Registration Dossier

Administrative data

Description of key information

No data available for 1,3 -BDDMA

 

1,3 -BDDMA is rapidly hydrolysed by carboxylesterases within a few minutes to methacrylic acid (MAA) and the respective alcohol, 1,3-Butanediol (1,3 -BD). The read across is justified in the attached read-across justification document. Following data were considered for read across:

Oral:

Chronic (2 yrs) study; oral (drinking water), rat, m/f (pre-guideline, pre-GLP): NOAEL ≥ 2000 ppm (=124 mg/kg bw/d in males and 164 mg/kg bw/d in females); read-across from the metabolite donor substance MMA (Borzelleca 1964)

Subchronic (90 d) study; oral (feeding), dog, m/f (pre-guideline, pre-GLP): NOAEL = 6000 mg/kg bw/d; read-across from the metabolite 1,3-BD (Reuzel 1978)

Chronic (2 yrs) study; oral (feeding), rat, m/f (pre-guideline, pre-GLP): NOAEL ≥ 10%; read-across from the metabolite 1,3-BD (Scala 1967)

Chronic (2 yrs) study; oral (feeding), dog, m/f (pre-guideline, pre-GLP): NOAEL ≥ 3%; read-across from the metabolite 1,3-BD (Scala 1967)

 

Inhalation:

The cited repeated dose studies via oral gavage administration (see above) do not exacerbate systemic toxicity effects which suggest bioavailability is low, thereby there is low toxicity potential. This intrinsic property/toxicity potential can be extrapolated to repeated inhalation route administration. The potential of inhalable forms is considered as low.

Subchronic (90 d) study; inhalation vapour, rat, m/f (OECD guideline 413, GLP); NOAEC local= 100 ppm (352 mg/m3) due to local irritation effects in the respiratory epithelium; NOAEC systemic= 100 ppm (352 mg/m3) due to reduced bw gain; read-across from the metabolite MAA (BASF 2008)

Chronic/ Carcinogenicity (2 yrs) study; inhalation (vapour), rat, m/f (comp. to OECD guideline 453, non-GLP): LOAEC local= 100 ppm (ca. 416 mg/m3) due to nasal lesions; NOAEC systemic= 400 ppm (ca. 1640 mg/m3) due to reduced bw gain read-across from the metabolite donor substance MMA (Lomax 1997)

Chronic/ Carcinogenicity (2 yrs) study; inhalation (vapour), rat, m/f (NTP protocol, GLP): LOAEC local= 250 ppm for female rats and 500 ppm for male rats due to nasal lesions; NOAEC systemic≥ 500 ppm for female rats and ≥ 1000 ppm male rats; read-across from the metabolite donor substance MMA (NTP 1986)

No reliable data is available for 1,3-BD.

 

Dermal:

The substance is unlikely to be inhaled, skin contact is unlikely and the physicochemical and toxicological properties suggest low potential for significant rate of absorption through the skin. The cited repeated dose studies via oral gavage administration (see above) do not exacerbate systemic toxicity effects which suggest bioavailability is low, thereby there is low toxicity potential. This intrinsic property/toxicity potential can be extrapolated to repeated inhalation route administration. The potential of inhalable forms is considered as low.

 

No reliable data available for either methacrylic or alcohol metabolite.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment.
Qualifier:
equivalent or similar to guideline
Guideline:
other: not known
Principles of method if other than guideline:
Chronic, repeated dose study with exposure via drinking water
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: "young" (unspecified)
The  animals were individually housed and provided food (finely ground Purina Dog Chow Kibbled Meal; questionable information in the publication) ad libitum
Route of administration:
oral: drinking water
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
polarographic analysis of monomer content
Duration of treatment / exposure:
104 weeks (2 years)
Frequency of treatment:
Daily, ad libitum
Remarks:
Doses / Concentrations:
6, 60 and 2000 ppm at the start of the study; raised after 5 months to 7, 70 and 2000 ppm (limited by palatability)
Basis:

