Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.73 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC 2010
Overall assessment factor (AF):
12
Modified dose descriptor starting point:
NOAEL
Value:
9.1 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
oral study; no adjustment is necessary
AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required
AF for differences in duration of exposure:
1
Justification:
chronic study
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling factor. Due to the known metabolism of Methacrylic acid derivatives via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations, an additional AF of 2.5 for remaining differences is not justified.
AF for other interspecies differences:
1
Justification:
see above.
AF for intraspecies differences:
3
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricaboxylic acid cycle) makes a lower variability likely, hence the AF of 3 by ECETOC (2010) is sufficiently conservative.
AF for the quality of the whole database:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for remaining uncertainties:
1
Justification:
The key studies were of high quality. No adjustment is required
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

The discussion is focused on the experimental data of the structurally closely related methacrylamide.

Discussion - Workers

 

Derivation of DNEL (Inhalation, systemic)

  

Methacrylamide is moderately toxic after oral administration and of lower toxicity when administered dermally or by inhalation.

It was demonstrated to be neurotoxic in different experimental animals (rat, mouse, Guinea pig, dog, cat) after single and repeated exposure. Effects observed were in the range of coordination and motion problems up to paralysis. Damage of nerve fibers can be observed histopathologically.

The chronic NOAEL (rat, 12m, drinking water) is at 9.1 mg/kg/d. This is equivalent to an inhalation dose of approximately 32 mg/m³.

At the highest dose administered in the 90 d inhalation study in rats, there was no evidence for neurotoxicity or any other signs of systemic toxicity.

The absence of systemic toxicity findings at that dose suggests the relevance of the major metabolic pathway with methacrylamide degradation via methacrylic acid and further via the citric cycle to physiological metabolites, as already described for the metabolism of methacrylic acid (esters).

Potentially (neuro)toxic metabolites are obviously not formed here in amounts leading to critical plasma- and tissue concentrations, respectively. They might become relevant at significantly higher systemically available doses, when the major metabolic pathway becomes overloaded.

The decreased body weight gains found in male animals in the 90 d inhalation study are not considered as systemic adverse effect as there is no evidence for changes in organs, tissues or other parameters. The only findings are signs of local irritation in nasal tissues. In particular, there is no evidence for neurotoxicity.

Considering a safety factor of 2 for the time extrapolation subchronic => chronic, a factor of 2.5 for the interspecies variability and 5 for the intraspecies variability for workers (cf. RIP 3.2 concise p-TGD, page 46) results in an overall safety factor of 25.

Based on the systemic NOAEL of 62.5 mg/m³ in the 90 d inhalation study, a DNEL (inhalation, workplace) of 2.5 mg/m³can be derived.

That value is in good accordance with a value derived from the chronic study (see above) with a NOAEL of 9.1 mg/kg/d which is equivalent to an inhalation dose of approximately 32 mg/m³ (time extrapolation has not to be applied, route extrapolation does not need an additional safety factor as the systemic toxicity after oral administration is higher than after inhalation in the view of all data. Therefore, the overall safety factor is 12.5 (combined for interspecies and intraspecies variability, see above).

 

Derivation of DNEL (dermal, systemic)

 

In principle, the same database as for the derivation of the DNEL (Inhalation) is used.

Key study is the chronic study with a NOEAL of 9.1 mg/kg/d (details see above).

Consideration of a safety factor of 2.5 for the interspecies variability and 5 for the intraspecies variability for workers (cf. RIP 3.2 concise p-TGD, p. 46) results in an overall safety factor of 12.5. An additional safety factor for route extrapolation is not appropriate as the existing data are indicating a minor toxic potential of the substance after dermal administration compared to oral administration.

Anticipating 100 % dermal uptake (worst case) the NOAEL of 9.1 mg/kg/d and the safety factor of 12.5 result in a DNEL (dermal) of 0.73 mg/kg/d.

Amendment to DNEL derivation on systemic toxicity

 

Considering the recently published ECETOC Guidance on Assessment Factors to derive a DNEL (ECETOC Report no. 110, 2010) and in accordance with the practice for the DNEL derivation with respect to systemic toxicity of structurally related methacrylic acid and methacrylate esters as methyl methacrylate in recently submitted dossiers, the overall assessment factor for a chronic oral study is 12 (details see above). Therefore, the originally derived assessment factor of 12.5 is confirmed to provide a sufficient margin of safety.

 

 

Derivation of DNEL on Toxicity to Reproduction

 

There is no evidence for teratogenicity or other effects on toxicity to reproduction in methacrylamide studies. The lowest NOAEL described for that endpoint is 49 mg/kg/d.

The observation of a temporarily slightly diminished grip strength in juvenile mice described by the study authors in the one-generation toxicity to reproduction study on methacrylamide (key study) is considered as irrelevant for the NOAEL determination on the following reasons:

 

Published data reveal a strong correlation between body weight of the test animals and grip strength (literature: Maurissen JP et al: Neurotoxicol Teratol. 2003 Sept-Oct; 25 (5): 543-53).

 

The data presented in the one-generation toxicity to reproduction study on methacrylamide show clearly diminished body weights of the dose group animals compared to the control groups at day 21 post partem. The average difference is 1.04 g for males and 0.89 g for females which is about 8.5 % (males) and 8 % (females) of the body weight at this age. Such a depression in body weights in the dose groups as a result of decreased palatability, especially in the beginning of administration, is a common effect which is reported in numerous oral toxicity studies.

 

Moreover, the difference in body weights is expected to be even aggravated as the age of the control animals during the grip strength measurements (average 29.2 days for males and females) was significantly higher than that of dose group animals (average 27.2 days [males and females] for the lowest dose group, 26.8 [females] and 27.3 [males] for the medium dose group and 28.2 [males and females] for the highest dose group).

It is expected that an age increase of 1 - 2 days will lead to significant higher body weights in mice during this phase of strong juvenile growth.

 

In this context it is important to notice that at the day of grip strength measurements, body weights of the animals are not reported. Therefore, the possibility for proof of a direct correlation between body weight and grip strength is lacking in this study.

 

 

In conclusion, taking into account the bias caused by diminished body weights of the dose group animals versus control animals the effect of temporarily slightly diminished grip strength described by the study author as slight indication of neurotoxicity in immature animals cannot be confirmed. The invalidity of that finding is aggravated by the lack of body weight data on the test days.

The minor manifestation and reversibility of the described effect is taken into consideration as well.

 

Consequently, in the absence of any relevant findings on toxicity to reproduction, the NOAEL for developmental toxicity in this study is at the highest administered dose.

The NOAEL (F1) is > 240 ppm (71.3 mg/kg bw/day in males, 69 mg/kg bw/day in females).

 

In conclusion, it can be stated that the systemic DNEL of 0.73 mg/kg/d (dermal) at the workplace provides a sufficient protection against toxicity to reproduction for female and male workers.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

The substance is used as an intermediate in closed systems only on industrial scale. Therefore, the determination of DNELs for the general population is not necessary.