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

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

NOAEL (reproduction/development) = 1000 mg/kg bw/d for males (no effect on copulation and fertility);

NOAEL (reproduction/development) = 300 mg/kg bw/d for females (low values of the number of corpora lutea and number of implantation sites after administration of 1000 mg/kg bw/d)

(OECD TG 422, rat, oral gavage, RL1, GLP); read-across from 2-Ethylhexyl methacrylate

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

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: supporting information

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: gavage

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

female

Basis for effect level:

other: low values of the number of corpora lutea and the number of implantation sites at 1000 mg/kg

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Sex:

male

Basis for effect level:

other: highest dose tested; no effect on copulation and fertility

Critical effects observed:

no

Remarks on result:

not measured/tested

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

300 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Remarks on result:

not measured/tested

Reproductive effects observed:

no

Conclusions:

On the basis of the results the NOEL(reproduction/developmental) was considered to be 300 mg/kg bw/day in males and females.

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

300 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

No experimental data on Isotridecyl methacrylate are available for the assessment of toxicity to reproduction. 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 reproductive and developmental toxicological NOAEL was 1000 mg/kg/day for males since there was no effect on copulation and fertility; 300 mg/kg/day for females since low values of the number of corpora lutea and the number of implantation sites were observed after administration at a dose of 1000 mg/kg bw/d.

 

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 of 300 mg/kg bw/d 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 Guideline 422 and GLP study, 2-Ethylhexyl methacrylate (EHMA) in corn oil was administered by oral gavage to 10 male and 10 female rats at 0, 30, 100, 300, or 1000 kg/kg bw/day. Male rats were dosed for 49 days and female rats were dosed from 14 days prior to mating through Day 3 of lactation. Only one high-dose female rat died during the study. Treatment-related decreases in body weight and food consumption were observed in high dose animals only. Relative to reproductive parameters, treatment-related effects observed primarily at 1000 mg/kg/day included: significantly low number of estrus cycles, prolonged gestation period, decreased number of corpora lutea and implantation sites, and decreased parturition index [77.8%]. Maldevelopment of the mammary gland was observed in one animal, and three dams’ neonates all died during the lactation period in the 1000 mg/kg/day dose group. There was a significantly low number of total offspring in the high dose group compared to controls. In the 300 mg/kg/day dose group, there was a significantly low number of neonates on Day 0 of lactation compared with the control group. At 1000 mg/kg/day, there were significantly low body weights of male and female neonates on Day 0 of lactation compared to controls. However, no gross abnormalities were observed in neonates at any dose level. Based on effects observed in parental females in the 1000 mg/kg/day dose group (i.e. decreases in the number of corpora lutea and the number of implantation sites), the NOAEL for reproductive toxicity is considered to be 300 mg/kg/day EHMA. There are two elements which indicate that the lower number of F1 at day 0 of lactation are biologically not significant: Firstly, the difference is transient and not statistically significant by day 4 of lactation (due to reduced survival of neonates in the control group) and secondly, the observed mean number of neonates (13.4) is within the range of newborn F1 in the controls of other 422 studies in the same laboratory (13.1 – 15.2, n=10).

 

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 toxicity to reproduction. There is no reason to believe that the results would not be relevant to humans.  

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

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