Remarks:
Doses / Concentrations:
ca. 14, 137, 3360 ppm
Basis:
other: for females based on dietary equivalents of fluid consumption
Remarks:
Doses / Concentrations:
ca. 12, 115, 3210 ppm
Basis:
other: for males based on dietary equivalents of fluid consumption
No. of animals per sex per dose:
25
Control animals:
yes, concurrent no treatment
Details on study design:
Twenty-five male and female albino (Wistar) rats were administered 6, 60 or 2000 ppm of methyl methacrylate in the drinking water. The concentrations of the low- and mid-dose groups were increased to 7 and 70 ppm at the beginning of the fifth month of the study.
Prior to the start of the study, it was apparent that methyl methacrylate was volatilizing at the tip of the water bottles. A special design was employed to reduce the volatilization and measurements showed that the methyl methacrylate concentrations remained within 15% of nominal for 72 hours.
The low and medium concentrations in the water were selected with the expectation that the diet equivalents would approximate 10 and 100 ppm. The high concentration was selected following preliminary tests that indicated that this level would significantly depress fluid consumption.
Observations and examinations performed and frequency:
Body weights were measured prior to study initiation, at weeks 1, 3, 6, 13, 26, 52, 78 and 104. Food and water consumption was measured over a three day period at the end of one and four weeks, monthly through month six and during even months thereafter. Hematological measurements, including hematocrit, hemoglobin, total white and differential white cell counts, were obtained from five rats from each sex in each treatment level at three month intervals. Pooled urine samples were collected from five rats per sex from each treatment group every three months to evaluate urinary concentrations of reducing substances and proteins.
Sacrifice and pathology:
Semiquantitative tests for urinary concentrations of reducing substances and protein were performed on urines pooled from 5 rats/sex per group at three month intervals. At two years, survivors were sacrificed and organ to body weight measurements were made for heart, spleen, kidney, liver and testes. Tissues preserved from all animals on study included heart, lung, kidney, liver, urinary bladder, spleen, gastrointeric, skeletal muscle, bone marrow, skin, brain, thyroid, adrenal, pancreas, pituitary and gonad. Histopathology was conducted on all tissues collected except from animals in the low dose group.
Details on results:
Body weight depression observed at 2000 ppm did not persist beyond the first few weeks of the study. Significant depression of fluid consumption was observed at 2000 ppm, although this tended to regress at the end of the study. Individual observations of depressed food consumption tended to parallel periods of depressed growth. These effects were considered as temporary non-adverse effects.
There were significantly increased kidney weight ratios for female rats at 2000 ppm. Since no substance-related effects were reported from histopathologic examinations in the kidneys, this effect is not considered as biologically relevant.
Dose descriptor:
NOAEL
Effect level:
>= 124.1 mg/kg bw/day (actual dose received)
Sex:
male
Basis for effect level:
other: based on fluid consumption and body weight (see attached document)
Dose descriptor:
NOAEL
Effect level:
>= 164 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: based on fluid consumption and body weight (see attached document)
Dose descriptor:
NOAEL
Effect level:
>= 2 000 other: ppm nominal
Sex:
male/female
Basis for effect level:
other: corresponding to ca. 3300 ppm in the diet on the basis of fluid and food consumption observations
Critical effects observed:
not specified

Mortality: A summary of the mortality data for methyl methacrylate is presented below.

Dose group (ppm)            Male           Female
Negative              (0)          12/25           9/25
                           6/7           7/25           7/25
          60/70          10/25           7/25
           2000          12/25          10/25

No statistical differences were noted in the mortality of the animals exposed to methyl methacrylate and those in the control group. A statistically significant decrease in body weight was observed in the first week for the female rats and in weeks one through three in the male rats administered 2000 ppm methyl methacrylate. Water consumption was reduced in the animals from the high-dose group; however, it was reported that this finding tended to regress towards the end of the study. Food consumption was not affected by the administration of methyl methacrylate in the drinking water. 

  

Hematologic values varied within normal ranges in all groups of rats throughout the study, and urine concentrations of protein and reducing substances showed no trends that appeared relatable to treatment.

Organ to body weight ratios obtained at sacrifice of 2-year survivors differed from the controls only in significantly increased kidney ratios in female rats receiving 2000 ppm of methyl methacrylate (controls 0.0082 ± 0.0019; treated 0.0094 ± 0.0011).

Histopathologic findings showed no abnormalities or lesions, in kind or incidence, not explicable on the basis of naturally occurring ones in this strain of rat at this age.

  

Diet equivalents of the test materials were calculated from the fluid and food consumption data.

In these calculations, corrections were not made for evaporation losses of the test materials from the drinking water, the orders of magnitude of which are given under methods described above (maximum 15%). Allowing for such losses, it would appear that the concentrations of test materials in the drinking water were equivalent to approximately 10, 100, and 3000 ppm in the diet.
Conclusions:
No relevant effects were observed up to the highest dose tested (2000 ppm, limited by palatability)
Executive summary:

No relevant effects were observed after exposure of rats in drinking water up to the highest dose tested (2000 ppm, limited by palatability).

Endpoint:
repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
Study conducted prior to GLP implementation. Publication has adequate details for assessment of quality
Principles of method if other than guideline:
2-year feeding study with 1,3-butanediol (administration in the diet)
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
2 yrs
Frequency of treatment:
daily
Dose / conc.:
1 other: %
Remarks:
corresponds to approx. 643 mg/kg in males and 844 mg/kg-bw /day in females
Dose / conc.:
3 other: %
Remarks:
corresponds to approx. 1960 mg/kg in males and 2330 mg/kg-bw /day in females
Dose / conc.:
10 other: %
Remarks:
corresponds to approx. 6230 mg/kg in males and 7300 mg/kg-bw /day in females
No. of animals per sex per dose:
30/sex/dose
60/sex control
Control animals:
yes
Details on study design:
Animals were necropsied after 2 years of exposure except for 10 animals per dose group which were necropsied after 1 year
Positive control:
no
Observations and examinations performed and frequency:
Data on body weight and food and compound consumption, and observations for pharmacologic effects were recorded regularly. Samples of blood for erythrocyte count, total and differential leukocyte count, and hematocrit and hemoglobin determinations were taken from representative animals in each group at 6 intervals during the two-year feeding period. At the same time, pooled samples of urine from each group were analyzed for specific gravity, pH, protein, sugar, acetone, urobilinogen, bilirubin, and occult blood. The gross appearance of the specimens as well as the microscopic appearance of the sediment were recorded.
Sacrifice and pathology:
After one year 10 animals from each group, and at two years all surviving animals, were sacrificed and autopsied. Representative organs were weighed and sections of brain, pituitary, thyroid, lung, heart, liver, spleen, kidney, adrenal, pancreas, stornach, small and large intestine, urinary bladder, gonads, hone, and hone marrow were submitted for histopathologic evaluation.
Statistics:
Survival was analyzed by the life-table technique. The other criteria examined were subjected to an analysis of variance or F test at the 5% probability Ievel.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Details on results:
Throughout the two-year test, feeding of butanediol caused no discernible toxic effects at any dietary level.
Experimental findings, not attributable to long-term ingestion of butanediol, included chronic in fammatory disease of the lungs, spleen, and kidneys of rats, and spontaneous subcutaneous neoplasms distributed among the control ( 16) and test ( 11) rats. These findings are common among laboratory animals of this age and strain.
Dose descriptor:
NOAEL
Effect level:
ca. 6 230 mg/kg diet
Based on:
test mat.
Sex:
male
Basis for effect level:
other: based on 10 % in diet
Dose descriptor:
NOAEL
Effect level:
ca. 7 300 mg/kg diet
Based on:
test mat.
Sex:
female
Basis for effect level:
other: based on 10 % in diet
Critical effects observed:
no
Conclusions:
1,3-butane diol has been tested in a chronic oral study over 2 years in high concentrations under the consideration of using it as a caloric supplement in food. A dose of 10 % in the diet (males approx. 6230 mg/kg bw/d, females approx. 7300 mg/kg bw/d) was the NOAEL in this study.
Executive summary:

1,3-butane diol has been tested in a chronic oral study over 2 years in high concentrations under the consideration of using it as a caloric supplement in food. A dose of 10 % in the diet (males approx. 6230 mg/kg bw/d, females approx. 7300 mg/kg bw/d) was the NOAEL in this study.

Endpoint:
repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
Study conducted prior to GLP implementation. Publication has adequate details for assessment of quality
Principles of method if other than guideline:
2-year feeding study with 1,3-butanediol (administration in the diet)
GLP compliance:
not specified
Limit test:
no
Species:
dog
Strain:
Beagle
Sex:
male/female
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Dosing was conducted by incorporating test material into food at 0.5, 1, or 3% by weight.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
2 yrs
Frequency of treatment:
daily
Dose / conc.:
0.5 other: %
Dose / conc.:
1 other: %
Dose / conc.:
3 other: %
No. of animals per sex per dose:
four males and four females per group
Control animals:
yes
Details on study design:
Animals were necropsied after 2 years of exposure except for 2 animals per dose group which were necropsied after 1 year
Positive control:
no
Observations and examinations performed and frequency:
Daily or weekly records were kept of appetite, appearance, elimination, signs of pharmacologic effect, body weight, and food and compound consumption. Samples of blood for erythrocyte count, total and differential leukocyte count, and determination of sedimentation rate, hematocrit, hemoglobin, blood urea nitrogen and bromosulphalein retention were taken from each dog at eight intervals during the study. Urinalyses, similar to those for the rats, were carried out at the same time.
Sacrifice and pathology:
Two animals from each group were sacrificed after one year and the remainder were sacrificed after two years of study. Autopsies were performed and the weight of representative organs was determined. Specimens of brain, pituitary, thyroid, lung, heart, lymph node, liver, spleen, kidney, adrenal, pancreas, stomach, small and large intestine, gall bladder, urinary bladder, gonads, hone, and bone marrow were submitted for histopathologic examination.
Statistics:
not specified
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
Throughout the two-year test, feeding of butanediol caused no discernible toxic effects at any dietary level.

In the dog study, some focal chronic nephritis characterized by radial scarring, mild lymphocytic and plasmocytic infiltration, cast formation, and tubular atrophy as well as mild to moderate glomerulitis were seen in control and test animals.
Dose descriptor:
NOAEL
Effect level:
3 other: %
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects observed
Critical effects observed:
no
Conclusions:
1,3-butane diol has been tested in a chronic oral study over 2 years in high concentrations under the consideration of using it as a caloric supplement in food. A dose of 10 % in the diet (males approx. 6230 mg/kg bw/d, females approx. 7300 mg/kg bw/d) was the NOAEL in this study.
Executive summary:

1,3-butane diol has been tested in a chronic oral study over 2 years in high concentrations under the consideration of using it as a caloric supplement in food. A dose of 10 % in the diet (males approx. 6230 mg/kg bw/d, females approx. 7300 mg/kg bw/d) was the NOAEL in this study.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
6 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Method and results sufficiently described, similar to OECD-guideline 453.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
GLP compliance:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc. (Wilmington, USA)
- Housing: group-housed by sex in wire mesh cages (seven per cage)
- Diet (e.g. ad libitum): Purina Laboratory Chow
- Water (e.g. ad libitum): water unspecified
- Acclimation period: 19 d


