Hexadecyl methacrylate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

WOE: There are no studies with hexadecyl methacrylate available, but there is a reliable study GLP OECD Guideline 422 study with dodecyl methacrylate (structual analogue) available (Klimisch score: 1, guideline study, GLP) (SAM, 2007). In this reproductive toxicity screening study according to OECD 422 with dodecyl methacrylate in rats, no impact on fertility was observed. NOAEL: 1000 mg/kg bw/day.
Neither the methacrylate moiety nor the basic short chain alkyl methacrylates appear to affect fertility. Furthermore dodecyl methacrylate showed no impact on fertility when tested in rats in an OECD 422 combined repeat dose and reproductive/developmental toxicity screening test (SAM, 2007).

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

There were no studies on toxicity to reproduction available for hexadecyl methacrylate, but for the structural analogue dodecyl methacrylate and the primary metabolite methyl methacrylate.

In a well performed OECD TG 422 / GLP study, 10 male and 10 female Sprague-Dawley rats received the test item, dodecyl methacrylate, by daily oral (gavage) administration for 15 days before mating, through mating, gestation and the beginning of the lactation period (until day 5 post-partum, p.p.). The dose-levels were 100, 300 and 1000 mg/kg/day. The study included check of clinical signs and mortality, body weight and food consumption, investigation of Functional Observation Battery; (FOB)) and motor activity, blood and urine analysis, macroscopic and microscopic examination, recording of corpora lutea and implantation sites, observation and examination of pups. Hypersalivation which was observed at 300 mg/kg/day and 1000 mg/kg/day was not considered to be a sign of toxicity to dodecyl methacrylate. There were neither 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. 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. On the basis of these results the NOEL (reproduction/developmental) was considered to be >= 1000 mg/kg bw/day in males and females (SAM, 2007).

 

In addition, a two-generation reproduction toxicity study in rats according to OECD TG 416 in compliance with GLP with the structural analogue methyl methacrylate (CAS 80-62-6) was used to assess the reproduction toxicity of the test substance (REACH Methacrylate Task Force, 2010). In this study, methyl methacrylate was administered to groups of 25 male and 25 female healthy young Wistar rats (P parental generation) as an aqueous preparation by stomach tube at dosages of 0; 50; 150 and 400 mg/kg body weight/day. At least 73 days after the beginning of treatment, P animals were mated to produce a litter (F1). Mating pairs were from the same dose group and F1 animals selected for breeding were continued in the same dose group as their parents. Groups of 25 males and 25 females, selected from F1 pups to become F1 parental generation, were treated with the test substance at dosages of 0; 50; 150 and 400 mg/kg body weight/day post weaning, and the breeding program was repeated to produce F2 litter. Control parental animals were dosed daily with the vehicle (1% CMC suspension in drinking water and four drops Cremophor EL and one drop hydrochloric acid).

The mid- and high-dose parental animals (400 mg/kg bw/d) showed clinical signs of systemic toxicity. There were no indications from clinical examinations as well as gross and histopathology, that the administration of methyl methacrylate via the diet adversely affected the fertility or reproductive performance of the P or F1 parental animals up to and including a dose of 400 mg/kg bw/day. Estrous cycle data, mating behavior, conception, gestation, parturition, lactation and weaning as well as sperm parameters, sexual organ weights and gross and histopathological findings of these organs (including differential ovarian follicle counts in the F1 females) were comparable between the rats of all test groups and ranged within the historical control data of the test facility. All data recorded during gestation and lactation in terms of embryo-/fetal and pup development gave no indications for any developmental toxicity in the F1 and F2 offspring up to a dose level of 400 mg/kg bw/day. Up to this dose level, the test substance did not adversely influence pup viability and pup body weights. Sex ratio and sexual maturation was not directly affected at any dose level, inclusive the high-dose group (400 mg/kg bw/day).

The NOAEL for general, systemic toxicity was 50 mg/kg bw/day for the P and F1 parental rats, based on adverse effects on food consumption observed at the LOAEL of 150 mg/kg bw/day in the P parental females.The NOAEL for fertility and reproductive performance for the P and F1 parental rats was 400 mg/kg bw/day, the highest dose tested. The NOAEL for developmental toxicity, in the F1 and F2 progeny, of the test substance was 400 mg/kg bw/day, the highest dose tested.

