dataesr/scientific-paragraphs-categorization huggingface dataset:
For ethanol a NOAEL of 1730 mg/kg/d, corresponding to 37. 6 mMol/kg/d, was identified in a 14 week gavage study with rats based on kidney effects at 3160 mg/kg/d. In the key study for i-butanol the highest dose level of 16,000 ppm in drinking water was the NOAEL in a 90 day study with rats, corresponding to 1450 mg/kg/d or 19. 6 mMol/ kg/d. For 2-ethylhexanol a NOAEL of 125 mg/kg/d, corresponding to 0. 96 mMol/kg/d, was identified in a 90 day gavage study with rats based on effects on liver and kidney weights at 1. 9 mMol/kg/d (LOAEL). A somewhat higher systemic NOAEL of 1. 42 mMol/kg/d (120 ppm) was obtained in a 90 day inhalation study, the highest exposure concentration tested. But the NOAEL after inhalation was below the LOAEL after oral dosing. These data show that on a mMol/kg/d basis the NOAELs for ethanol and i-butanol are far above the NOAELs derived for EMA and i-BMA by interpolation from MMA and n-BMA for systemic effects after oral and inhalation exposure.
Extrapolation to the other group members Based on the common metabolite MAA, the lack of a systemic carcinogenic effect of MMA can be extrapolated to the other members of the group according to scenario 5 of  ECHA (2015 ECHA ( , 2017a)). Their noncarcinogenicity is further supported by the negative data base for genotoxicity and mutagenicity (scenario 6 of  ECHA, 2015 ECHA, , 2017a)). As inhalation of MMA leads to the most prominent local effects, a neoplastic response in the upper respiratory tract driven by chronic irritation is not to be expected for the other lower methacrylate esters at inhalation concentrations up to 1000 ppm. But the question remains whether systemic tumors may occur in potential carcinogenicity studies with exposures up to the maximal tolerable dose (MTD). Because the database is more robust for rats than for mice the following considerations will concentrate on the rat.
No carcinogenicity studies were identified for n-and i-butanol from the ECHA (2017b) website. There is only a "weight of evidence" entry that i-butanol does not contain structural biophores for a carcinogenic potential. This conclusion was derived from a QSAR-model (Quantitative Structure Activity Relationship)  (Rosenkranz and Klopman, 1990)  and adds further confidence to the assessment based on the negative genotoxicity database of the methacrylate esters. In total, there is some good but indirect evidence that n-BMA and i-BMA are not carcinogenic. The saturated vapor concentration of 2-EHMA is 64. 5 ppm (Table  1 ). Therefore an inhalation study with concentrations similar to that with MMA is not possible and assessment of carcinogenicity would only be feasible by the oral route apart from exposure to extremely high (and irrelevant) aerosol concentrations.
52 mMol/kg/d). In a 90-day gavage study with 2-EHMA in rats reproductive organs were not affected (organ weights and histopathology) at the highest dose level. The overall NOAEL of the study was 120 mg/kg/d for systemic effects (defined by decreased body weights) and 360 mg/kg/d (corresponding to 1. 82 mMol/kg/d) specifically for the reproductive organs  (BASF, 2009a). It is noted that the lowest NOAELs were obtained from the oral OECD 422 studies for effects in pregnant females. 4. 9. 1. 1. Comparison of methacrylate esters with their alcohols. The data are summarized in Table  8. MMA vs. methanol: In a 2-generation study with methanol by inhalation, parameters related to fertility were not affected at the highest dose of 1. 3 mg/l (1000 ppm). This leads to a systemic body burden of 39 mMol/kg/d taking into account the daily exposure duration of 20 h.
These data are not taken into consideration here as the findings of the first study were inconsistent and the second study only retested the lowest dose. n-BMA vs. n-butanol: In a 2-generation study with n-butanol in rats   (2001). In an oral 13 week study with n-butanol complete histopathology did not show adverse effects of the male and female sex organs up to the highest dose with a NOAEL of 500 mg/kg/d corresponding to 6. 8 mMol/kg/d. Taken together these comparisons show much higher NOAELs for n-butanol as compared to n-BMA for sex organs in males and non-pregnant females as well as for pregnant females in the 2-generation study as compared to the OECD TG 422 screening protocol. It is noted that the effects observed in the OECD TG 422 screening study with n-BMA were not found in the 2-generation study with n-butanol.