ENVIRONMENTAL CONDITIONS
not reported
Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
1. Original study (Reno FE, 1979):  The test substance was administered in 6000-liter inhalation chambers with pyramidal tops and bottoms, under  dynamic conditions of 1000 liters/minute of airflow. Control animals were exposed to filtered room air in the same manner as the treated animals. 
2. Re-Evaluation of the study (Lomax LG et al., 1997):  Animals were exposed to the test substance vapor in 6000 liter inhalation chambers under dynamic conditions of 1000  liters/minute of air flow. The control animals were exposed to filtered room air in a chamber with similar air-flow characteristics.  
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentration of MMA in each chamber was monitored, when possible, at hourly intervals during each 6-hr exposure using an Infrared 6-Station Analyzer (Wilks-Miran, Foxboro, MA, USA).
Duration of treatment / exposure:
2 years (104 weeks)
Frequency of treatment:
6 hr/day, 5 days / week
Remarks:
Doses / Concentrations:
25, 100 and 400 ppm (corresponding to ca. 0.10, 0.41 and 1.64 mg/L, respectively)
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
25.0, 99.8 and 396.1 ppm
Basis:
analytical conc.
No. of animals per sex per dose:
70 males and 70 females were assigned to each of the four exposure groups (including the  control). 
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: Not applicable
Observations and examinations performed and frequency:
1. Original study (Reno FE, 1979):
-NOTE: This study is also summarized with further evaluation of nasal passage microscopy in Lomax et al. (1997).
Methods: Groups of 70 male and 70 female (total animals = 280 males and 280 females) rats were randomly assigned to either a control or one of three test groups. The animals were group housed (7/cage) and provided food and water ad libitum, except during the exposure period. The animals were exposed to the test substance six hours a day five days per week for a total of 104 - 106 weeks. The test substance was administered in 6000-liter inhalation chambers with pyramidal tops and bottoms, under dynamic conditions of 1000 liters/minute of airflow. Control animals were exposed to filtered room air in the same manner as the treated animals. Concentrations of the test substance in each chamber were measured hourly during each exposure period using an infrared analyzer. Animals were observed daily for mortality and moribundity. Body weights and clinical observations were recorded prior to study initiation, weekly during weeks 1 though 12, biweekly from week 14 through 24, every fourth week from week 28 through 78 and biweekly from week 80 through 104. Ophthalmoscopic exams were performed on all rats prior to treatment using an indirect ophthalmoscope at weeks 13, 52 and 102.
2. Re-Evaluation of the study (Lomax LG et al., 1997): Animals: Three hundred male and 300 female rats were received from Charles River Breeding Laboratories, Inc. (Wilmington, MA, USA). Animals were maintained under quarantine for 19 days, during such time all rats were evaluated for clinical signs of disease and an ophthalmoscopic examination. Following the quarantine period, 70 males and 70 females were assigned to each of the four exposure groups (including the control). The animals were housed by sex in wire mesh cages (seven/cage). Animals were provided feed and water ad libitum, except during the exposure period. Exposure conditions: Animals were exposed to the test substance vapor in 6000 liter inhalation chambers under dynamic conditions of 1000 liters/minute of air flow. The control animals were exposed to filtered room air in a chamber with similar air-flow characteristics. Observations: All animals were observed for mortality and morbidity daily. Individual body weight data were collected at the start of the study, weekly for the first twelve weeks and biweekly to week 24, every fourth week to week 78 and biweekly until study termination (week 104). At such time, a more detailed evaluation of gross toxicity and tissue masses was performed. Ophthalmoscopic evaluations were conducted at weeks 13, 52 and 102.
Sacrifice and pathology:
1. Original study (Reno FE, 1979):
Blood samples were collected from ten males and ten females in each group at weeks 13, 52 and 102 and from ten males and ten females in the control and high-exposure group at weeks 26 and 78 for hematological evaluation via segmental amputation of the tail. The following parameters were examined: hematocrit, hemoglobin, erythrocyte count, erythrocyte morphology, total leukocyte count and differential leukocyte count. In addition, coagulation and prothrombin times were determined from all blood samples taken at 13, 52 and 104 weeks and from the samples collected from the control and high-exposure groups at week 78. Femoral bone samples were collected from all sacrificed animals at weeks 13 and 52 and from 10 animals/sex/group at termination. The number of myeloid and erythroid cells and the myeloid/erythroid ratios were determined. Blood samples were collected for clinical chemistry evaluations from the abdominal aorta of all animals sacrificed at weeks 13 and 51 and from ten males and ten females per group at study termination. The following parameters were evaluated: fasting glucose, blood urea nitrogen, serum glutamic pyruvic transaminase, alkaline phosphatase, total protein, total albumin, albumin/globulin ratio. In addition, total cholesterol and triglycerides were also determined from blood samples taken from all animals sacrificed at week 52 and from ten animals/sex/group at week 104. Twenty-four hour urine samples were collected from 10 animals/sex/group at weeks 13, 52 and 104 by individually housing the rats overnight in stainless steel cages. The following parameters were evaluated: appearance, pH, ketones, total protein, specific gravity, bilirubin, glucose and occult blood. Necropsy: Ten rats/sex/group were sacrificed by exsanguination after 13 and 52 weeks of exposure. Animals found moribund during the course of the study were sacrificed at the time of the observation. The remaining animals were sacrificed after 102-104 weeks of exposure to the test substance. A gross necropsy was performed on all animals that were sacrificed and most of the animals that died during the study. Brain, kidneys, lungs, spleen, thyroids, adrenals and testes/ovaries from each animal were weighed and the organ to body weight ratio was calculated. The following tissues were collected and preserved in formalin or Bouin's solution: brain, pituitary, thoracic spinal chord, esophagus, salivary glands, thyroids, lungs, thymus, heart, spleen, kidneys, adrenals, stomach, duodenum, ileum, jejunum, colon, skin, mesenteric lymph nodes, urinary bladder, ovaries, uterus, mammary gland costochondral junction, liver, sciatic nerve, skeletal muscle, pancreas, nasal turbinates, unusual lesions, eyes and the testes with epididymides. Intraperitoneal body fat was recorded without exception at week 52 and by exception at all subsequent intervals. Histopathology was performed on the brain, spinal cord, pituitary, thyroid, adrenal, heart, lung, spleen, liver kidney, and ovaries/testes from 10/animals/sex in the low- and mid-exposure groups; and the nasal turbinates of all low- and mid-level animals. Also, the adrenals, ovaries/testes, heart (with coronary vessels), kidneys, liver, lungs, nasal turbinates, pituitary and thyroid were evaluated from 10 animals/sex/group from the control and high-exposure groups sacrificed at weeks 13 and 52.

