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Description of key information

For the endpoint repeated dose toxicity no study is available with n-octyl methacrylate. Therefore a read across using the category approach lower alkyl (C1 -C8) methacrylates was used to predict the repeated dose toxicity of n-octyl methacrylate. As source substances 2-ethylhexyl methacrylate was chosen.

In an oral OECD 408 study performed according GLP, the no observed adverse effect level (NOAEL) of 2 -Ethylhexyl methacrylate was 120 mg/kg body weight/day

in male and female Wistar rats (BASF, 2009). Data on the primary metabolites methacrylic acid and 2-ethylhexanol do not reveal critical effects like specific target organ toxicity. Toxicity of 2-ethylhexanol is lower than the parent ester toxicity based on NOAELs.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
120 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

For the endpoint repeated dose toxicity no study is available with n-octyl methacrylate. Therefore a read across using the category approach lower alkyl (C1 -C8) methacrylates

was used to predict the repeated dose toxicity of n-octyl methacrylate. As source substances 2-ethylhexyl methacrylate was chosen.

Data availability

For 2-EHMA a combined repeated dose and reproductive toxicity screening study (OECD 422) is available and a subchronic toxicity study (OECD 408), both by the oral route. The dermal route of exposure is considered leading to lower toxicity due to the limited skin penetration behavior of 2-EHMA and inhalation is not considered a relevant route of exposure due to the low vapour pressure (cf. chapter Toxicokinetics).

A chronic study does not have to be performed, because the substance is rapidly metabolised. Data on the primary metabolites methacrylic acid and 2-ethylhexanol do not reveal critical effects like specific target organ toxicity. Toxicity of 2-ethylhexanol is lower than the parent ester toxicity based on NOAELs.

ORAL

2-Ethylhexyl methacrylate was studied for oral toxicity in rats in an OECD combined repeat dose and reproductive/developmental toxicity screening test at doses of 0, 30, 100, 300 and 1000 mg/kg/day (Ito, 1998).

Local effects

There were no local effects in the oral cavity or in the intestinal tract – the site of first contact on oral dosing or any other tissue investigated.

Systemic effects

The NOEL for 2-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. 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 haematology (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 extreme dullary haematopoiesis 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.This study has been independently reviewed (RSA, 2008) and compared to published historical control data from the same test laboratory. As in the conclusion of the OECD review, effects seen at 30 mg/kg/d in females were not statistically significant when compared with historical controls. The other findings were confirmed in the review. Hence, the NOAEL for systemic effects in this study is 100 mg/kg/d in male and female rats.

Body weight effects

In both males and females, there were weight gain depression and a decrease in food consumption at a dose of 1000 mg/kg. The NOAEL for body weight effects was 300 mg/kg.

Summary (OECD 422)

In conclusion, the oral administration of 2-EHMA by gavage in an OECD 422 study revealed toxicologically relevant signs of systemic toxicity at the mid and high dose levels of 300 and 1000 mg/kg bw/day, The NOAEL in this study was 100 mg/kg body weight/day in both males and females.

 

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, 60, 120 and 360 mg/kg body weight/day over a period of 3 consecutive months (BASF, 2009). 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 sex of all dose groups were sacrificed. The remaining 5 animals per sex of control and high-dose groups were maintained for another 28 days without administration of the test substance (recovery groups). Food consumption and body weight were determined weekly. The animals were examined for signs of toxicity or mortality at least once a day. Detailed clinical examinations in an open field 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 haematological 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.

Local effects

There were no local effects in the oral cavity or in the intestinal tract – the site of first contact on oral dosing or any other tissue investigated.

Body weight effects

A statistically significant lower body weight was only observed in female animals at 360 mg/kg body weight/day 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 significant 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 significant lower terminal body weight in female animals (9% less compared to the controls). During the recovery period the body weights of the female animals remained below the control animals (13.2% less on study day 119). This is interpreted as being due to reduced food consumption that was observed in female animals at this concentration during the entire administration period and recovery period.The NOAEL for body weight effects was 120 mg/kg.

Systemic effects

At 360 mg/kg body weight/day a statistically significantly increased potassium levels in both sexes, and a statistically significantly increased chloride levels and decreased globulin levels was observed in females. However, the clinical pathology parameters reverted to a normal physiological range.At 120 and 60 mg/kg body weight/day, no treatment-related, adverse findings were observed concerning clinical examinations, clinical pathology and pathology parameters.Hence, the NOAEL for systemic effects in this study is 120 mg/kg/d in male and female rats.

Summary (OECD 408)

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.

Data on the primary metabolite 2-Ethylhexanol: In a repeat dose 90-day oral toxicity study in the rat effects on the liver, stomach, and kidney degeneration were reported. The NOAEL was 125 mg/kg/d.

The primary metabolite methacrylic acid revealed a low systemic toxicity potential in a 90 day inhalation study in rats (NOAEC: 350 ppm [1232 mg/m³]).

In an overall conclusion, repeated dose toxicity of 2 -EHMA can be clearly determined to be > 100 mg/kg/d either directly or derived from data of the primary metabolites. No findings indicating any specific target organ toxicity do exist.

 

 

 

 

Justification for classification or non-classification

According to the available data and CLP criteria, no classification is warranted for specific target organ toxicity-repeated exposure.