key information:
Standard OECD 422 Reproductive/development and repeated dose toxicity screen.
Read across information:
Oral OECD 421 uisng AMP
2-Generation study using 4,4-dimethyloxazolidine

Effects on developmental toxicity

Description of key information

Studies on AMP
Standard Guideline OECD 421 Reproductive screening study (rat, oral, diet)
Standard Guideline OECD 414 Developmental toxicity study (rat, dermal)
Mode of action studies similar in protocol to OECD 421 
2 Whole embryo culture studies
Studies on CS1135 (4,4-dimethyloxazolidine)
2-Generation reproductive toxicity study
OECD Guideline 414 Oral Developmental toxicity study (rabbit, gavage)
OECD Guideline 414 Oral Developmental toxicity study (rat, gavage)

Effect on developmental toxicity: via oral route

Dose descriptor:

NOAEL

7.1 mg/kg bw/day

Additional information

Developmental

In the OECD 422 study there was evidence of post implantation loss. In the highest dose group (300 mg/kg 2-AB-HCl) all females failed to produce a litter. This absence of litters was caused by resorption of the embryos rather than failure to conceive and as such was considered as a developmental effect. In the mid dose group (50 mg/kg 2-AB-HCl) the average litter size was not significantly different to control however there did appear to be a non-significant reduction in average litter size. This was highlighted by comparing the mean percentage post implantation loss in the control and mid dose group which showed a significant difference between the mean percentage post implantation loss (24% in the mid dose group compared to 3% in the control). In addition there was one female with a completely resorbed litter, and one female that failed to conceive. The failure to conceive was not considered as a treatment related effect on fertility in this female since a female in the control group also failed to conceive and the incidence was within the historical control range. In light of the complete litter loss in the high dose females, the increase in mean percentage implantation loss in the mid dose group was considered a treatment related effect. The bodyweight data and pathology of the uteri indicated that the post implantation loss in this group and the high dose group occurred early in pregnancy. There were no treatment related effects in the low dose group (10 mg/kg 2-AB-HCl). Since the hydrochloride salt of 2-aminobutanol was used the corrected dose levels for 2-aminobutanol in this study were 7.1, 35.5, and 213 mg/kg bw/day.

In addition to the reproductive findings, there were also signs of systemic toxicity. In the 300 mg/kg/day group, male and female adult toxicity included decreased body weight and feed consumption, dermal irritation (acanthosis, inflammation, erosions and/or ulcers) possibly induced by feed contact during grooming, and an increased incidence of very slight centrilobular/midzonal hepatocyte hypertrophy, a finding associated with increased liver weights in males but not females. In high-dose males there were treatment-related increases in serum urea nitrogen, alanine aminotransferase, aspartate aminotransferase, and cholesterol, with the increased urea nitrogen and cholesterol likely being secondary to the lower body weight and reflective of a marginal change in protein catabolism and fat mobilization. In the 50 mg/kg/day group, parental toxicity was limited to increases in relative liver weights in males and adrenal weights in females. In the absence of associated clinical chemistry and histopathologic findings these weight differences were not interpreted to be adverse but possibly adaptive. There was no systemic toxicity in the animals given 10 mg/kg/day. There were no neurologic effects in any dose level tested.

It is unlikely that the maternal toxicity in the high dose group was responsible for the complete litter loss observed and this is supported by the litter loss in the mid dose group in the absence of any significant maternal toxicity.

The characteristics of the observed reproductive/developmental toxicity (steep dose response, early post-implantation loss, evidence of hepatotoxicity) are consistent with effects observed in rats exposed via the diet to a structurally related compound, 2-amino-2-methyl propanol (AMP).

In order to better characterize the toxicity observed with 2-aminobutanol data from the analogue AMP is used since the structural similarity and the similarity in the effect indicate a common mechanism may be responsible, although differences in potency appear to exist.

The developmental toxicity of AMP has been assessed in a number of developmental studies and reproductive screening studies using the hydrochloride salt of AMP and the AMP base. In addition, data from 4,4-dimethyloxazolidine can be used as support since this substance hydrolyzes in the stomach releasing AMP and formaldehyde in a 9:1 molar ratio.

Data on AMP

In a standard guideline OECD 421 study (Carney et al.,2005) where rats were dosed via the diet with either 0, 100, 300 or 1000 mg. kg bw AMP-HCl salt (approximately equivalent to 72, 220 and 720 mg/kg bw/day AMP base), an increased incidence of post implantation loss in the mid dose group (mean loss per litter of approx 70%) and the high dose group (complete litter loss in all dams). There were no effects at the lowest dose level and no evidence of any other developmental toxicity at any dose level. In the litters where a partial litter loss had occurred, the surviving pups were slightly heavier than control pups and this was likely due to the smaller number of pups being supported by the dams.