2. Re-Evaluation of the study (Lomax LG et al., 1997):
Blood samples were collected from 10 males and 10 females per dose group at weeks 13, 52 and 104 and 10 males and 10 females in the control and the high-dose group at weeks 26 and 78. The following hematological parameters were evaluated at each sampling interval: hematocrit, hemoglobin, red blood cells counts, erythrocyte counts, total white blood cell counts, erythrocyte morphology and prothrombin time. Bone marrow samples were collected from the femurs of all rats killed at week 13 and 52 and from 10 males and 10 females from each group at study termination. Blood also was obtained from the abdominal aorta of all rats killed at week 13, 52 and study termination. The following clinical chemistry parameters were evaluated: glucose, blood urea nitrogen, serum glutamic-pyruvic transaminase, alkaline phosphatase, total protein, total albumin, total cholesterol (except for week 13) and triglycerides (except for week 13). Twenty-four hour urine samples were collected from 10 animals per sex per group at weeks 13, 52 and 104. The following parameters were evaluated: appearance, pH, specific gravity, glucose, ketones, total protein, bilirubin, and occult blood. Necropsy: Ten rats per sex per group were sacrificed after 13 and 52 weeks of exposure. The remaining animals were sacrificed after 104 - 106 weeks of exposure. Necropsies were performed on all decedents. The brain, kidneys, lungs spleen, adrenal and thyroid glands and the testis or ovaries were weighed and the organ to body weight ratios were calculated. The following tissues were preserved in buffered 10% formalin: brain, pituitary, spinal cord, esophagus, salivary glands, thyroid glands with parathyroid, lungs, mediastinal lymph nodes, thymus, heart, aorta, larynx, spleen, kidneys, adrenals, stomach, duodenum, ileum, jejunum, colon, skin, mesenteric lymph nodes, urinary bladder, uterus, mammary gland, prostate, seminal vesicles, costochondral junction, liver, sciatic nerve, skeletal muscle, pancreas, nasal cavity and gross lesions. The eyes from all rats and the testes with epididymides were preserved in Bouin's fixative. Microscopic evaluations were made using the tissue listed above in the control and the high-dose groups at study termination. The brain, spinal cord, pituitary, thyroid, adrenal, heart, lung, liver, spleen, kidney, and ovaries/testes from 10 animals per sex in the low- and mid-dose groups and the nasal cavities from all animals in the low- and mid-dose groups were evaluated microscopically. Sections from the adrenals, testes or ovaries, heart, kidneys, pituitary, thyroids, liver, nasal cavities and lungs of control and high-dose animals were examined microscopically after the week 13 and 52 interim sacrifices. Following the issuance of the original report, tissue blocks of the nasal cavities from the animals killed at the terminal sacrifice and the control and high-dose group at week 13, were obtained and a composite cross-sectional map of representative nasal cavity lesions with the approximate distribution was prepared for the mid- and high-dose groups.
Statistics:
1. Original study (Reno FE, 1979): Data Analysis: Pairwise comparisons of the mean body weights from weeks 12, 24, 36, 48, 52, 60, 72, 78, 90 and 104 were conducted using the F test for equality of two variances and Student's t-test. Clinical laboratory data (except urinalysis and leukocyte differentials), terminal body weights and absolute and relative organ weights (organ/body weight) of all animals sacrificed at weeks 13, 52 and term were subjected to a preliminary test for equality of variance followed by one-way analysis using Bartlett's test for homogeneity and Snedecor and Cochran, respectively. When statistical significances were observed, an additional set of analyses was conducted using Scheffe's method for judging all contrast in analysis of variance.
2. Re-Evaluation of the study (Lomax LG et al., 1997): Data analysis: Pair-wise comparisons of the mean body weights were performed. Clinical laboratory data, with the exception of urinalysis and leukocyte differentials, terminal body weights and absolute and relative organ weights of all animals killed at weeks 13 and 52 and at study termination were subjected to a preliminary test for the equality of variance. To evaluate tumor incidence, Fisher's one-sided exact test was conducted between the control and high-dose groups. For all analyses, statistical significance was determined by a p value < 0.05.
Dose descriptor:
NOAEC
Remarks:
systemic (gross pathology histopathology, clinical effects)
Effect level:
ca. 1 640 mg/m³ air
Sex:
male/female
Basis for effect level:
other: corresponding to 400 ppm
Dose descriptor:
LOAEC
Remarks:
local effects (Histopathology, olfactory epithelium)
Effect level:
ca. 416 mg/m³ air
Sex:
male/female
Basis for effect level:
other: nasal lesions; corresponding to 100 ppm
Dose descriptor:
NOAEC
Remarks:
local effects (Histopathology, olfactory epithelium)
Effect level:
ca. 104 mg/m³ air
Sex:
male/female
Basis for effect level:
other: corresponding to 25 ppm
Critical effects observed:
not specified

1. Original study (Reno FE, 1979):

-----------------------------------

The mean analytical concentration was evaluated. The overall mean concentrations of MMA vapour were 25.0, 99.8 and 396.1 ppm for the 25, 100 and 400 ppm exposure groups, respectively.

 

Mortality: Mortality rates were relatively low through week 78. High mortality was observed through week 104. The author indicates that the increase in mortality was probably due to aging, not related to test substance exposure. The mortality rates for treated groups were comparable to the control group. A summary of the mortality rates (%) is provided below.

