Registration Dossier

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Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Zenolide did not show fertility effects in a reproduction/developmental toxicity in an oral gavage OECD TG 421 in which a NOAEL of ≥1000 mg/kg bw/day was derived (OECD 421, GLP). In addition, reproductive organs were not affected at >=1000 mg/kg bw in a 28-day repeated dose toxicity study (OECD TG 407).

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The reproduction/developmental toxicity screening study is of sufficient quality and is adequate for this dossier.
Additional information

Introduction: The potential adverse effects of the test material on reproduction including offspring development were studied in an OECD 421 Reproduction/Developmental Toxicity Screening Test following GLP. The test material was administered by gavage to three groups, each of ten male and ten female Wistar rats at dose levels of 100, 300 and 1000 mg/kg bw/day. A control group of 10 rats/sex received the same dose volume (5 mL/kg/day) of the vehicle (Corn oil). Males were treated for 28 days, i.e. 2 weeks prior to mating, during mating and up to termination. Females were treated during 2 weeks prior to mating, during mating, during gestation and up to the day before necropsy (i.e. on day 13 of lactation for females that delivered.

Method: Mortality, clinical signs, body weight, food consumption, estrous cycle determination, measurement of thyroid hormone T4, macroscopy at termination, organ weights and histopathology on a selection of tissues were determined. In addition, the following reproduction/developmental parameters were determined: mating and fertility index, precoital time, number of implantation sites, gestation index and duration, parturition, maternal care, sex ratio and early postnatal pup development (mortality, clinical signs, body weights, sex, anogenital distance, areola/nipple retention and macroscopy).

Results on systemic toxicity: There was no compound-related mortality. Compound-related clinical signs were restricted to higher incidences (animals and/or occasions) of hypersalivation, abnormal foraging and pedalling for both males and females in all treated groups generally in a dose-related manner during all phases of the study, including gestation and lactation, compared with sporadic cases in the control group. At 1000 mg/kg/day, overall mean body weight gain was slightly lower for the males during the dosing period (Days 1 to 29) and for the females during the pre-mating period (Days 1 to 15) compared with the control. However, in the absence of any effect on absolute mean body weight through to termination for either sex, the differences were considered to be of no toxicological significance. There was no compound-related effect on mean food consumption for either sex in any group.

T4: No biologically relevant differences in total T4 levels were noted among the different groups of F0-males.

Pathology findings at 1000 mg/kg bw/day included irregular surface of the kidneys (bilateral), on a few occasions accompanied by bilateral enlarged appearance, and increased absolute and relative mean kidney weights that correlated histologically with minimal to moderate interstitial inflammation, cortical tubular degeneration/regeneration with tubular dilatation accompanied by multifocal intratubular crystals for males. Microscopic examination with polarised light showed presence of intratubular translucent crystals of Calcium oxalate. These crystals are considered to be the result of one metabolite of Zenolide, which is Ethylene glycol which further metabolises into Oxalic acid and is called Oxalic acid nephropathy. Only minor increases in mean kidney weights were noted at 300 or 100 mg/kg bw/day but with no Calcium Oxalate crystal formation.

Results on fertility: There were no compound-related effects on estrous cycles, mating performance or fertility, including mean sperm counts (testis and cauda epididymis), sperm motility and sperm morphology. There were 9/9, 9/9, 8/9 and 8/10 pregnant females in the control, 100, 300 and 1000 mg/kg bw/day groups, respectively, that completed delivery. The mean duration of gestation was comparable. Two pregnant females in the 1000 mg/kg bw/day group were unable to complete delivery and were sacrificed for ethical reasons. There were no test item-related effects on the number of implantation, pre-birth loss and litter size.

Results on developmental toxicity: All females that delivered had live-born pups. There were no test item-related effects on pup viability or pup body weight. There was no compound-related effect on male areola/nipple retention in any group. No nipples were observed for any male in any group on PND13. There was no compound-related effect on anogenital distance (normalized for body weight) for the male or female pups. No biologically relevant differences in total T4 levels were noted among the different groups of PND 13 pups.