2-EHMA vs. 2-ethylhexanol: A 2-generation feeding study with rats is available for bis  (2-ethylhexyl) terephthalate, a chemical that is rapidly metabolized to terephthalic acid and 2-ethylhexanol similarly to many other esters. Calculated for 2-ethylhexanol the NOAEL ranged from 149 to 516 mg/kg/d for male and female parental animals of the F0 and F1 generation, corresponding to 1. 15-3. 97 mMol/kg/d. This was the highest dose tested. But the rate of ester cleavage for both of the alcohol moieties of this bifunctional ester is unknown. Therefore the data obtained with this chemical will not be used here. 90 day oral and inhalation studies have been performed with complete histopathology for 2-ethylhexanol. In the oral study relative testes weights were significantly increased at the highest dose (500 mg/kg/d) but this corresponded to a reduced body weight at this dose level.
For inhalation exposure the database is limited to repeated dose studies with MAA and MMA. Therefore for this route of exposure, prediction is based on oral NOAELs taking into consideration the respiratory volume of rats. In most investigations with methacrylic esters the NOAELs for potential effects on fertility correspond to the highest dose tested. The only exemptions are the oral OECD TG 422 studies with n-BMA and 2-EHMA with NOAELs of 2. 11 and 1. 52 mMol/kg/d, respectively, based on effects in pregnant females. In both of these studies, a high degree of maternal toxicity was also observed at dose levels affecting fertility. The LOAEL for n-BMA related to fertility is 7. 0 mMol/kg/d defined by decreased numbers of corpora lutea and implantations. The LOAEL for 2-EHMA is 5. 1 mMol/kg/d because of low number of estrus cycles, prolonged gestation period, decreased number of corpora lutea and implantation sites, decreased parturition index, and reduced number of offspring.
This assumption is supported to a certain extent by the fact that the NOAEL of 2-EHMA is lower than that of n-BMA corresponding to the increased half-life of the intact ester with molecular weight. Due to the remaining uncertainties in this respect, a conservative read-across is used for i-BMA taking the lowest NOAELs observed with pregnant females in the OECD TG 422 screening test in pregnant females with 2-EHMA, 1. 52 mMol/kg/d. As for MMA an oral guideline 2-generation study has been carried out with a NOAEL of 4 mMol/kg/d, this data point is used for EMA in preference to a readacross from the screening test with n-BMA. The close structural similarity between MMA and EMA supports this approach. Under these premises, a NOAEL for fertility of 4 mMol/kg/d, corresponding to 456 mg/kg/d (oral exposure) and 350 ppm (inhalation) is obtained for EMA.
By allometric scaling with a factor of 4/7 based on ECHA (2012), this can be extrapolated to rats giving 170 mMol/kg/d. For i-butanol a 2-generation inhalation study is listed as key investigation. No effects on fertility and its parameters were found at the highest concentration tested, 7500 mg/m 3 (2500 ppm) corresponding to 29 mMol/kg/d. In addition, in the 90 days drinking water study mentioned above reproductive organs were not affected at the highest dose level of 1450 mg/kg/d (19. 6 mMol/kg/d). These studies show that on a mMol/kg/d basis the NOAELs for ethanol and ibutanol are far above the NOAELs derived for EMA and i-BMA by extrapolation from MMA and 2-EHMA. This comparison of the available data shows that the predicted NOAELs of the methacrylate esters are lower than those of the corresponding alcohols.
Developmental toxicity In Table  9  the observed and predicted NOAELs of the methacrylate esters for developmental toxicity in rats after inhalation and oral exposure (including rabbits) are summarized. In addition, the NOAELs of the corresponding alcohols are listed. Information on developmental toxicity can be derived from data obtained by test protocols of different levels of complexity: studies specifically designed to assess prenatal developmental toxicity, reproduction/developmental toxicity screening tests, and multi generation studies. The following studies are available for the members of the category: guideline studies for prenatal developmental toxicity for MAA, MMA, EMA, and n-BMA, reproduction/ developmental toxicity screening studies (OECD 422) for n-BMA and 2-EHMA and a guideline two-generation reproductive toxicity study for MMA.
The authors also reported at 300 mg/kg/d a decreased number of neonates  (Furuhashi et al. , 1998). But this could not be verified in a subsequent reanalysis  (Müllerschön, 2014; personal communication). Hence, the NOAEL for maternal and developmental toxicity was 300 mg/kg/d (corresponding to 1. 5 mMol/kg/d). In summary, no malformations or fetal death (apart from 2-EHMA) were observed for any of the substances tested. Apart from the OECD TG 422 screening test with 2-EHMA, signs for fetal toxicity generally were only unspecific and associated with maternal toxicity. 4. 9. 2. 1. Comparison of methacrylate esters with their alcohols. The data are summarized in Table  9. The interpretation of the relationship of the NOAELs for the methacrylate esters and the alcohols is partly compromised because several NOAELs stem from the highest doses tested and the real NOAELs and LOAELs cannot be precisely determined.