In an OECD guideline 414 dermal developmental toxicity study (Carney and Thorsrud 2006) where doses of up to 300 mg/kg bw/day of the AMP base were applied to the skin of rats from gestation day 6 to 20 there was no evidence of any post-implantation loss or developmental toxicity in any dose group. Considering the estimated dermal penetration of approx 40% (Saghir et al.,2007), the potential systemic dose would have been between 100 and 150 mg/kg/bw. The NOEL from this study is consistent with that available from the OECD 421 and two generation reproduction study (described below).

Data on 4,4-dimethyloxazolidine

4,4-dimethyloxazolidine is a reaction product of formaldehyde and AMP. This compound breaks down in the gastrointestinal tract releasing AMP and formaldehyde in a 9:1 molar ratio. This hydrolysis is almost immediate and results in systemic exposure to AMP (Saghir et al.,2007). Subsequently, data produced using 4,4-dimethyloxazolidine can be considered as relevant for the assessment of AMP and subsequently 2-aminobutanol. 

There are two developmental toxicity studies available on 4,4-dimethyloxazolidine, one in the rat and one in the rabbit (Nemec 1989; Rasoulpour and Marshall 2008a). In the rat study (a probe study), animals were dosed with 0, 250, 500, 750, 1000 or 1500 mg/kg bw/day via gavage from days 6-15 of gestation. All animals at doses 750 mg/kg bw/day or higher died. At 250 and 500 mg/kg bw/day there were no developmental effects observed and maternal toxicity was limited to findings relating to the irritancy of the test material to the gastrointestinal tract. In the rabbit study, animals were dosed daily by gavage from gestation day 7 to 27 with doses ranging from 0 to 40 mg/kg bw/day. There was gastric irritation and a significant decrease in maternal bodyweight in the high dose group but there were no effects on fetal development at any dose level.

In a two-generation reproductive toxicity study of 4,4-dimethyloxazolidine (Carney et al.,2008) the high dose group (200 mg/kg bw/day) experienced a statistically significant increase in mean post implantation loss in both generations. Other than the postimplantation loss observed at the highest dose there was no other evidence of reproductive or developmental toxicity. Animals at all doses developed normally through the F1 generation and were capable of successfully producing a second generation therefore there were no effects on the subsequent development of surviving embryos. In this study the high dose of 200 mg/kg bw/day 4,4-dimethyloxazolidine was equivalent to approximately 180 mg/kg bw/day of AMP. Assuming that the AMP released was associated with the observed increase in implantation loss, the level of postimplantation loss in both the P1 and P2 generation was far lower than that observed in the mid dose of the OECD 421 study (approx 18% versus 70%). The degree of postimplantation loss was also consistent between generations indicating that the P2 generation was no more susceptible to the effect than the P1 generation (i.e. there was no ‘trans-generational effect’). The study also demonstrates that the longer dosing period prior to gestation in this study design did not increase the severity of the effect.

Interpretation of findings

In the available standard guideline teratogenicity studies there is no evidence of developmental toxicity (oral or dermal dose routes). However the studies that included a dosing period prior to gestation day 6 on 2-aminobutanol hydrochloride, AMP-HCl and 4,4-dimethyloxazolidine identified post implantation loss, indicating that that exposure to these substances for a period prior to implantation can lead to a reduced litter size or complete litter loss. The pathology of the uteri in affected animals indicated that the implantation loss was occurring early on in the pregnancy. Post implantation loss is generally considered to be a developmental effect, however since this effect was not identified in the standard developmental toxicity studies additional studies were performed to further characterize the effect and assess its relevance to humans. In the mode of action studies the AMP-hydrochloride salt was used; dosed either via the diet or via gavage. The conclusions on mode of action and relevance of the effect to humans are considered to be relevant to 2-aminobutanol due to their structural similarity and the similarity between the effects observed with these two chemicals.

