Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
no
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
Age at study initiation was 10 weeks old (males: 382-414 g, females: 245-282 g)
Route of administration:
oral: gavage
Vehicle:
corn oil
Duration of treatment / exposure:
Duration of test:
Males: 46 days
Females: 40-47 days

Post exposure observation period: 1 day

Duration of exposure:
Males: 45 days
Females: from 14 days before mating to day 3 of lactation
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
10, 30, 100 mg/kg/day
Basis:
nominal in diet
No. of animals per sex per dose:
12
Details on study design:
Statistical analysis: multi-comparison analysis for continuous data and Fisher's exact test for quantal data
Details on results:
Male:
At 30 mg/kg: Salivation at day 25 to day 40 of administration in 5 of 12 animals (This symptom disappeared within 10 minutes after the appearance).
Squamous hyperplasia in forestomach (0: 1/12, 10 mg/kg: 1/11, 30 mg/kg: 11/12, 100 mg/kg: 11/11).

At 100 mg/kg: Salivation continuously after 19 days of administration in all animals (This symptom were observed immediately after administration and almost disappeared within 30 minutes).
Increase in absolute and relative kidney and adrenal weights.
Increase in total protein and albumin.
Squamous hyperplasia in forestomach.

Female:
At 100 mg/kg: Cellular infiltration in forestomach (0: 0/12, 10 mg/kg: 2/12, 30 mg/kg: 3/12, 100 mg/kg: 4/12).

Remarks:
Two males died at 10 mg/kg on day 21 of administration and at 100 mg/kg on day 26 of administration, respectively. Although the reason of two males’ death was not clear, authors concluded it might be no chemical-related.
Salivation and increased serum protein in males was not considered as adverse effects.
Histological change observed in forestomach was considered to be due to irritation of this chemical.
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: local adverse effect: squamous hyperplasia in forestomach
Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: local adverse effect: squamous hyperplasia in forestomach
Dose descriptor:
LOAEL
Effect level:
30 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: local adverse effect: squamous hyperplasia in forestomach
Dose descriptor:
LOAEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: local advers effect: squamous hyperplasia in forestomach
Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: systemic adverse effect: increase in absolute and relative kidney and adrenal weights; increase in total protein and albumin
Dose descriptor:
LOAEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: systemic adverse effect: increase in absolute and relative kidney and adrenal weights; increase in total protein and albumin
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
30 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Unspecified test guideline and unpublished
Guideline:
other: no data
GLP compliance:
not specified
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
Age at study initiation was 8 weeks old.
Route of administration:
inhalation: vapour
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 hours per day, 5 days per week
Remarks:
Doses / Concentrations:
0.5, 2 and 15 ppm (2.9, 12 and 87 mg/m3, calculated daily dose 0.35, 1.46 and 10.59 mg/kg/day)
Basis:
nominal conc.
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
Post exposure observation period: 1 day.
Statistical analysis: Statistical significance by Dunnett’s test or Wilcoxon Rank-Sum test with a Bonferroni correction for multiple comparisons.
Age at study initiation was 8 weeks old.
Statistics:
Statistical analysis: Statistical significance by Dunnett’s test or Wilcoxon Rank-Sum test with a Bonferroni correction for multiple comparisons.
Details on results:
MALE:
At 87 mg/m3 Hyperplasia of respiratory epithelium of the nasal tissues, graded as very slight, in all animals. The hyperplastic respiratory epithelium was approximately two to three times as thick as that of control animals, and was located in the anterior portions of the nasal passages, involving the tips of the turbinates and the lateral walls of the nasal passages.

FEMALE:
At 87 mg/m3 Hyperplasia of respiratory epithelium of the nasal tissues, graded as very slight, in all animals. The hyperplastic respiratory epithelium was approximately two to three times as thick as that of control animals, and was located in the anterior portions of the
Dose descriptor:
NOAEL
Effect level:
12 mg/m³ air (nominal)
Sex:
male/female
Basis for effect level:
other: Hyperplasia of respiratory epithelium of the nasal tissues, graded as very slight, in all animals.
Dose descriptor:
LOAEL
Effect level:
87 mg/m³ air (nominal)
Sex:
male/female
Basis for effect level:
other: Hyperplasia of respiratory epithelium of the nasal tissues, graded as very slight, in all animals.
Critical effects observed:
not specified

Remarks:

There were no treatment related in-life observations, and no significant treatment-related effects on body weight, urinalysis, clinical chemistry or hematology parameters, as well as gross pathologic changes or organ weights at any exposure levels.

The changes observed in respiratory tract were likely resulted from the irritation of glycidyl methacrylate.