Read-across to 2-EHMA requires extrapolation that is always associated with higher uncertainty than interpolation. A conservative approach is selected starting from the oral NOAEL for 2-EHMA in the OECD TG 422 study, i. e. 1. 5 mMol/kg/d, corresponding to 130 ppm, far above its saturated vapor concentration of 64. 5 ppm (cf. Table  1 ). To fill in the data gaps after oral exposure for i-BMA and EMA, the NOAEL of the rabbit prenatal developmental toxicity study for n-BMA (2. 1 mMol/kg/d) is used giving NOAELs of 240 mg/kg/d for EMA and 300 mg/kg/d for i-BMA. The lower NOAEL in the rabbit for n-BMA is preferred to the one of MMA (4. 5 mMol/kg/d) as the more conservative approach. For the oral prenatal toxicity of 2-EHMA only the NOAEL obtained by the OECD TG 422 screening study is available (1.
5 mMol/ kg/d). In spite of screening data being less reliable than observations in a prenatal toxicity study, this NOAEL will be retained for the oral route as it is more conservative than the NOAEL after inhalation of 2-ethylhexanol (2. 21 mMol/kg/d). The predicted NOAEL of EMA after oral exposure (2. 1 mMol/kg/d) is much lower than that of ethanol reported in the IUCLID data set (ECHA, 2017b) for inhalation, i. e. 16,000 ppm corresponding to 224 mMol/kg/d (see above). For i-butanol prenatal toxicity studies similar to present guidelines are reported in ECHA (2017b). Both in rats (gd 6-15) and rabbits (gd 7-19) NOAELs were obtained at 10,000 mg/m 3 by inhalation, the highest exposures tested. For the rat this corresponds to 39 mMol/kg/d. Slight maternal toxicity occurred in rabbits (transient, statistically non-significant retardation of body weight gain) but not in rats at this dose level.
Summary of results for the different endpoints A category approach is proposed for the toxicological assessment of short chain methacrylate esters (MMA, EMA, n-BMA, i-BMA, 2-EHMA) to fill in data gaps by read-across. The scenarios described by ECHA (2015, 2017a) have been used to describe the mechanisms relevant for the different endpoints. The scheme proposed by  Blackburn and Stuard (2014)  is applied to define the level of uncertainty of each read-across (cf. electronic supplement). The focus is to satisfy information requirements of the EU REACH regulation and identify NOAELs for different toxicological endpoints after oral and inhalation exposure. Implications on classification and labelling are not discussed. MMA by virtue of it being the largest volume chemical of the category has the most comprehensive dataset covering all toxicological endpoints.
The common primary metabolite, MAA, is subsequently cleared again rapidly from blood mainly in the liver by entering into the physiological valine pathway with the majority of the administered dose being exhaled as CO 2  (Jones, 2002). The other metabolites, short-chain alkyl alcohols, are high production volume chemicals with a broad database and well characterized standard metabolic pathways. For humans the most relevant routes of exposure are inhalation or dermal contact. Toxicity after inhalation is governed by ester cleavage in the olfactory epithelium leading to local tissue destruction by intracellular acidic MAA. This effect depends not only on metabolism but also on local deposition. It is most prominent for MMA, followed by EMA, while the butyl esters only exhibit a very low toxicity to the olfactory tissue.
(1997)  may be directly extrapolated to EMA in a conservative manner, as EMA led to a less pronounced olfactory degeneration in comparison to MMA after acute exposure  (Jones, 2002). The local NOAEL of n-BMA of 310 ppm was obtained in a 28 day inhalation study. Local effects after inhalation of methacrylate esters will at most only slightly increase with prolongation of exposure when comparing the data of  Lomax et al. (1997)  with a NOAEL of 25 ppm after 2 years and  Hext et al. (2001)  with a LOAEL of 110 ppm in the course of a 28 day study that normalized within the 28 day exposure period. Therefore a factor of 2 is considered sufficiently conservative for time extrapolation and the local chronic NOAEL for n-BMA can be defined at 150 ppm. The difference between the chronic local NOAEL for MMA (25 ppm) and the extrapolated one for n-BMA is consistent with the acute data of  Jones (2002)  showing at 200 ppm clear olfactory lesions with MMA but not with the butyl esters.