No direct embryotoxicity

To understand if post implantation loss was a consequence of a direct action on the embryo in the early stages of development, two whole embryo culture assays (Rasoulpour and Marshall, 2008a; Rasoulpouret al.,2010) were conducted. These assays showed that embryos cultured in serum containing AMP (at concentrations up to three-fold higher than measured in rats given 300 mg/kg/day AMP-HCl; 3, 9, or 27 μg/mL of AMP-HCl) or the serum of rats exposed to 300 mg/kg/day AMP-HCl for at least three weeks showed no signs of embryotoxicity and developed normally. These data indicate that under the conditions of these studies, AMP was not directly toxic to the developing embryo, nor did AMP appear to affect the ability of maternal serum to support an embryo. This is consistent with the absence of developmental effects in surviving offspring in the reproductive toxicity screening study and the two-generation study.

Since AMP was not directly toxic to the developing embryo it is concluded a maternally mediated effect is most likely driving the implantation loss. Given the structural similarity between AMP and 2-aminobutanol it is likely that based on these findings, 2-aminobutanol is unlikely to be directly embryo toxic.

Dose response assessment

The dose response for the post implantation loss appears to be very steep. For aminobutanol, a dose of 50 mg/kg bw aminobutanol hydrochloride produced approximately 24% implantation loss and the complete loss of litters at 300 mg/kg bw. AMP had no effect at 72 mg/kg bw, 18% implantation loss at approximately 180 mg/kg and 70% implantation loss at 216 mg/kg bw/day. The steep slope of the dose response curve suggests that repeated oral exposure triggers a specific threshold event that is responsible for the effect leading to the implantation loss rather than a generalized systemic embryotoxicity. It is also clear when considering the data on AMP that extending the dosing period prior to gestation does not produce implantation loss at lower dose levels. Therefore there appears to be a “window of susceptibility” during which the triggering event must occur. Comparing these dose response curves it is also clear that 2-aminobutanol is almost an order of magnitude more potent than AMP yet the shape of the dose response curves is still very similar.

In order to verify if such a window of susceptibility existed, studies were conducted to determine exactly when the embryo death was occurring and also to identify whether there was a critical exposure window necessary for AMP to induce embryo loss (Rasoulpour and Zablotny, 2009). These studies also assessed differences between dietary and gavage routes of administration to determine whether the toxicity was greater following a bolus dose compared to diet.

In a study using a similar protocol to the OECD 421, a group of rats was exposed to 300 mg/kg bw/day of AMP-HCl for 2 weeks prior to breeding, during breeding and then up to Gestation Day (GD) 14. At GD 14 the animals were sacrificed and assessed for the number of successful/viable implantations. In a second study the same dosing regime was used, however animals were sacrificed at GD8, 10, 12. These studies identified that postimplantation loss initiated shortly after implantation (between GD 6 and 8). Therefore the effects of AMP were being expressed close to the time of, or at implantation, rather than a further stage in development. This suggests a potential incompatibility between maternal tissues and the implanting embryos.

In a subsequent study, groups of 12 female rats were dosed daily with 300 mg/kg bw/day AMP-HCl for different periods prior to and during gestation. One group was dosed via the diet from 2 weeks prior to breeding, through to gestation day 8. A second group was dosed via gavage for the same period. Subsequent groups were dosed via gavage from GD 1-8, 6-8 or 9-11. Animals were sacrificed at the end of their respective dosing period and assessed for number of viable implantation sites.

Dosing AMP-HCl via the diet from 2 weeks prior to breeding through to GD8 produced approximately 70% implantation loss, dosing via gavage for the same period produced approximately 40% implantation loss, and dosing from GD 1-8 produced approximately 14% implantation loss. These results were considered significant compared to the historical control range (between 3 and approximately 10%). Dosing from GD 6-8 and 9-11 did not result in an increase in the percentage implantation loss compared to historical controls. From this data it is clear that in order to produce an increase in post implantation loss AMP had to be administered for at least 8 days prior to implantation; a short dosing period around the implantation period (e.g. GD 6-8) was insufficient to cause postimplantation loss. Dosing after GD 6 had no effect on embryo viability.

These data support the earlier conclusion that AMP itself is unlikely to be directly embryotoxic. It is more likely that AMP exposure for a sufficient period prior to implantation leads to physiological changes that ultimately result in an incompatibility between the implanting embryo and the maternal tissue. Taking into consideration the results of the two-generation study where the second generation had a similar level of postimplantation loss to the first generation it is also apparent that whilst a certain period of exposure prior to implantation is necessary (at least 8 days) increasing the exposure period prior to implantation from three weeks to thirteen weeks did not lead to an increase in postimplantation loss. Thus there is clearly a critical window during which a specific dose level must be administered in order to cause an effect. Dosing outside of this window does not produce any apparent effects on fertility or embryo survival.