Short description of key information:
In an OECD Guideline 422 and GLP study with structural analogue dodecyl methacrylate, the NOAEL for reproductive toxicity is considered to be 1000 mg/kg/day for all relevant endpoints, which was the highest dose tested (Klimisch score: 1, guideline study, GLP) (SAM, 2007).
Supporting information: No indication to reproductive toxicity for primary metabolite methyl methacrylate. A two-generation reproduction toxicity study in rats according to OECD TG 416 in compliance with GLP was performed with the structural analogue methyl methacrylate (CAS 80-62-6) which was used to assess the reproduction toxicity of methyl methacrylate (REACH Methacrylate Task Force, 2010). The NOAEL for reproductive toxicity (fertility and reproductive performance) was considered to be 400 mg/kg bw/day for P and F1 parental animals, which was the highest dose tested .

Effects on developmental toxicity

Description of key information

In an OECD Guideline 422 and GLP study with dodecyl methacrylate in rats, the NOAEL for development of offspring was determined to be 1000 mg/kg/day (highest test dose). 
Supportingly, there is extensive information available for structurally analogous methacrylate esters. The absence of a teratogenic potential was demonstrated in teratogenicity studies in rats and rabbits (OECD 414) for methyl methacrylate and n-butyl methacrylate. 
In conclusion, based on studies in experimental animals, there is no evidence for toxicity of hexadecyl methacrylate and the long-chain alkyl methacrylate esters to the reproductive/developmental system. 

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

WOE: There are no studies with hexadecyl methacrylate available, but there is a reliable study GLP OECD Guideline 422 study with dodecyl methacrylate (structual analogue) available (Klimisch score: 1, guideline study, GLP) (SAM, 2007). In this reproductive/developmental toxicity screening study according to OECD 422 with dodecyl methacrylate in rats, no impact on developmental toxicity was observed. NOAEL: 1000 mg/kg bw/day.
This study is supported by developmental toxicity data with the primary metabolite methyl methacrylate (Methacrylate Task Force, 2010), both indicating an absence of developmental toxicity.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

In an OECD Guideline 422 and GLP study with dodecyl methacrylate in rats, the NOAEL for development of offspring was at the highest test dose 1000 mg/kg/day.

 

Supportingly, there is extensive information available for structurally analogous methacrylate esters.

 

In an inhalation developmental toxicity study with methyl methacrylate in rats (OECD 414), exposure to concentrations up to 8.3 mg/L (2028 ppm) resulted in no embryo or fetal toxicity or malformations even at exposure levels that resulted in maternal toxicity. 

In a study comparable to OECD guideline no. 414, groups of 22-25 pregnant female rats were given whole-body inhalation exposures to n-butyl methacrylate at target concentrations of 0, 100, 300, 600 or 1200 ppm for 6 hr/day, during days 6 to 20 of gestation. Maternal toxicity was observed at 300 to 1200 ppm. The NOAEL for developmental toxicity was 300 ppm n-BMA. There was no evidence of embryo lethality or teratogenicity with n-butyl methacrylate. 

With methyl methacrylate an oral OECD 414 study in rabbits was performed with doses of 50, 150, and 450 mg/kg/d. The no observed adverse effect level (NOAEL) for prenatal developmental toxicity was 450 mg/kg bw/d. No adverse foetal findings of toxicological relevance were evident at any dose, even in the presence of maternal toxicity.

From the alcohol side chain there are no alerts regarding specific developmental toxicity.

In conclusion, based on studies in experimental animals, there is no evidence for toxicity of hexadecyl methacrylate and the long-chain alkyl methacrylate esters to the reproductive/developmental system.

Justification for classification or non-classification

Overall, in consideration of all data available for hexadecyl methacrylate and its metabolites or structurally analogous methacrylate esters, there is no convincing evidence of reproductive or developmental toxicity.

In summary, classification of hexadecyl methacrylate for reproductive/developmental toxicity is not required.

EU classification according to Annex VI of the Directive 67/548/EEC:

- No classification required.

GHS classification according to Annex I 1272/2008 CLP (EU GHS):

- No classification required.