The chronic local NOAEL for n-BMA (150 ppm) is directly taken for i-BMA and 2-EHMA. For 2-EHMA this NOAEL would clearly be above the saturated vapor concentration. When comparing systemic and local NOAELs after inhalation, for MMA and EMA the observed and predicted local NOAELs are lower than the systemic NOAELs, while the inverse is found for n-BMA, i-BMA and 2-EHMA. This is explained by the rapidly decreasing cytotoxicity to the olfactory epithelium with increasing molecular weight. Reproductive toxicity is defined by the same principles as systemic repeated dose toxicity, namely predominantly by the products of ester cleavage. Again, quantitative comparisons between the members should preferably use a mMol/kg/d basis. Fertility: Data from subchronic studies with detailed investigations of reproductive organs and the OECD TG 422 screening studies indicate no or low toxicity with respect to fertility.
In this respect ECHA (2015, 2017a) defines 5 levels of confidence as assessment options for regulators when reviewing a readacross submitted under REACH. While these levels align well with the REACH regulatory process they do lack detailed definition. In contrast, the approach described by  Blackburn and Stuard (2014)  set out very clearly the most important criteria for defining uncertainty. Both systems are very similar (see Table  11 ), although the  Blackburn and Stuard (2014)  process uses the term "uncertainty" as opposed to "confidence" and has 4 levels rather than 5. We chose to use the system described by  Blackburn and Stuard (2014)  to score all endpoints, i. e. the number of contributing data, robustness of the data set, concordance of effects, concordance of potency, and severity of critical effect (cf.
-Ester cleavage to MAA and the corresponding alcohol. For this AOP the impacts of the products of ester cleavage (MAA and the corresponding alcohol) are different for systemic and local effects. Both hydrolysis products can be assumed to have only low systemic toxicity because MAA is rapidly metabolized by physiological pathways and for the corresponding alcohols the NOAELs were always found to be higher than those of the source and extrapolated data. A different situation exists for local effects, especially after inhalation. Here local toxicity is driven by intracellular production of MAA leading to cytotoxicity by decreased pH and a broad database is available for this pathway enabling a read-across over the total category. The more specific elements for uncertainty analysis according to  Blackburn and Stuard (2014)  are presented in the electronic supplement and show that the uncertainties are generally low for all endpoints analyzed.
This is especially important for repeated dose toxicity after oral and inhalation exposure since these are key endpoints from both data requirement and animal protection perspectives. It should be recognized that a robust read-across approach is only as good as the data on the donor chemistry. In this regard we were very fortunate since in general, -the number of donor substances contributing data was sufficient for both exposure routes -the vast majority of available studies followed present days' guidelines -effects noted at the LOAELs were unspecific and not life threatening (and for fertility and developmental effects often associated with maternal toxicity) -the NOAELs were in similar ranges (also including MAA as secondary source chemical) -NOAELs of alcohols (the other metabolic cleavage products) were always higher than the source and extrapolated NOAELs finally, whenever several options existed for extra-or interpolation, the most conservative option was selected.
However, ECHA recognises that the basis for the readacross may vary between endpoints and upon data availability, so there is an expectation that the most appropriate scenario, with its associated AEs, is identified and addressed for each and every endpoint. While scientifically justified this requirement introduces some real challenges in terms of switching back and forth between scenarios when going through an assessment using the traditional sequence. From our experience with this category there is no simple answer although some advantage can be gained by grouping endpoints by MOA since they often share the same scenario.
e. , 3 times the wavelength of the Gabor patches of the configuration). In the present study, the spatial frequency was kept fixed at 1 cpd, therefore λ = 1 cpd. In this case, this distance also corresponds to the PF size and facilitation is considered as a between-PFs effect. When the same stimulus is presented in peripheral vision, the PF size increases, so that the 3λ configuration elicits within-PF, collinear inhibition. In order to restore facilitation, flankers must be placed outside the PF. Previous studies  [19] [20] [21]  showed that this critical distance is 8λ at an eccentricity of 4°. luminance of 47. 6 cd/m 2. Stimuli were generated with Matlab Psychtoolbox  36, 37. Each pixel subtended 2. 14 arcmin. A digital-to-analogue converter (Bits#, Cambridge Research Systems, Cambridge UK) was used to increase the dynamic contrast range (13-bit luminance resolution).
Statistical analyses. Given the small sample of participants in the Experiments, we conducted non-parametric statistical analyses. In particular, to explore the main effects, we used an Aligned Rank Transformation (ART) as described by Wobbrock, Findlater, Gergle and Higgins  39  with the r package ARTool  40. To test for interactions, we used a non-parametric ART test for interactions in designs with repeated measures as described by Beasley & Zumbo  41  with the r package "npIntFactRep"  42. However, while this last package permits to test effects for mixed models with one 'within' and one 'between' factors, it does not allow for testing interactions with more than one 'within' factors, hence we only ran interaction tests for the Threshold elevation data. Post-hoc tests on the main effects were performed using linear models of the aligned data, as reported in Wobbrock et al.