Conclusion: The NOAEL for parental toxicity was 300 and 1000 mg/kg bw/day for males and females, respectively, due to the presence and absence of compound-related Oxalic acid nephropathy. The high dose of 1000 mg/kg/day was the reproduction and developmental NOAEL for both sexes.

Effects on developmental toxicity

Description of key information

Several information sources are available on developmental toxicity

Zenolide shows no developmental toxicity ≥1000 mg/kg bw, in a reproduction/developmental toxicity screening study (rats, oral gavage, OECD TG 421)

Habanolide shows no developmental toxicity at ≥1000 mg/kg bw in an OECD TG 414.

Ethylene glycol NOAEL for developmental toxicity in rat is ≥1000 mg/kg bw (e.g. ATSDR, 2010)

Dodecanedioic acid NOAEL for developmental toxicity in rat is ≥1000 mg/kg bw (ECHA dissemination site, April 2019)

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The reproduction/developmental toxicity screening study with Zenolide and the Prenatal developmental toxicity study of Habanolide are of sufficient quality and are sufficiently adequate for this dossier.
Additional information

For Zenolide, developmental toxicity is derived from its OECD TG 421 study, its key metabolite Ethylene glycol and the close structural analogue Habanolide. The summaries of the experimental information available are presented first and thereafter the read across rationale.

Prenatal developmental toxicity of Zenolide (OECD 421)

In a Reproduction/Developmental Toxicity Screening Test in accordance with OECD TG 421 and following GLP, rats were exposed via oral gavage to the test substance at dose levels of 100, 300, and 1000 mg/kg bw/day for four weeks, including a 2-week pre-mating period for males and females, and during gestation and lactation for females. All females that delivered had live-born pups. There were no test item-related effects on pup viability or pup body weight. There was no compound-related effect on male areola/nipple retention in any group. No nipples were observed for any male in any group on PND13. There was no compound-related effect on anogenital distance (normalized for body weight) for the male or female pups. No biologically relevant differences in total T4 levels were noted among the different groups of PND 13 pups. The developmental NOAEL was determined to be ≥ 1000 mg/kg bw/day.

The full description of the experimental information on developmental toxicity (from the OECD TG 421) is included in the fertility section above.

Prenatal developmental toxicity study with Habanolide (OECD 414)

For Habanolide a developmental toxicity study in rats, performed according to GLP and OECD guideline 414, was available. Groups of twenty-four mated female Sprague-Dawley strain rats were dosed orally, by gavage, with the test material from Day 5 to 19 of gestation. The dose levels were 50, 250 and 1000 mg/kg bw/day. A concurrent control group was dosed with vehicle (carboxymethyl cellulose) only. At all dose levels up to and including 1000 mg/kg bw/day there were no significant treatment related effects on maternal bodyweight gain and food consumption during gestation. No clinical signs of reaction and no significant macroscopic findings at post mortem examination were observed. At caesarian necropsy, there were no significant treatment-related effects on any of the parameters examined. In the offspring, at all dose levels up to and including 1000 mg/kg bw/day there were no significant treatment related effects on foetal viability, growth and development. Furthermore, no visceral or skeletal anomalies were observed. The NOAEL for maternal toxicity and developmental toxicity of Habanolide was determined to be ≥1000 mg/kg bw/day.

Prenatal developmental toxicity of Ethylene Glycol

Zenolide is metabolized in two key metabolites. The first key metabolite is Ethylene Glycol. Ethylene Glycol has been extensively studied for developmental toxicity in mouse, rat, and rabbit. From all data available two main conclusions can be drawn:

1) High dose bolus administration of Ethylene Glycol to rodents causes adverse developmental effects while dietary administration does not. This can be explained by the fact that bolus administration results in higher maximum plasma concentrations of Glycolic acid, because the metabolism into Glyoxylic acid (intermediate of Oxalic acid), by Glycolate oxidase or Lactate dehydrogenase, is saturated (See Figure 2 in the Toxico-kinetics section). This happens at Ethylene Glycol dosages of 125-500 mg/kg bw (Fowles et al. 2017).