In the study that examined if the timing of the dose was critical, it was also noted that dosing via gavage produced a less severe degree of postimplantation loss compared to the same dose and duration via the diet (approximately 40% postimplantation loss compared to 70%). The lower level of postimplantation loss following gavage dosing is unlikely to be just a random variation since in the mechanistic studies conducted to date, oral dosing of 300 mg/kg bw AMP-HCl via the diet has consistently resulted in a mean of 70% postimplantation loss. This reduced severity following gavage is unusual since it is more often the case that the bolus dose provided by gavage administration is more effective than dosing via the diet. The fact that the AMP data run counter to this trend indicates that C_maxmay not be an important factor in the observed postimplantation loss, or that interactions in the gut when dosed via the diet play some role in the effect. For instance, AMP and aminobutanol will exist in the small intestine in an ionized form (due to the pH in the intestine) therefore it is likely to be using some form of active absorption process since systemic bioavailability following an oral dose was approximately 100% (Saghiret al.,2007). Due to the similarity between choline, ethanolamine, aminobutanol and AMP, it is probable that the active transport process for choline uptake in the gut is being used by aminobutanol and AMP. This uses a sodium ion dependant carrier mechanism (Hegazy and Schwenk, 1984; Huerga and Popper, 1952) and appears to be saturable. Therefore when a bolus does of AMP (or possibly aminobutanol) is administered it is possible that the active transport mechanism becomes saturated and less AMP is absorbed.

This indicates that routes that do not allow sufficient uptake (dermal/Inhalation) would be less likely to produce developmental effects. This is important when assessing relevance to humans since oral exposure is very rarely a relevant route of exposure to industrial chemicals.

Interactions with Choline and Postimplantation loss at levels that induce liver toxicity

Two studies were performed to assess the interaction with Choline and AMP and the significance for implantation loss since it was considered possible that interference with endogenous, structurally similar substances may play a role in the implantation loss. In the first study (Stottet al., 2006) the effect of AMP administration on the choline pools in the liver was assessed. Two groups of 6 female rats were fed either a control diet or a diet containing 300 mg/kg bw/day AMP-HCl for 2 weeks prior to breeding through to GD13, then sacrificed and examined for evidence of implantation loss. Samples of livers were either fixed for pathology or frozen and used to assess the levels ofcholine (Cho), betaine, glycerophosphocholine (GPCho), phosphocholine (PCho), phosphatidyl choline (PtdCho), and sphingomyelin (SM).

Post implantation loss was observed (67%) in the AMP-HCl treated rats in conjunction with evidence of fatty liver (hepatocyte vacuolation) and a decrease of between 20-25% in PCho. GPCho was elevated 2-3 fold compared to control dams indicating a conversion of PtdCho to Cho. All other metabolites were at similar levels to control. These data indicated that AMP treatment was capable of altering choline homeostasis in the pregnant dams. It was therefore considered possible that alterations in choline homeostasis could also be linked to the implantation loss. Subsequently a choline “rescue” experiment was performed to determine whether providing additional choline to AMP dosed animals had any effect on the degree of postimplantation loss (Rasoulpour and Ellis-Hutchings, 2009). Supplementing with choline (9000ppm in diet compared to 1800ppm) did not prevent postimplantation loss; however, it did ameliorate the degree of postimplantation loss compared to AMP treated animals (39% versus 66% loss). Thus whilst a simple choline deficiency was unlikely to be the key event leading to postimplantation loss, clearly AMP interactions with choline metabolism do play some role in the hepatic toxicity and may also be linked to the postimplantation loss. 

Relationship between hepatotoxicity and implantation loss

In both the OECD 421 and the two-generation study, AMP treated male and female rats had increased accumulation of lipid vacuoles in periportal hepatocytes at doses lower than those leading to postimplantation loss. In the study using aminobutanol this hepatotoxicity was only evident at the high dose. There are a number of publications that have examined this effect of aminoalcohols such as AMP and aminobutanol on hepatocytes (Humeet al., 1965; Russellet al.,1965; Yueet al., 1970; Wells and Remy, 1961 and Akesson 1977) and it is hypothesized to be due to disruption of lipid transport out of hepatocytes subsequent to interference with phospholipid production, inhibition of ethanolamine and choline uptake into hepatocytes and inhibition of de-novo choline synthesis. Aminobutanol is more potent compared to AMP in disrupting incorporation of ethanolamine and choline into phospholipids. The transport of lipids out of hepatocytes is dependent on the production of the phospholipids that package them, such as phosphatidyl choline and phosphatidyl ethanolamine. Interfering with the production of these subsequently inhibits the release of lipids from hepatocytes.

