2-Propenoic acid, 2-methyl-, C11-14-isoalkyl esters, C13-rich

Endpoint summary

Description of key information

NOAEL = 120 mg/kg bw/d, subchronic (OECD TG 408; rat, oral gavage; RL1, GLP): general (unspecific) systemic toxicity in male as well as female rats at a dose level of 360 mg/kg bw/day (body weight, clinical chemistry); read-across from 2-Ethylhexyl methacrylate

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substances have similar physicochemical, ecotoxicological and toxicological properties because
• they are manufactured from similar or identical precursors under similar conditions
• they share structural similarities with common functional groups: methacrylate esters
• the metabolism pathway leads to comparable products (methacrylic acid and medium chain alcohol).

Therefore, read-across from the existing physicochemical, ecotoxicity and toxicity studies on the source substances is considered as an appropriate adaptation to the standard information requirements of REACH regulation

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
see “Justification for read-across” attached to IUCLID section 13

3. ANALOGUE APPROACH JUSTIFICATION
see “Justification for read-across” attached to IUCLID section 13

4. DATA MATRIX
see “Justification for read-across” attached to IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: gavage

Description (incidence and severity):

There were no treatment-related findings at histopathological examination.

Dose descriptor:

NOAEL

Effect level:

120 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: Effects on body weight gain and some blood chemistry parameters at 360 mg/kg bw/d

Critical effects observed:

no

Conclusions:

In conclusion, the oral administration of the source substance 2-Ethylhexyl Methacrylate by gavage over a period of 3 months with a recovery period of 28 days revealed signs of general systemic toxicity in male as well as female rats at a dose level of 360 mg/kg bw/day.
Therefore, under the conditions of the present study, the no observed adverse effect level (NOAEL) was 120 mg/kg body weight/day in male and female Wistar rats.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

120 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

No experimental data on Isotridecyl methacrylate are available for the assessment of repeated dose toxicity. However, studies are available for the source substances 2-Ethylhexyl methacrylate and Dodecyl methacrylate. A detailed justification for read-across is attached to IUCLID section 13.

 

Summary

In a combined repeated dose toxicity study with the reproduction / developmental toxicity screening test, the NOAEL of 2-Ethylhexyl methacrylate was 100 mg/kg/day for males since high absolute and relative kidney weights were observed after administration at a dose of 300 mg/kg, and 30 mg/kg/day for females since a high relative kidney weight was observed after administration at a dose of 100 mg/kg.

Additionally, a subchronic toxicity study conducted with 2-Ethylhexyl methacrylate is available, which revealed signs of general systemic toxicity in male as well as female rats at a dose level of 360 mg/kg body weight/day. Therefore, the no observed adverse effect level (NOAEL) was 120 mg/kg body weight/day in male and female Wistar rats.

 

In contrast to that, Dodecyl methacrylate did not elicit any signs of toxicity when administered to Sprague-Dawley rats at 100, 300 or 1000 mg/kg/day in a combined repeated dose toxicity study with the reproduction / developmental toxicity screening test. Based on the experimental conditions of this study, the No Observed Adverse Effect Level (NOAEL) for parental toxicity was considered to be 1000 mg/kg/day and the No Observed Effect Level (NOEL) for toxic effect on reproductive performance and on developmental toxicity was greater than or equal to 1000 mg/kg/day.

 

The cause for this difference in toxicity is not clear. This might be due to slightly higher bioavailability of 2-Ethylhexyl methacrylate compared to Dodecyl methacrylate. It cannot be completely excluded, that the presence of branched alkyl chains in 2-Ethylhexyl methacrylate has an influence as well.

The presence of branches in close proximity to the ester function is likely to have a negative influence on hydrolysis rates due to steric hindrance. Branching in more remote positions did not have a pronounced effect on hydrolysis rates (Jones, 2002). Therefore, is can be concluded, that the presence of branched alkyl chains in the target substance is not likely to influence ester cleavage.

In general, branched fatty alcohols are not expected to exhibit higher toxicity than linear fatty alcohols, as branched fatty alcohols are abundant in the diet and are metabolised via the fatty acid α-oxidation and β-oxidation pathways.

Although Dodecyl methacrylate is closer to the target substance Isotridecyl methacrylate with respect to physicochemical properties (both substances have a log Kow > 6.5 and a water solubility < 1 µg/L) and thus, bioavailability, lower NOAEL obtained in the study with 2-Ethylhexyl methacrylate will be used as key value for the target substance Isotridecyl methacrylate for precautionary reasons.

 

Hypothesis for the analogue approach

The read-across hypothesis relies on the close structural similarity between the source substances 2-Ethylhexyl methacrylate and Dodecyl methacrylate and the target substance Isotridecyl methacrylate. his read-across hypothesis corresponds to scenario 2 - different compounds have qualitatively similar properties - of the read-across assessment framework i.e. properties of the target substance are predicted to be quantitatively equal to those of the source substance. Namely, the structurally similar source substances 2-Ethylhexyl methacrylate and Dodecyl methacrylate predict the toxicological properties of the target substance Isotridecyl methacrylate.