2) Species differences: Ethylene Glycol caused developmental toxicity in rats and mice, while administration to rabbits at a dose of 2000 mg/kg bw/day by gavage did not result in any developmental effect. Studies suggest that the Mono Carboxylate Transporter proteins (MCT1 and MCT4), which are responsible for the placental flux of Monocarboxyic acids, are reversed between mouse and rat versus rabbit and humans, which results in lower exposure of the embryo. MCT1 (high substrate affinity) is in rat and mouse located on the maternal side while the low-affinity MCT4 is located at the fetal side. This means that Monocarboxylic acids are easily transported into the placenta (and fetus) and slowly transported back, resulting in high concentrations Glycolic acid in the fetus. In humans and rabbits, this is the other way around. This is shown by Carney et al. (2008), who showed that the embryo:maternal blood concentration ratio of Glycolic acid is 1.5 and 0.3 in rats and rabbits, respectively. In humans the ratio is predicted to be 0.5, which is comparable to rabbits (Fowles et al., 2017).

Overall, studies performed in rodents are not relevant for humans and the developmental toxicity of Ethylene Glycol is best predicted in the study with rabbits, in which no developmental toxic effects were observed. This is becaus the clearance of Ethylene glycol in rats is slower compared to other species. Also, Glycolic acid concentration will be higher in rat fetus compared to rabbit and human. Metabolic saturation during testing of rats does not reflect normal human exposure.

For Zenolide assessment this means that exposure to Zenolide results in much lower internal Ethylene Glycol than tested in the developmental studies as exposure to 1000 mg/kg bw Zenolide results after full absorption and metabolism to only a dose level of 240 mg/kg bw Ethylene Glycol.

Prenatal developmental toxicity of Dodecanedioic acid

The second key metabolite of Zenolide is Dodecanedioic acid. This substance has been tested in a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test

OECD TG 422 study, following GLP. In this study, rats were exposed to 100, 500, and 1000 mg/kg bw/day via oral gavage. In this study, no developmental effects were observed and the NOAEL was determined to be 1000 mg/kg bw (ECHA disseminated dossier on Dodecanedioic acid).

References:

Agency for Toxic Substances and Disease Registry (ATSDR), Toxicological Profile For Ethylene Glycol, 2010, https://www.atsdr.cdc.gov/toxprofiles/tp96.pdf.

Carney, E., Tornesi, B., Markham, D., Rasoulpour, R., Moore, N., 2008, Species-specificity of ethylene glycol-induced developmental toxicity: toxicokinetic and whole embryo culture studies in the rabbit, Birth Defects Res B Dev Reprod Toxicol.;83(6):573-81

Fowles, J., Banton, M., Klapacz, J., Shen, H., 2017, A toxicological review of the ethylene glycol series: Commonalities and differences in toxicity and modes of action, Toxicology Letters, 278, 66–

83, https://www.sciencedirect.com/science/article/pii/S0378427417302345

Dodecanedioic acid, REACH dossier: https://echa.europa.eu/nl/registration-dossier/-/registereddossier/14886, site visited April 2019

The read across justification is presented below

Developmental toxicity of Zenolide (CAS #54982-83-1) using read across from Habanolide (CAS #111879-80-2), Ethylene Glycol (CAS #107-21-1), and Dodecanedioic-acid (CAS # 693-23-2)

Introduction and hypothesis for the analogue approach

Zenolide is a cyclic aliphatic double ester. For this substance, a screening for reproductive toxicity study (Repro-screen, OECD TG 421) is available but no information on developmental toxicity from a (similar to) OECD TG 414 study. In accordance with Article 13 of REACH, lacking information should be generated whenever possible by means other than vertebrate animal tests, i.e. applying alternative methods such as in vitro tests, QSARs, grouping and read-across. For assessing the developmental toxicity of Zenolide the analogue approach is applied from Habanolide and developmental toxicity information from Zenolide’s metabolites Ethylene Glycol (EG) and Dodecanedioic-acid (DDDA) is included.