 

 

Dose group (ppm)

Week 0-13

Week 0-52

Week 0-104

MALES

 

 

 

Negative Control (0)

0

0

16

25

0

1.7

20

100

0

1.7

16

400

0

0

20

FEMALES

 

 

 

Negative Control (0)

0

0

24

25

0

3.3

36

100

1.4

3.3

26

400

0

5.0

30

 

Clinical signs

No signs of test substance-related toxicity were observed in any of the treated animals throughout the 104-week exposure period. The most frequent observations included cloudy eye(s) and bloody crust around one or both eyes. The author reported that these findings occurred with approximately the same frequencies in treated and control groups.

Body weight

Male body weights were significantly higher in the mid-level exposure group at week 24, lower weights in the low-level exposure group at week 104, and lower weights of the high-level exposure group at weeks 28 and 78. In the females, the low-level exposure groups showed a significant decrease in body weight at weeks 60, 72 and 78 and an increase at weeks 12 and 24. The females in the mid-level exposure group showed a significant decrease at weeks 52, 60 and 78 and in the high-level exposure group at weeks 28, 36, 52, 60, 72, 78 and 90. The author concluded, the body weight reduction observed in the females exposed to ca. 1.64 mg/L (400 ppm) MMA was test substance-related.

 

Ophthalmoscopy

Ophthalmoscopic observations were noted at weeks 13, 52 and 102. The author reports that no consistent ocular abnormalities were noted at weeks 13 and 52. Ocular findings noted at week 102 included cataracts, pale coloration, corneal cloudiness and red discharge. The cataract findings were considered to be caused by aging.

Haematology/ Clinical chemistry

Evaluation of the haematology and clinical chemistry data did not reveal any remarkable trends. Statistical analyses showed numerous significant differences between the treated and the control groups; however, these differences were considered sporadic and were considered by the author a reflection of sampling and biological variability. A transitory appearance of occult blood was observed in all groups at week 52. All remaining intervals were generally unremarkable.

 

Organ weights

A statistically significant increase in absolute and relative organ weights of the females exposed to ca. 1.64 mg/L (400 ppm) MMA was observed in the lungs, liver, kidneys, and ovaries at week 13. A statistically significant decrease in absolute and relative thyroid and adrenal weights were observed in both males and females in the high-level exposure group at week 52. Absolute thyroid and adrenal weights were significantly higher in the males exposed to ca. 0.41 mg/L (100 ppm), MMA for 52 weeks. Other significant differences were noted at weeks 52 and 104; however, the author concluded that no consistent dose-related pattern was established.

 

Gross pathology

Findings noted in animals that were sacrificed at weeks 13 and 52 were mainly discolorations of the lung and liver. None of the findings were considered treatment-related. Tissue mass findings for animals sacrificed at week 104 were typical for the age and the species of rats. No treatment-related differences with respect to the frequency were observed.

 

Histopathology 

Week 13

No treatment-related histopathological findings were noted in the rats exposed to ca. 1.64 mg/L (400 ppm) MMA for 13 weeks. Findings were consistent among groups and were typical for rats of this age and strain.

Week 52

No treatment-related histopathological findings were noted in the rats exposed to ca. 1.64 mg/L (400 ppm) MMA for 13 weeks. Findings were consistent among groups and were typical for rats of this age and strain.

Week 104

Treatment-related histopathological findings were limited to a very slight increase in the lesions of mild rhinitis observed in the mucosal lining of the nasal turbinates. A summary of the lesions is provided below.

 

Incidence of Lesions in Nasal Mucosa

 

 

Males

 

 

 

Females

 

 

 

Group No.*

1

2

3

4

1

2

3

4

No. of Nasal Turbinates Examined

48

49

49

48

44

48

45

46

Serous Exudate

3

11

12

16

15

8

17

23

Purulent Exudate

2

6

4

8

2

9

6

6

Pleocellular Infiltrate

1

4

6

19

3

14

9

11

Distended Submucosal Glands

5

21

21

12

3

14

12

9

Squamous Metaplasia (focal)

2

3

1

5

0

5

1

2

Inflammatory Polyp

0

0

1

2

0

0

0

0

*Groups 1, 2, 3 and 4 were exposed to ca. 0, 0.10, 0.41 and 1.64 mg/L (0, 25, 100 and 400 ppm) MMA, respectively.

 

No clear treatment-related effect could be established. Although lesions of mild rhinitis occurred more often in treated rats than control rats, it could not be determined if the rhinitis was a result of direct chemical insult to the turbinate area or whether the presence of MMA vapors predisposed the rats to an increase in spontaneous disease. [NOTE - Subsequent evaluation of the nasal lesions (Lomax et al., 1997) indicated that there were exposure related nasal lesions at ca. 0.10 and 0.41 mg/L (100 and 400 ppm)]. Neoplasms and spontaneous disease lesions were observed with comparable frequency in control and treated rats. Chronic nephritis was observed in most rats; however, it was more pronounced in males.

 

2. Re-Evaluation of the study (Lomax LG et al. (1997)):

-------------------------------------------------------

 

The mean analytical concentrations of the test substance in the exposure chambers were 25.0, 99.8 and 396.1 ppm less than 10% per dose level.

 

Mortality rates for the treated animals were similar to those of the controls. No signs of treatment-related toxicity were observed. At the 13, 52 and 104-week observation intervals, cloudy eyes and bloody crusts around one or both eyes were noted in all of the treatment groups, as well as the control animals. Body weights for males were lower than the control at various intervals but overall were considered equivalent over the 104-week period. Mean body weights for females were lower than the controls at ca. 1.64 mg/L (400 ppm) after week 52. Haematology, clinical chemistry and urinalyses did not indicate any treatment-related effects in any of the parameters evaluated.