 

Based on the available data, including physicochemical data (water solubility and log Kow) and acute oral toxicity, the read-across strategy is supported by close structural analogy and similar toxicological profile of the substances.

 

Toxicological data are summarised in the data matrix; robust study summaries are included in the Technical Dossier in the respective sections.

 

Therefore, read-across from the existing toxicity studies conducted with the source substance is considered as an appropriate adaptation to the standard information requirements of the REACH Regulation for the target substance, in accordance with the provisions of Annex XI, 1.5 of the REACH Regulation.

A detailed justification for the proposed read-across approach is attached to Iuclid section 13.

 

1. Identity and characterisation of the source substance

 

There is close structural similarity between the source and the target substances and the identity and characterisation of these substances is unambiguous thereby giving a high level of confidence in the validity of the read across.

The target and source substances are manufactured from similar compounds by esterification of methacrylic acid with the corresponding fatty alcohol. Typical trace impurities are water and the corresponding alcohols as well as < 1 % methacrylic acid, which are not of toxicological concern.

The carbon chain length distribution of the resulting mix of long-chain aliphatic methacrylate esters mirrors the chain length distribution of the alcohol(s) used.

 

2. Link of structural similarities and differences with the proposed prediction

Structural similarities:

The target substance Isotridecyl methacrylate is an ester of Methacrylic acid and branched C12-C18 alcohols. The source substance 2-Ethylhexyl methacrylate contains branched alkyl chains as well, though it has shorter C-chains (C8). The source substance Dodecyl methacrylate is comparable to the target substance with respect to chain length, but contains only linear C-chains.

 

Structural differences:

There are differences in alkyl chain length between the target and the source substances as well as differences in the presence of branched alkyl chains.

The source substance 2-Ethylhexyl methacrylate can be expected to have a slightly higher bioavailability due to lower molecular weight compared to the target substance.

The physicochemical properties (low water solubility and high log Kow) are, however, quite similar. Thus, no large differences in bioavailability are expected.

Dodecyl methacrylate is closer to the target substance Isotridecyl methacrylate with respect to physicochemical properties (both substances have a log Kow > 6.5 and a water solubility < 1 µg/L), but the target substance Isotridecyl methacrylate contains branched alkyl chains in contrast to the source substance Dodecyl methacrylate, which contains only linear alkyl chains.

 

The presence of branches in close proximity to the ester function is likely to have a negative influence on hydrolysis rates due to steric hindrance. Branching in more remote positions did not have a pronounced effect on hydrolysis rates (Jones, 2002). Therefore, is can be concluded, that the presence of branched alkyl chains in the target substance is not likely to influence ester cleavage.

In general, branched fatty alcohols are not expected to exhibit higher toxicity than linear fatty alcohols, as branched fatty alcohols are abundant in the diet and are metabolised via the fatty acid α-oxidation and β-oxidation pathways.

Nevertheless, in the repeated dose toxicity studied conducted with both source substances 2-Ethylhexyl methacrylate and Dodecyl methacrylate it was evident that 2-Ethylhexyl methacrylate produced signs of unspecific general toxicity at dose levels of 300 and 1000 mg/kg bw/d, whereas Dodecyl methacrylate showed no adverse effects up to 1000 mg/kg bw/d. The cause for this difference in toxicity is not clear. This might be due to slightly higher bioavailability of 2-Ethylhexyl methacrylate. It cannot be excluded, that the branching has an influence as well. For precautionary reasons, the lower NOAEL obtained in the study with 2-Ethylhexyl methacrylate will be used as key value for the target substance Isotridecyl methacrylate.

 

Consistency of properties in the data matrix

The results of the acute oral toxicity studies demonstrate a low acute toxicity for the target and the source substances.

 

Reliability and adequacy of the source data

All available studies have been conducted according to OECD guidelines and have been assigned a reliability of 1 or 2 as documented in the data matrix (see detailed justification for read-across attached to Iuclid section 13).

 

Overall, the study design of the respective source studies is adequate and reliable for the purpose of this read-across. The results of the selected key studies are adequate for classification and labelling and for risk assessment purposes.

 

 

Data availability

In an OECD 408 study performed according GLP, 2-Ethylhexyl Methacrylate was administered daily by gavage to male and female Wistar rats at dose levels of 0 (test group 0), 60 (test group 1), 120 (test group 2) and 360 (test group 3) mg/kg body weight/day over a period of 3 consecutive months. Control and high-dose groups consisted of 15 animals per sex and group, whereas low- and mid-dose groups consisted of 10 animals per sex and group. After 3 months of treatment, 10 animals per sexof all dose groups were sacrificed (main groups). The remaining 5 animals per sex of controland high-dose groups were maintained for another 28 days without administration of the testsubstance (recovery groups). Food consumption and body weight were determined weekly. The animals were examinedfor signs of toxicity or mortality at least once a day. Detailed clinical examinations in an openfield were conducted prior to the start of the administration period and weekly thereafter. A functional observational battery (FOB) and measurement of motor activity were carried out during the last week of exposure. Clinico-chemical and hematological examinations as well as urinalyses were performed towards the end of the administration period. All animals were assessed by gross pathology, followed by histopathological examinations.