Conclusion:

Repeated dose toxicity in rats by inhalation is hyperplasia in nasal tissues and NOAEL is 2 ppm (equivalent to 12 mg/m3 or 1.46 mg/kg/day).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
12 mg/m³
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Unspecified test guideline and unpublished
Guideline:
other: no data
GLP compliance:
not specified
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
Age at study initiation was 8 weeks old.
Route of administration:
inhalation: vapour
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 hours per day, 5 days per week
Remarks:
Doses / Concentrations:
0.5, 2 and 15 ppm (2.9, 12 and 87 mg/m3, calculated daily dose 0.35, 1.46 and 10.59 mg/kg/day)
Basis:
nominal conc.
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
Post exposure observation period: 1 day.
Statistical analysis: Statistical significance by Dunnett’s test or Wilcoxon Rank-Sum test with a Bonferroni correction for multiple comparisons.
Age at study initiation was 8 weeks old.
Statistics:
Statistical analysis: Statistical significance by Dunnett’s test or Wilcoxon Rank-Sum test with a Bonferroni correction for multiple comparisons.
Details on results:
MALE:
At 87 mg/m3 Hyperplasia of respiratory epithelium of the nasal tissues, graded as very slight, in all animals. The hyperplastic respiratory epithelium was approximately two to three times as thick as that of control animals, and was located in the anterior portions of the nasal passages, involving the tips of the turbinates and the lateral walls of the nasal passages.

FEMALE:
At 87 mg/m3 Hyperplasia of respiratory epithelium of the nasal tissues, graded as very slight, in all animals. The hyperplastic respiratory epithelium was approximately two to three times as thick as that of control animals, and was located in the anterior portions of the
Dose descriptor:
NOAEL
Effect level:
12 mg/m³ air (nominal)
Sex:
male/female
Basis for effect level:
other: Hyperplasia of respiratory epithelium of the nasal tissues, graded as very slight, in all animals.
Dose descriptor:
LOAEL
Effect level:
87 mg/m³ air (nominal)
Sex:
male/female
Basis for effect level:
other: Hyperplasia of respiratory epithelium of the nasal tissues, graded as very slight, in all animals.
Critical effects observed:
not specified

Remarks:

There were no treatment related in-life observations, and no significant treatment-related effects on body weight, urinalysis, clinical chemistry or hematology parameters, as well as gross pathologic changes or organ weights at any exposure levels.

The changes observed in respiratory tract were likely resulted from the irritation of glycidyl methacrylate.

Conclusion:

Repeated dose toxicity in rats by inhalation is hyperplasia in nasal tissues and NOAEL is 2 ppm (equivalent to 12 mg/m3 or 1.46 mg/kg/day).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
12 mg/m³
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
30 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Repeated toxicity

[SIDS data] Oral toxicity study of glycidyl methacrylate was performed in SD (Crj: CD) rats by an OECD combined repeated dose and reproductive/developmental toxicity screening test (OECD TG 422). Administration was conducted at doses of 10, 30 and 100 mg/kg/day by gavage for 45 days in males and from 14 days before mating to day 3 of lactation in females. (MHW, Japan: 1997)

Salivation was observed at 30 mg/kg (5/12) and 100 mg/kg (12/12) in males. In males, there was an increase in absolute and relative kidney and adrenal weights at 100 mg/kg. In blood chemistry of males, increase in total protein and albumin was observed. These changes were not considered as adverse effects. In histological examination, squamous hyperplasia in forestomach was observed at 30 and 100 mg/kg in males and cellular infiltration in forestomach at 100 mg/kg in females. These histological changes were considered to be due to the irritation of glycidyl methacrylate. NOAEL for oral repeat toxicity was considered to be 10 mg/kg/day for males and 30 mg/kg/day for females.

The NOAEL for repeated dose toxicity (systemic effects) was considered to be 30 mg/kg/day (both sexes). This key study was used for the derivation of oral and dermal DNELs.

Two other orally repeated toxicity studies were reported.

One-year study is very limited (Hadidian et al., 1968). Rats (3 males and 3 female) were dosed 5 days/week by gavage at 0.1 mg/kg. Groups of 15 male and 15 female rats were also dosed at 0.3 mg/kg. The authors concluded that no tissue effects related to the treatment were found. These dosages are considered to be too low.

In another study, five male and female rabbits were given orally at 50 mg/kg daily for 15 days (Ou- Yang et al.: 1988). Some animals showed slow reactions, head shaking and prostration, and two animals died. There were several hematological and pathological changes including bleeding, necrosis and so on in heart, liver, kidneys and stomach.