 

Gross necropsy of the rats sacrificed at weeks 13 and 52 did not show any treatment-related effects.

 

The following information was obtained from the reevaluation of the nasal tissues from this study originally conducted by Reno et al.(1979) - see also summary for this study in this Dossier. Microscopic evaluation of the nasal cavity sections obtained from the animals exposed to the test substance for 13 weeks showed degeneration of the neuroepithelial cell lining of the dorsal meatus in conjunction with atrophy of Bowman's glands and focal basal cell hyperplasia. Lesions were identified on the tips of the maxilloturbinates and nasoturbinates and focally along the nasal septum in the more anterior regions of the nose. These lesions were characterized by chronic active inflammation, respiratory epithelial hyperplasia and squamous metaplasia. No microscopic findings were identified in the ocular tissue or the lungs or other tissues. Blocks of the nasal cavities of animals from the 52-week sacrifice were unable to be located and, therefore, were not evaluated. No new findings were identified in the tissues that were available for animals exposed to the test substance for 52 weeks. Spontaneous disease lesions included early respiratory disease in both the control animals and the animals exposed to 400 ppm of the test substance. Also focal areas of pneumonitis were observed in two females in the control group.

Gross necropsy after two years of exposure to the test substance showed no treatment-related effects. The nasal cavity was the target organ for chronic toxicity. Rats exposed to the 100 and 400 ppm dose group had dose-dependent lesions in the anterior portions of the nasal cavity. The olfactory epithelium lining the dorsal meatus in the anterior region of the nasal cavity was affected by exposure to higher concentrations of the test substance. The microscopic changes consisted of degeneration of the olfactory epithelium and underlying Bowman's glands, hyperplasia of basal cells, replacement of olfactory epithelium by ciliated epithelium and inflammation of

the mucosa and/or submucosa. Lesions tended to be bilateral in distribution. The olfactory lesions in rats exposed to 100 ppm were localized in the more posterior (level 3) portion of the dorsal meatus, while those in animals exposed to ca. 1.64 mg/L (400 ppm) were found in levels 2 and 3. Hyperplasia of glands in the lamina propria and/or goblet cells and inflammation of the mucosa/lamina propria were observed in the respiratory epithelium in the high exposure group animals. No effects were seen in nasal epithelium of rats exposed to ca. 0.10 mg/L (25 ppm) MMA. No statistically significant differences were observed in the frequency of tumours between the rats exposed to ca. 1.64 mg/L (400 ppm) of the test substance and that of the controls. In female rats exposed to ca. 1.64 mg/L (400 ppm) of the test substance, a statistically significant decrease in pituitary adenoma/carcinomas and mammary gland fibroadenomas was recorded. In male rats, a decreased incidence of pheochromocytoma was observed.

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

Repeated dose toxicity: inhalation - local effects

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

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 study is available for 1,3-BDDMA. Reliable, relevant and adequate studies are however available on repeated dose toxicity conducted with the structurally closely related isomer 1,4-BDDMA, and the primary metabolites MAA/MMA and 1,3-BD after oral and inhalative exposure as follows. 1,3 -BDDMA is rapidly hydrolysed by carboxylesterases within a few minutes to methacrylic acid (MAA) and the respective alcohol, 1,3-Butanediol (1,3 -BD). The read across is justified in detail in the attached category document.

 

In a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test according to OECD Guideline 422 (22 March 1996), 1,4-BDDMA was administered to groups of 10 Hsd: Sprague Dawley SD rats/sex/dose orally by gavage at dose levels of 0 (control), 100, 300 and 1000 mg/kg bw/d. The treatment schedule included 2 weeks before pairing, during pairing, post coitum and post partum periods up to day 3 post partum. Animals were administered for approximately 5 and 8 weeks for males and females, respectively.

No mortality occurred in the study. No clinical signs of toxicological significance were reported. Body weight and body weight gain as well as food consumption were lower in the high dose group compared to controls throughout the study.

No relevant differences were noted in motor activity and sensory reaction to stimuli between control and treated groups. Haematology and urin analysis revealed no changes of toxicological significance. The main relevant change in clinical chemistry was an increased value of bile acids in treated groups compared to controls with a clear dose-relation in males.

Measurements of oestrus cycle, pre-coital intervals and copulatory index did not show differences between treated and control groups. No significant differences were observed in the number of implantation, corpora lutea, total litter size, pre-implantation loss, pre-birth loss and gestation length between control and treated groups.

On the contrary, fertility index was markedly reduced in the high dose group (40% compared to 90% of the control group).

Reduced litter and mean pup weights were found in the high dose group compared to controls. The percentage of cumulative pup loss on Day 4 post partum starting from the total litter size at birth, was increased in the high dose group. No differences were found in sex ratio between the groups.

Small pups were generally observed in all groups including the control group. Cold to touch and apparently no food intake were the signs noted in pups of the treated groups only. No relevant differences were recorded in decedent pups between the groups. No abnormalities were observed in pups sacrificed at term.

At necropsy statistically significant higher kidneys weight was observed in high dose males and females compared to controls. In addition, thymus weight was significantly decreased in high dose males. No treatment-related changes were noted at macroscopic examination.

Treatment-related microscopic findings were limited to the high dosed animals and were seen in the stomach of both sexes and in the liver of the females only.