AMP and aminobutanol exposure related interference in phospholipid synthesis has been reported in other tissues such as swine coronary arteriesin vitro(Morin 1969), rabbit and human endometrial tissuesin vitro(Morin 1970), house fly larvae (Bridges and Ricketts, 1967), and murine fibroblastsin vitro(Schroeder 1980). The significance of these findings towards the reproductive toxicity of AMP and aminobutanol is unclear since the studies used high doses of these substancesin vitrothat would be very difficult to achieve systemicallyin vivoparticularly considering the irritancy of these substances and the probable route of potential exposure. Thiseffect on phospholipid biochemistry is the only other consistent effect observedin vitroand with repeated oral dosing of AMP and aminobutanol to animals so it is plausible that it is related to the increase in postimplantation loss. This is supported to some degree by the research done into the importance of phospholipids in embryo implantation, particularly in relation to their spatial and temporal distribution during the implantation phase and their function as a source of fatty acids such as arachadonic acid (Burnumet al.,2009).

Whilst the available data do not allow a clear and direct association between the hepatotoxicity and reproductive toxicity to be made they do indicate a potential non-specific, physiological disturbance may be occurring in the tissues, and that the reproductive toxicity could be secondary to this. It is probable however that there are differences in tissue specific mechanisms and sensitivities due to the different dose responses in the liver and the uterus.

Maternally mediated mode of action

In a final study (Rasoulpour et al., 2010), animals were treated with AMP-HCl at 300 mg/kg/day for two-weeks pre-breeding, through breeding and up to GD 6 (i.e., at the start of implantation). Extensive histopathology of the implantation sites and gene array data of the decidual swellings were generated. The purpose of this study was to examine the maternal/embryo interface at implantation in greater detail to identify whether effects in the uterus could be causing the implantation loss.

The histopathology of the implantation sites indicated the presence of non-lipid vacuoles in the uterine cells immediately adjacent to the embryo in AMP treated dams, but not in controls. The nature of these vacuoles is unknown; however, since they appeared only in treated dams, they do indicate that a physiological effect occurred within the uterine tissue. The severity of vacuolation varied across the uterus and the dams, with some implantation sites more heavily vacuolated than others. The embryos in the implantation sites appeared completely normal indicating that the vacuoles precede resorption. The interpretation of this finding is complicated by the limited published data on what happens physiologically during an embryo resorption. For instance, is the vacuolation a natural precursor to the resorption process, or is it evidence of an adverse physiological effect that is causing a resorption to occur? In the repeated dose oral toxicity studies in dogs, rats and mice there have not been any reported effects observed in the uterine tissue indicative of a toxic effect. This lack of any observations in the uterine tissues in three species in the standard repeated dose protocols indicates that the uterus is not a specific target organ for toxicity, at least in the absence of pregnancy.

Gene expression analysis of the cells taken from decidual swellings from treated and control dams were analyzed to identify if there was any effect at the transcriptional level. Genes associated with the formation of tight junctions (e.g., claudins and occludins) were found to be less active in treated rats compared to control. It is plausible that this difference in expression is associated with the postimplantation loss, particularly since these changes are occurring at the start of implantation rather than during or subsequent to the postimplantation loss. By influencing the formation of tight junctions, the decidual swelling surrounding the embryo could be made more ‘leaky’ and implantation sites may not be completely isolated from the maternal circulation. This, for example, could result in penetration of the maternal immune system into the implantation site leading to rejection and resorptions of the embryo.

When interpreting this data it is important to understand that this level of detailed gene array analysis has not been performed on other implantation sites where resorption of embryos is suspected. Taking this into account, it is not possible to conclude whether the changes in gene expression were due to direct interaction with the test material or indirectly as a result of other effects. If AMP or aminobutanol are capable of directly interfering with the transcription of genes involved in tight junction formation it seems plausible that adverse effects in other tissues would be noticed, and this is not the case. In addition it is also not possible to conclude whether the lower gene activity observed is a direct consequence of AMP exposure or alternatively, preparation by the uterus for the resorption of an embryo; i.e. the changes in gene activity could be casually related rather than causally related to the observed effect. Further research would be needed to fully understand the relevance and importance of this information to the postimplantation loss observed.

Additional research into the differences in susceptibility between rat and human endometrial tissue to these amino-alcohols would also be of great use in assessing the relevance of this effect on implantation to humans.