This study can not be adapted to hazard assessment because of unreliability such as no Test Guideline, no GLP, only single dose and unlikely severe systemic toxicity compared to other reliable oral and inhalation toxicity studies using rats and rabbits, and insufficient information on protocol and data analysis including purity of chemical and pathological data.

Subacute inhalation toxicity studies were performed in rats and rabbits. Rats were exposed to glycidyl methacrylate at concentrations of 58.2, 233 or 931 mg/m3 for 2 weeks (6 hours/day, 5 days/week) (Landry et al.: 1991). These three concentrations were calculated as 7.09, 28.4 or 113 mg/kg/day. Decrease in body weight was observed at 233 and 931 mg/m3. At 931 mg/m3, general debilitation with noisy and difficult respiration (mouth breathing), eye irritation, corneal clouding and distended abdomen (day 4) were observed. The animals at 931 mg/m3 were terminated early on day 4 because of the severity of the respiratory and ocular effects. Microscopically, there was severe multifocal necrosis and inflammation of the olfactory epithelium in the nasal cavity. At 233 mg/m3, there were slight to moderate multifocal necrosis, and inflammation of the respiratory and olfactory nasal epithelium. At 58.2 mg/m3, microscopically there was very slight multifocal necrosis of individual respiratory epithelial cells in 3 of 5 males and in 2 of 5 females. These changes in respiratory tract were considered due to irritation of glycidyl methacrylate. There were no histopathological changes in any other tissues. Therefore, 58.2 mg/m3 (7.09 mg/kg/day) was considered to be LOAEL because of tissue damages in respiratory tract.

Rabbits were exposed at 2.91, 11.6, 29.1, 58.2 mg/m3, 6 or 7 hours/day, daily for 13 consecutive days. (Cieszlak et al., 1996, Vedula et al., 1996. Two separate studies) Treatment-related degeneration of the nasal olfactory epithelium was observed at 11.6 mg/m3. At 29.1 and 58.2 mg/m3, there were olfactory epithelial degeneration, and the hyperplasia, erosions, ulcers and inflammation of the nasal epithelium. After 4-week recovery period, there was complete reversibility of these changes except for olfactory epithelial degeneration observed at 29.1 and 58.2 mg/m3, which showed only partial reversibility. At 11.6 mg/m3, nasal tissue was indistinguishable from controls at one month post-exposure. 2.91 mg/m3 (0.26 mg/kg/day) was considered to be NOAEL.

Subchronic inhalation toxicity study was conducted in rats at concentrations of 2.9, 12 or 87 mg/m3 for 13 weeks (6 hours/day, 5 days/week) (Landry et al.: 1996). These three doses were calculated as approximately 0.35, 1.46 or 10.6 mg/kg/day, respectively. There were no treatment related in-life observations, and no significant treatment-related effects on body weight, urinalysis, clinical chemistry or hematology parameters, as well as gross pathologic changes or organ weights at any exposure level. Treatment-related effects were limited to hyperplasia of respiratory epithelium of the nasal tissues in all animals at 87 mg/m3. In all affected animals, the hyperplastic respiratory epithelium was approximately two to three times as thick as in control animals, and was located in the anterior portions of the nasal passages, involving the tips of the turbinates and the lateral walls of the nasal passages. These changes were considered to be resulted from reparatory irritation. Therefore, NOAEL was considered 12 mg/m3 (1.46 mg/kg/day) for both sexes.

This key study was used for the derivation of inhalation DNELs.

There was 26 weeks inhalation toxicity study at concentrations of 15.3 and 206 mg/m3 in rats and rabbits (Ouyang Guoshun et al.: 1990). A wide range of toxic effects, such as lesion in central nervous system, cardiovascular system, liver and kidney, were observed in both species at the low and high doses. However, because of the higher vapor pressure and lower purity, the author suggested that the test material used in this study contained components other than glycidyl methacrylate, which may have contributed to the toxicity observed. Therefore these systemic toxicities observed in the studies are questionable.

Based on all above information, the major toxicity was tissue damages in the first exposure sites such as forestomach by oral administration and respiratory tract by inhalation, due to the irritation of chemical and NOAELs were 30 mg/kg for rat oral (systemic effects), 10 mg/kg bw/day for rat oral (local effects), 12 mg/m3 for rat inhalation and 2.91 mg/m3 for rabbit inhalation.

Justification for classification or non-classification

Based on the available studies and based on the other classifications already presented, no further classification of glycidyl methacrylate for this endpoint is required under REACH and CLP