Hypothesis: No developmental toxicity of Zenolide is anticipated based on the absence of developmental toxic effects for Zenolide, its analogue Habanolide and its metabolites EG and DDDA.

Available information: For Zenolide a Reproductive toxicity screening study (OECD TG 421) is available, showing absence of developmental effects ≥1000 mg/kg bw (Klimisch 1). For Zenolide’s analogue, Habanolide, a developmental toxicity study is available performed according to OECD TG 414 in which no effects are seen at ≥1000 mg/kg bw (Klimisch 1).

Developmental toxicity information from reviews and publications is available for EG, which is one of the two key metabolites of Zenolide (covering OECD TG 414 for several species). For EG, rat skeletal and other malformations appear to be the most sensitive indicators of toxicity, when EG was dosed via gavage resulting in bolus effects at ≥1000 mg/kg bw. Effects on fetal body weight and fetal viability occur at higher doses (ATSDR, 2010, page 111, Fowles et al., 2011).

For the other metabolite of Zenolide, DDDA, no developmental toxicity was seen at ≥1000 mg/kg bw in an OECD TG 422 study (ECHA, dissemination site).

Target chemical and source chemical(s)

Chemical structures of the target chemical and the source chemicals are shown in the data matrix, including relevant physico-chemical properties.

Purity / Impurities

Zenolide is a mono-constituent with a high purity of >95% and therefore the impurities are not expected to influence the results.

Analogue approach justification

According to Annex XI 1.5 read across can be used to replace testing when the similarity can be based on a common backbone and a common functional group and/or when the substance is a key metabolite of the parent substance. When using read across the result derived should be applicable for C&L and/or risk assessment and it should be presented with adequate and reliable documentation, which is presented below.

Analogue and metabolite selection: For Zenolide the analogue Habanolide is selected being a close analogue for which a developmental toxicity study (OECD TG 414) is available. In view of Zenolide’s complete metabolisation into EG and DDDA (CRL, 2019) the available developmental toxicity data on these metabolites are also used for Zenolide’s developmental toxicity assessment.

Structural similarities and differences: Zenolide is a cyclic aliphatic di-ester. Habanolide is also a cyclic aliphatic ester with only a single ester bond, but Habanolide has a double bond in the cyclic alkyl-chain not present in Zenolide. These differences between Zenolide and Habanolide are further discussed below. These structural differences between Zenolide and its metabolites are not relevant for internal exposure because the backbone and functional groups of Zenolide are separated during metabolisation.

Toxico-kinetic: Absorption: Zenolide and Habanolide are expected to have similar absorption via all routes because of their similar structural and physico-chemical characteristics. Though the log Kow is somewhat lower and the water solubility somewhat higher for Zenolide compared to Habanolide, both substances are anticipated to be absorbed via all routes. For EG and DDDA the similarity with Zenolide is not relevant because these are metabolites of Zenolide.

Metabolism: Zenolide will be fully metabolised into EG and DDDA by carboxyl esterases, which are abundantly available in all tissues, including gut, liver and plasma (Toxicological handbooks, Belsito et al., 2011 and Saghir et al. 2017). This is supported with experimental in vitro rat plasma, where no Zenolide could be detected within seconds at 37°C (CRL, 2019, See toxico-kinetic section, and Figure 1). Habanolide will be de-esterified for the same reason and result in an aliphatic fatty acid similar to DDDA (15-Hydroxypentadecanoic acid (CAS #4617-33-8)) also presented in Figure 1.

Figure 1: Zenolide and Habanolide and their Phase 1 metabolism in which Zenolide is metabolised into the short-living hypothesized intermediate, Ethylene glycol and Dodecanedioic-acid, while Habanolide will have a short living hypothesised intermediate and result in 15-Hydroxypentadecanoic acid.

 

The other metabolite of Zenolide, EG, will not be formed from Habanolide because it only has a single ester. The metabolisation of EG is presented in Figure 2 as is presented in the ATSDR review for this substance (2010). EG is further metabolised to Glycolic acid and finally in Oxalic acid.