Target-to-flankers distances (3λ, 4λ, 6λ, 8λ). The interaction was calculated using the r package npInt for Nonparametric Interaction Tests for Factorial Designs with Repeated Measures (Feys, 2015). Results showed a main effect of Target-to-flankers distance (F 3,24 = 17. 808, p < 0. 001) and the interaction between factors (F 3,24 = 5. 39, p = 0. 00554). Post-hoc analysis (ART pairwise comparisons, holm adjusted) showed that overall threshold elevation at 3λ was significantly higher than all the other separations (p = 0. 0391, p < 0. 001 and p < 0. 001 for 4λ, 6λ and 8λ, respectively). Additionally, we explored post-hoc tests for the interaction. Since tests of differences of combinations of levels between factors have issues in ART (Kay, 2014), it is recommendable to test for differences of differences; (i.
DNA-barcoding Specimens with a DNA barcode are indicated in the text by a GenBank accession number and/or a BOLD Process ID. GenBank accession numbers starting with KX05 and BOLD IDs starting with SYC were generated using the protocols explained in  Ramage et al. (2017)  as part of the SymbioCode initiative (https://doi. org/10. 5883/DS-SYMC). New DNA barcodes generated for this study as well as other marker sequences (GenBank accession numbers starting with MF44 or MH28) were produced using the DNA primers and PCR amplification protocols described in  Mengual et al. (2008 Mengual et al. ( , 2012) )  at the ZFMK. Entire specimens or remnants of specimens were preserved and labelled as DNA voucher specimens for the purpose of morphological studies, except for one male of Melanostoma polynesiotes sp.
Genetics The GenBank accession numbers for this species are: 28S gene (MF446468, specimen ZFMK-DIP-00019705), 18S gene (MF446423, specimen ZFMK-DIP-00019705), protein-coding COI gene (MF446518, specimen ZFMK-DIP-00019705; MF446520, specimen ZFMK-DIP-00019704). The BOLD Process ID for the DNA barcodes (5′-COI) for this species is SYC4342-14 (= GenBank accession number KX051597, specimen symbiocode_04422). The Barcode Index Number (BIN) for these specimens is BOLD:AAZ6685 (https://doi. org/10. 5883/BOLD:AAZ6685).
Genetics The GenBank accession numbers for this species are: 28S gene (MF446488, specimen ZFMK-DIP-00019720), 18S gene (MF446444, specimen ZFMK-DIP-00019720), protein-coding COI gene (MF446540, specimen ZFMK-DIP-00019720; MF446516, specimen ZFMK-DIP-00019721). The BOLD Process IDs for the DNA barcodes (5′-COI) for this species are: SYC1600-14 (= KX053515, specimen symbiocode_01632), SYC2519-14 (= KX053518, specimen symbiocode_02597), SYC3765-14 (= KX053516, specimen symbiocode_03845), SYC4375-14 (= KX053520, specimen symbiocode_04455), SYC4907-14 (= KX053519, specimen symbiocode_04987), SYC5089-14 (= KX053521, specimen symbiocode_05172), SYC5521-14 (= KX053513, specimen symbiocode_05606), SYC7453-14 (= KX053514, specimen symbiocode_07570), SYC7894-14 (= KX053517, specimen symbiocode_08018) and SYC7895-14 (= KX053522, specimen symbiocode_08019).
Genetics The GenBank accession numbers for this species are: 28S gene (MF446466, specimen ZFMK-DIP-00019707), 18S gene (MF446421, specimen ZFMK-DIP-00019707), protein-coding COI gene (MF446515, specimen ZFMK-DIP-00019707; MF446522, specimen ZFMK-DIP-00019706). The BOLD Process IDs for the DNA barcodes (5′-COI) for this species are: SYC2242-14 (= KX054855, specimen symbiocode_02320), and SYC4350-14 (= KX054856, specimen symbio-code_04430). The Barcode Index Number (BIN) for these specimens is BOLD:ACN3906 (https://doi. org/10. 5883/BOLD:ACN3906).
Genetics The GenBank accession numbers for this species are: 28S gene (MF446467, specimen ZFMK-DIP-00019746; MF446470, specimen ZFMK-DIP-00019731), 18S gene (MF446422, specimen ZFMK-DIP-00019746; MF446425, specimen ZFMK-DIP-00019731), protein-coding COI gene (MF446517, specimen ZFMK-DIP-00019746; MF446521, specimen ZFMK-DIP-00019731).