Reaction mass of dodecyl methacrylate and tridecyl methacrylate

Endpoint summary

Description of key information

NOAEL = 1000 mg/kg bw/d, subacute (OECD TG 422; rat, oral gavage; RL1, GLP): no adverse effects up to and including 100 mg/kg bw/d; read-across from Dodecyl 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: supporting information

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

corn oil

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Hypersalivation: recorded in a dose-related incidence in males and females: 300 or 1000 mg/kg/day during premating (for males) and furthermore during gestation and lactation (for females).

Mortality:

no mortality observed

Description (incidence):

There were no premature deaths during the study.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Females given 1000 mg/kg/day gained 18% less weight than the controls between day 0 and day 7 post-coitum. This weight difference was statistically insignificant (limited to the first week of gestation). No other treatment-related effects on body weight were noted.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Males
The food consumption of treated males was similar to that of the controls during the study.

Females
There was no effect of treatment on group mean food consumption during the premating or lactation periods.
Between day 7 and day 10 post-coitum, all groups given Lauryl MA consumed less food than the controls, with no dose-relationship trend, achieving statistical significance at 100 and 1000 mg/kg/day (-17%, p<0.05 and -25%, p<0.001, respectively). Due to the lack of dose response and lack of consistency with other time periods in the study, these differences in food consumption were not considered of toxicological importance.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Description (incidence and severity):

There was no treatment-related effect on any of the hematological parameters examined.
When compared with the mean control values, a lower value in total white cell count was recorded for females in the 1000 mg/kg/day group (4.95 vs 7.34 g/L: -33%, not statistically significant). This change was not considered related to treatment with the test item because of the great variability and the great inter-individual variations of this parameter and the lack of effects on other related parameters (differential cell counts).

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

There was an increase in blood glucose concentration in male rats given 1000 mg/kg/day (7.63 mmol/L, p<0.01) when compared with the controls (5.78 mmol/L); a relationship to the treatment with the test item cannot be excluded. However, this variation was not considered to be of toxicological importance since the number of animals/group was limited to five, all values were within historical data range (mean: 6.69 mmol/L,
[5.22-9.04 mmol/L]) and there were no histopathological findings in the liver.
All other differences were considered not to be relevant since either no clear dose-relationship was evident (increased triglyceride and cholesterol plasma concentration in test item-treated females), or differences were slight (decrease in plasmatic protein concentration and increase in liver enzyme activities in females).

Urinalysis findings:

no effects observed

Description (incidence and severity):

There was no effect of treatment on pH, specific gravity or volume of urine produced by the males in any group.

Behaviour (functional findings):

no effects observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

There were no treatment-related effects on absolute or relative organ weights in any dose groups.

Gross pathological findings:

no effects observed

Description (incidence and severity):

At clinical pathology investigations, there was an increase in blood glucose concentration in male rats at 1000 mg/kg/day when compared with the controls. This difference was not considered to be adverse since all values were within historical background data and no histopathological findings were observed in the liver, although statistically different from controls.

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

There were no treatment-related findings at histopathological examination.

Histopathological findings: neoplastic:

no effects observed

Other effects:

no effects observed

Description (incidence and severity):

There was no effect of treatment on mating at any dose-level. The male and female fertility indices were unaffected by treatment; all mated females, except one given 1000 mg/kg/day, were pregnant with live fetuses. The duration of gestation was similar between the control and test item-treated groups. There was no effect of treatment on the mean number of liveborn pups or on pup death after birth. There were no external pup abnormalities in the control or test item-treated groups.

There was no effect of treatment on mean pup body weight or body weight gain for males or females. The sex ratios on days 1 and 5 post-partum were similar in the control and test item-treated groups. No relevant findings were observed in the pups sacrificed on day 6 post-partum.

Dose descriptor:

NOAEL

Remarks:

(parental toxicity)

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed up to limit dose

Dose descriptor:

NOEL

Remarks:

(toxic effect, reproductive performance and on developmental toxicity)

Effect level:

>= 1 000 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed up to limit dose

Critical effects observed:

no

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

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 Reaction mass of dodecyl methacrylate and tridecyl methacrylate are available for the assessment of repeated dose toxicity. However, studies are available for the source substance Dodecyl methacrylate. A detailed justification for read-across is attached to IUCLID section 13.

 

Summary

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.

 

Hypothesis for the analogue approach

The read-across hypothesis relies on the close structural similarity between the source substance Dodecyl methacrylate and the target substance Reaction mass of dodecyl methacrylate and tridecyl methacrylate. This 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 substance Dodecyl methacrylate predicts the toxicological properties of the target substance Reaction mass of dodecyl methacrylate and tridecyl 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 Reaction mass of dodecyl methacrylate and tridecyl methacrylate is an ester of Methacrylic acid and mainly linear C12 / C13 alcohols.The source substance Dodecyl methacrylate is comparable to the target substance with respect to chain length and contains only linear C-chains.

 

Structural differences:

The difference alkyl chain length between the target and the source substance is negligible.

The physicochemical properties (both substances have a log Kow > 6.5 and a water solubility < 1 µg/L) are very similar. Thus, no large differences in bioavailability are expected.

The target substance contains small amounts of branched alkyl chains, which is not considered toxicologically relevant.

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.

 

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

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, Reaction mass of dodecyl methacrylate and tridecyl 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.