The occurrence of this pathway has been shown in Repro-screen study with Zenolide in which Oxalic acid nephropathy was seen including Calcium oxalate crystals.

Figure 2: Metabolic pathway of EG as presented in ATSDR (2010).

 

Mode of Action (MoA) for developmental toxicity

Zenolide and Habanolide both present absence of adverse effects regarding developmental toxicity in a Repro-screen and OECD TG 414 study, respectively. Also, for one of the metabolites of Zenolide, DDDA, absence of adverse developmental effects in a Repeated Dose-Repro-screen study is observed (OECD TG 422, ECHA dissemination site, April 2019). This implies that the ester and the fatty acid metabolites do not cause developmental toxicity.

For the other metabolite of Zenolide, EG, developmental toxicity information is available. EG has been extensively studied for developmental toxicity in mice, rat, and rabbit, which is reviewed i.a. by ATSDR (2010) and by Fowles et al. (2017). First, the possible EG developmental toxic effects of gavage dosing resulting in a bolus effect will be discussed and thereafter the species differences between rat and rabbit and the similarity between rabbit and humans.

Developmental toxic effects of Zenolide due to gavage dosing versus those for EG: In the Zenolide Repro-screen study where the doses were administered via gavage, no developmental toxicity was seen at 1000 mg/kg bw. For EG, developmental toxicity effects have been observed after gavage dosage in rodents, but not after dietary dosage in rodents. This indicates that either insufficient high plasma concentrations of EG were achieved in the Zenolide Repro-screen study, while full metabolisation of Zenolide into EG and DDDA is anticipated as is presented earlier, or that not all developmental toxic effects are noted in the Repro-screen study. Therefore, more information is gathered on EG.

The EG gavage dosing and its developmental toxic effects are considered to be due to overloading of the metabolic pathway (ATSDR, 2010). Such overloading effects do not have to be considered for the risk assessment because during normal use of substances such overloading effects will not occur (Public Health England, 2015, https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/455702/Ethylene_Glycol_PHE_TO_210815.pdf.

Overloading of the metabolic pathway of EG into Oxalic acid: An intermediate in the EG metabolic pathway is the formation of Glycolic acid, which is considered the key developmental toxicant of EG (Figure 2). The metabolic overloading occurs when the metabolism of Glycolic acid into other metabolites such as Oxalic acid is saturated (ATSDR, 2010 and Fowles et al., 2017). This saturation can occur from 125-500 mg/kg bw EG onwards (2-8 mMol).

It can be calculated whether this saturation occurred during Zenolide Repro-screen testing. During Zenolide metabolisation the maximum doses EG is 3.9 mMol (1000 mg/kg bw Zenolide is 3.9 mMol with 256 MW for Zenolide). This means that sufficiently high doses of EG may have occurred to casue overloading, because 3.9 mMol (MW EG is 62) is in between 2-8 mMol. This overload is, however, not obvious because no developmental effects were seen in the Zenolide study.

EG developmental effects in rats and mice versus rabbits and humans: The actual developmental toxicant of EG is Glycolic acid (as reviewed in ATSDR, 2010 and Fowles et al., 2017). This acid can be transported in and out of the placenta by means of Mono-Carboxyl Transport proteins (Fowles et al., 2017). The Glycolic acid effects resulting from EG in rats is probably due to the location of the Mono-Carboxylate Transporter (MCT) proteins MCT1 and MCT4 (Nagai et al., 2010). These proteins are responsible for the placental flux of mono-carboxylic acids (such as lactate) and can be extrapolated to Glycolic acid (Fowles et al., 2017). MCT1 has a high affinity for Carboxylic acid and MCT4 a low affinity. In rat, the MCT1 is on the maternal side and MCT4 on the fetal side. This means that in rat mono-carboxylic acids are transported from the maternal blood into the placenta but not transported back due to the low affinity of MCT4 for these acids in the placenta.