The following test substance-related, relevant findings were noted in test group 3 (360 mg/kg body weight/day): a statistically significantly lower body weights in female animals from study day 35 onwards until the end of the administration period (max. of 11.0% lower on study day 84) and during the recovery period (12.5% lower on study day 112), a statistically significantly lower body weight changes in female animals from study day 28 onwards until the end of the administration period (max. of 25.5% lower) and during the recovery period (-28.8% on study day 119), a statistically significantly lower terminal body weight in female animals (9% less compared to the controls), a statistically significantly increased potassium levels in both sexes, and a statistically significantly increased chloride levels and decreased globulin levels in females. During the recovery period the body weights of the female animals remained below the control animals (13.2% less on study day 119). However, the clinical pathology parameters reverted to a normal physiological range.

In test groups 2 and 1 (120 and 60 mg/kg body weight/day), no treatment-related, adverse findings were observed concerning clinical examinations, clinical pathology and pathology parameters.

In conclusion, the oral administration of 2-Ethylhexyl Methacrylate by gavage over a period of 3 months with a recovery period of 28 days revealed signs of general systemic toxicity in male as well as female rats at a dose level of 360 mg/kg body weight/day. Therefore, under the conditions of the present study the no observed adverse effect level (NOAEL) was 120 mg/kg body weight/day in male and female Wistar rats.

 

In an OECD Guideline 422 and GLP study, 2 -ethylhexyl methacrylate in corn oil was administered by gavage to 10 male and 10 female rats at dose levels of 0, 30, 100, 300, or 1000 mg/kg/day. The NOAEL for EHMA was 100 mg/kg/day in male rats and 30 mg/kg/day in females. One high-dose (1000 mg/kg/day) female died during the study. Treatment-related decreases in body weight and food consumption occurred in high dose animals only. Salivation was observed after administration in both male and female animals at doses of 30 mg/kg/day or higher appeared not to be treatment related. Male rats in the 300 and 1000 mg/kg/day groups had significantly high absolute and relative kidney weight and increased relative weights of the pituitary gland, and liver. The 300 mg/kg/day level was considered a LOAEL for males based on organ weight changes despite lacking histopathology because of corresponding changes at the high dose (1000 mg/kg/day) in serum BUN (kidney); protein, enzymes and A/G ratio (liver), and hematology (spleen and pituitary). In high dose females, there were significantly high absolute kidney weights and increased relative weights of thyroid gland, liver and brain. There was increased relative (but not absolute) kidney weights in females at both 100 and 300 mg/kg, however the effect at 100 mg/kg value was considered biologically insignificant based on the magnitude of the change compared to controls. The LOAEL for females is considered to be 300 mg/kg/day based on organ weight changes in both liver (absolute and relative) and kidney (relative only). Blood samples were not taken from the pregnant females, unlike males. Gross findings included yellowish white nodules in the tail of the right epididymis in one male animal at 300 mg/kg/day and atrophied thymus in one female of the 1000 mg/kg/day dose group. Treatment-related microscopic changes were observed in the liver and spleen of high dose males and in the thymus, spleen and brain of high dose females. These changes consisted of mild focal necrosis of the liver in two male rats, mild decreased extramedullary hematopoiesis in the spleen of three male rats and four female rats, mild atrophy of the thymus in four female rats, and a softened lesion of the medulla oblongata in two female rats at 1000 mg/kg/day.

 

The test item, Lauryl Methacrylate (Lauryl MA; CAS RN 142-90-5), was administered to male and female Sprague-Dawley rats by the oral route (gavage) at the dose-levels of 100, 300 or 1000 mg/kg/day. At 1000 mg/kg/day, hypersalivation was recorded in males and females, lower body weight gain was recorded in females during the GD 0-7 interval and increased plasma glucose concentrations were recorded in males. At 300 mg/kg/day, a few animals had hypersalivation. At 100 mg/kg/day, no treatment-related effects were detected. Hypersalivation was not considered to be a sign of toxicity to Lauryl MA. There were no substance-induced effects on the male and female reproductive performance, nor on the progeny of the parental rats at any dose-level. There were no treatment-related findings at histopathological examination. Based on the experimental conditions of this study, the No Observed Adverse Effect Level (NOAEL) for parental toxicity was considered to be 1000 mg/kg/day and the No Observed Effect Level (NOEL) for toxic effect on reproductive performance and on developmental toxicity was greater than or equal to 1000 mg/kg/day.

 

 

There are no data gaps for the endpoint repeated dose toxicity. There is no reason to believe that the results would not be relevant to humans. 

 

Justification for classification or non-classification

Based on the available data, Isotridecyl methacrylate does not need to be classified for repeated dose toxicity according to the criteria given in regulation (EC) 1272/2008. Thus, no labelling is required.