Conclusions of mode of action experiments

Assuming that the mode of action of aminobutanol is consistent with that of AMP, oral administration of aminobutanol hydrochloride to rats prior to and during pregnancy is associated with an increase in postimplantation loss via a threshold, specific maternally mediated mechanism. The postimplantation loss occurs during or shortly after implantation (gestation day 6 to 8), and requires exposure for a period of at least 8 days prior to implantation via a dose route that provides significant systemic exposure (oral). There is a clear threshold for this effect and the dose response is steep.

The potential for such an effect to be observed following dermal or inhalation dosing is limited by 2 key factors; 1) 2-aminobutanol is corrosive and as such repeated daily exposure to this substance in an un-neutralized form is very unlikely; 2) the neutralized form (for example the salt form) will have a lower dermal penetration due to the lower lipid solubility of such salts. The absorption of the structural analogue AMP through human skin was between 7 and 15%. The 7% penetration was associated with a salt form of AMP in a ‘lotion’. Aminobutanol would be expected to behave in a similar manner.

Thus this developmental toxicity appears only relevant to those exposure routes where significant systemic availability is possible (oral).

Justification for classification or non-classification

Summary of 2-aminobutanol induced toxicity

• Data are only available on a neutralized salt of 2-aminobutanol.
• Aminobutanol-HCl administration was associated with an increase in early post implantation loss. This effect has a well defined and consistent dose response with a clear threshold, below which there is no developmental/reproductive toxicity even when the dosing period is increased significantly.
• The effect is clearly maternally mediated and 2-aminobutanol is unlikely to be directly toxic to the embryo or developing fetus after implantation based on data coming from the structural analogue AMP. All surviving embryos develop normally.
• The post implantation loss has only been demonstrated in rats and there is no certainty that such an effect could occur in humans. 2-aminobutanol is most likely excreted unchanged therefore differences in xenobiotic metabolism between humans and rats are therefore unlikely to make humans more vulnerable to such an effect.
• The data generated to assess the reproductive toxicity of 2-aminobutanol use the oral route of exposure and a test material that has been neutralized to allow oral dosing. This substance is corrosive and so oral dosing would not normally be possible (or relevant) thus by altering the test material it was possible to dose far higher doses than would be possible if the base was used instead. It is acknowledged that aminobutanol acts as a pH neutralizer and as such dermal exposure to a lower pH formulation containing aminobutanol is possible. However it is argued that whilst the data indicate a potential effect, the relevance of this effect to humans must be questioned since the oral exposure route is not considered a relevant route of exposure for this corrosive substance or the neutralized form. Classification should take into account relevant routes of exposure to humans. In this case, corosivity and the lack of oral exposure scenarios reduces the relevance of orally generated data to humans. This does bring in an element of ‘risk’ into the traditional ‘hazard’ assessment; however it is important to label those hazards relevant to man rather than label for every technically possible hazard no matter whether they are relevant to human exposures or not.
• Due to the corrosivity of aminobutanol it is not technically possible to dose sufficient aminobutanol to produce the same effect via the dermal route. The pH will either limit the maximum dose that could be applied to the skin, or the fact that aminobutanol is acting as a neutralizer and forms salts will significantly decrease its ability to penetrate the skin. The same would be true for inhalation, where the irritancy would also limit the exposure via a mist or aerosol exposure. Thus if a dermal or inhalation reproductive screening study were performed using aminobutanol it is highly unlikely that any adverse reproductive effects would have been observed at the highest dose that could be tested. Therefore the relevance of this effect to humans is called into question considering the fact that aminobutanol is used in applications where exposure will be limited to dermal or inhalation routes.

 

Conclusion on Classification

According to the guidance for classification for reproductive/developmental toxicity under the Dangerous substances Directive and the CLP regulation; where developmental toxicity is occurring only in the presence of maternal toxicity or by a specific maternally mediated-mechanism, where there are significant toxicokinetic differences that bring into question the relevance of the effects to man, or where the data were generated using a route of exposure not considered appropriate for humans, it can be argued that classification is not warranted. Considering the available evidence, aminobutanol exposure via the oral route causes an increase in post implantation loss via a specific (yet not fully defined) maternally mediated mechanism. The relevance of this effect observed in rats to humans is unclear given the differences in absorption between humans and rats, the specific nature of the maternal effect, the lack of evidence from other species and differences between exposure routes in experimental studies versus human exposure. Therefore it is proposed not to classify this substance for reproductive toxicity at this time.

 

 

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