In rabbits and humans these MCTs are placed the other way around: MCT4 is present on the maternal side and therefore less acid transport into the placenta takes place and MCT1 is on the fetal side resulting in a high turnover from the placenta into the maternal blood stream (Nagai et al, 2010 and Fig 6 from this publication, the figure depicting the rat transport) (Figure 3 below). This means that in rabbits (and humans) the Glycolic acid exposure to the fetus is much less compared to rats.

 

Figure 3: Mono-Carboxylic Acid transporters (MCT) in rat, transporting mono-carbocylic acids to the fetus from the maternal blood. MCT1 has a high affinity for these acids and therefore in rat Glycolic acid will be faster transported into the fetus and slower back to the maternal blood stream.

 

This difference in transport is confirmed in the study by Corley et al. (2008) who showed that the embryo:maternal blood concentration ratio of Glycolic acid is 1.5 in rats while in rabbits it is only 0.3. Humans are predicted to have a ratio of 0.5, which is comparable to rabbits.

In summary, it can be seen that the EG developmental toxicity observed in rats at ≥1000 mg/kg bw is likely due to a saturation of the Glycolic acid pathway and therefore Glycolic acid, being the key toxicant, concentration increases in the systemic circulation. In addition, in rats the Glycolic acid is easier transported into the placenta than pumped out when compared to rabbits and humans. Therefore, there is overall no concern for EG for developmental toxicity in humans.

Conversion NOAELs to Zenolide: In view of the NOAEL of ≥1000 mg/kg bw of Habanolide, and Zenolide having a slightly higher molecular weight, conversion will not change the conclusion and therefore conversion is not needed. The rat NOAELs for EG is set to 1000 mg/kg bw (16 mMol EG, MW 62) and converting this value to Zenolide would result in a NOAEL of 4129 mg/kg bw (MW 256, which is close to the LD50 of Zenolide). This latter value is not a relevant dose in risk assessment, where the limit dose is 1000 mg/kg bw (OECD TG 414).

Uncertainty of the prediction: The read across to Zenolide from Habanolide is convincing when considering the systemic exposure to the fatty acid type of metabolites. The difference between Zenolide and Habanolide is the double ester and the formation of EG in Zenolide, which will not be formed after exposure of Habanolide. To capture the exposure from Zenolide to EG, developmental toxicity assessment of EG is included and therefore covering this difference between these two substances.

Data matrix

The relevant information on physico-chemical properties and relevant toxicological properties are presented in the Data Matrix below.

Conclusions on developmental toxicity

For Zenolide reproductive toxicity information is available from a Reproduction Developmental Toxicity Screening Test (OECD TG 421), which does not present a concern for fertility and developmental toxicity. For the current Annex IX registration developmental toxicity information is needed similar to an OECD TG 414 study. This type of information is available from the structural analogue Habanolide, which can be used for read across. Also, developmental toxicity from Zenolide’s metabolite Ethylene glycol and Dodecanedioic-acid are used to conclude on the developmental toxicity of Zenolide. When using read across the result should be applicable for classification and labelling and risk assessment as well as presented with reliable and adequate documentation. This documentation is presented in the current document.

Habanolide does not show adverse effects in a developmental toxicity study (OECD TG 414, Klimisch 1) in which the NOAEL is ≥1000 mg/kg bw, which can be directly used for read-across to Zenolide. Also, Zenolide’s metabolite DDDA does not show developmental toxicity in a Repeated dose Reproductive Developmental test (OECD TG 422, Kl. 1). In addition, for EG, the key toxic metabolite of Zenolide, it is shown that high dosing can overload the metabolic pathway of its metabolite Glycolic acid, which is the key developmental toxicant, at high doses (2 mMol onwards). In rat, EG developmental toxicity at high doses occurs due to a higher transport rate of Glycolic acid into the placenta compared to rabbits and humans. Based on these two phenomena there is no developmental concern for EG. This means that there is also not a concern for Zenolide. Based on all information available it can be concluded that Zenolide will not be a developmental toxicant in studies similar to OECD TG 414.

Final conclusion: Zenolide is not a developmental toxicant: NOAEL of ≥ 1000 mg/kg bw in studies similar to OECD TG 414.

 

Data matrix to support the read across to Zenolide (Target) from Habanolide (Key source), Ethylene Glycol (Supporting source), and Dodecanedioic-acid (Supporting source) for developmental toxicity

Common names

Zenolide

Habanolide

Ethylene Glycol

Dodecanedioic-acid

 

Target

Key source

Supporting Source

Supporting Source

Chemical structures

CAS no

54982-83-1

111879-80-2

34902-57-3

107-21-1

693-23-2

EC no

259-423-6

422-320-3

203-473-3

211-746-3

Registration information

Yes

Yes

Yes

Yes

Empirical formula

C14H24O4

C15H26O2

C2H6O2

C12H22O4

Molecular weight

256

238

62

230

Phys-chem data

 

 

 

 

Physical state

Liquid

Liquid

Liquid

Solid

Water solubility (mg/l)

75

0.95

Miscible

30

Log Kow

3.65

5.45

-1.36

3.2

Human health

 

 

 

 

Acute oral toxicity (mg/kg bw)

4500

>2000

7712

>3000

Repeated dose toxicity (mg/kg bw) - 28 days

≥1000

(OECD TG 407)

300

(OECD TG 421)

≥1000

(OECD TG 407)

-

≥1000

(OECD TG 422)

Repeated dose toxicity (mg/kg bw) - 90 days

Read across Ethylene Glycol

≥1000

(OECD TG 408)

150

≥1000

(OECD TG 408)

Fertility toxicity (mg/kg bw)

≥1000

(OECD TG 421)

≥1000

(OECD TG 415)

≥1000

(3-gen. test)

≥1000

(OECD TG 422)

Developmental toxicity (mg/kg bw)

≥1000

(OECD TG 421)

≥1000

(OECD TG 414)

≥2000

≥1000

(OECD TG 422)

References

- Agency for Toxic Substances and Disease Registry (ATSDR), Toxicological Profile For Ethylene Glycol, 2010https://www.atsdr.cdc.gov/toxprofiles/tp96.pdf

-Carney, E.W.,Tornesi, B.,Markham, D.A.,Rasoulpour, R.J.,Moore,N., 2008, Species-specificity of ethylene glycol-induced developmental toxicity: toxicokinetic and whole embryo culture studies in the rabbit, 83, 573-81.

- Corley, R., Wilson, D., Hard, G., Stebbins, K., Bartels, M., Soelberg, J., Dryzga, M., Gingell, R., McMartin, K., Snellings, W., 2008, Dosimetry considerations in the enhanced sensitivity of male Wistar rats to chronic ethylene glycol-induced nephrotoxicity, Toxicol Appl Pharmacol. Apr 15;228(2)

- Charles River Laboratory (CRL), 2019, Feasibility assessment of Zenolide in EDTA Rat Plasma, Study report, 20180030.

- Dodecanedioic acid, REACH dossier:https://echa.europa.eu/nl/registration-dossier/-/registered-dossier/14886, site visited April 2019.

- Fowles, J., Banton, M., Klapacz, J., Shen, H., 2017, A toxicological review of the ethylene glycol series: Commonalities and differences in toxicity and modes of action, Toxicology Letters, 278, 66–83.https://www.sciencedirect.com/science/article/pii/S0378427417302345.

- Nagai, A., Takebe, K., Nio-Kobayashi, J., Takahashi-Iwanaga, H., Iwanaga, T, 2010, Cellular Expression of the Monocarboxylate Transporter (MCT) Family in the Placenta of Mice, Placenta, 31, 126–133

- Saghir. M., Werner, J., Laposta, M., 1997, Rapid in vivo hydrolysis of fatty acid ethyl esters, toxic nonoxidative ethanol metabolites, Am. J. Physiol., 273, G184-G190.

Justification for classification or non-classification

Based on the absence of adverse effects on fertility and developmental toxicity the substance does not need to be classified for reproduction toxicity according to EU CLP (EC 1272/2008 and its amendments).

Additional information