Stomach (non-glandular):

The treatment-related change seen in the high dosed animals (1/10 and 5/10, respectively in males and females), consisted of mild diffused hyperplasia of the squamous epithelium in the non-glandural stomach, which was associated with mild thickening (i.e., hyperkerathosis) of the keratin layer. This change was not associated with any indication of inflammation and/or ulceration

Liver:

In 3/10 high dose animals (females), minimal degree of multifocal perilobular hepatocytic vacuolaiton, which is suggested to be consistent with fatty change, was noted. The vacuoles were of mixed type (i.e., micro- and macrovesicular) and no presence of inflammation and/or necrosis was noted.

 

Slight toxic effects were seen in parental animals as indicated by the reduced body weight, body weight gain and food consumption in the animals receiving 1000 mg/kg bw/d. The reduced mean litter/pup weights in the high dose group may be related to the maternal toxicity.

Concerning the reproductive parameters, the fertility appeared to be treatment-related as indicated by the reduced number of pregnant females in the high dose group respect to the control group.

On the basis of the results obtained in the study, the NOAEL for both, general toxicity and reproduction/developmental toxicity was 300 mg/kg bw/d (males/females). The LOAEL was 1000 mg/kg bw/d.

 

The observed effects in the high dose group were only slight indicating only little likelihood that effects of greater severity at the same effect doses or effects at lower doses would occur in studies of longer duration (e.g. 90 day study).

The DNEL was derived using the default ECHA assessment factor = 6 for extrapolation from subacute to chronic exposure. Thus, a maximal uncertainty for potential effects of study duration was assumed for purposes of calculating a DNEL.

The slight effects observed in the study of subacute duration at a limit dose of 1000 mg/kg bw/d do not justify the conduct of studies of longer duration. Thus, also animal welfare is respected. In terms of repeat dose systemic toxicity the members of the category of multifunctional methacrylates demonstrate non-specific toxicity, i.e. effects on body weight gain, organ weight changes and slight histopathological changes. Severe target organ effects have not been observed. Within the concentration range of NOAELs reported here, there is also an absence of specific alerts from the primary metabolites (Methacrylic acid and the specific alcohol/diol – 300 mg/kg 1,3-BDDMA correspond to approx. 75 mg/kg 1,3-butanediol) even in studies of longer duration.

 

There are no data gaps for the endpoint repeated dose toxicity. No human data are available. However, there is no reason to believe that these results from rat would not be applicable to humans.

 Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint: OECD guideline 422 study, no deviations, GLP

 

MAA (common primary methacrylic metabolite of all category substances)

In an OECD 413, 90-day vapour inhalation study in Sprague Dawley rats, MAA revealed general toxicity at 350 ppm (1253 mg/m3, the highest tested dose) in male animals (BASF, 2008). Local, marginal irritation of the respiratory epithelium in the nasal cavity was observed in two female animals. No changes in sexual organs or sperm mobility and sperm head counts were noted. The NOAEC was 100 ppm (352 mg/m3) for local irritation effects in male and females The NOAEC for systemic effects based upon reduced body weight gain in the presence of reduced feed intake but no other systemic effects was also 100 ppm (352 mg/m3) in male and females.

 

MMA (donor substance for the common primary metabolite MAA)

In an early 2-year chronic drinking water study with 25 male and 25 female rats administered with 6, 60 and 2000 ppm MMA no adverse effect were observed other than elevated kidney weights without corresponding histopathology in female rats at 2000 ppm (Borzelleca et al., 1964). The NOAEC was reported as 2000 ppm (124 and 164 mg/kg bw/d) in male and female rats.

--

EU ESR on MMA (2002) concluded: “The combined chronic toxicity/carcinogenicity study of methyl methacrylate in F344 rats (Rohm and Haas, 1979a; the nasal tissues were reevaluated by Lomax, 1992; Lomax et al., 1997) was assessed for the requirements of the regulation 793/93/EEC as a valid study with restrictions. In comparison to the minimal requirements of a 28-day inhalation study (OECD 412), the list of organs to be weighted did not include the liver and the heart. 70 male and 70 female f 344 rats were exposed to vapor concentrations of 0, 25, 100 or 400 ppm methyl methacrylate for two years. Ten male and ten female rats from all groups were sacrificed after 13 and 52 weeks of exposure and all surviving rats were killed during week 104-106. Histological examination was conducted on more than 35 tissues including 3-4 cross-sections of the nasal cavity. Tissues from the trachea and the pharynx/larynx were not preserved for histopathologic examination. Mortality rates of treatment and control groups did not show significant differences. No compound-induced clinical signs were observed. After week 52, mean body weight of high dose females was generally lower than controls gaining intermittently significance. Reduced growth represented the only adverse effect outside the respiratory 'tract. Evaluation of hematology, clinical chemistry and urinalysis data did not reveal any methyl methacrylate associated effect.

At the end of the study, there were weight changes of some organs in mal es or females without any consistent relationship to the treatment. Similarly, no treatment-related macroscopic findings were observed in any of the dose groups. No histomorphological lesions other than nasal lesions were attributable to methyl methacrylate exposure of any exposed group. The examination of nasal cavities from male and female rats exposed to 400 ppm for 13 weeks or 52 weeks revealed a degeneration of the neuroepithelial olfactory cells lining the dorsal meatus of the anterior portions of the nasal cavities in conjunction with atrophy of Bowman's glands and focal basal cell hyperplasia. Chronic active inflammation, respiratory epithelial hyperplasia and squamous metaplasia characterized the lesions on the tips of the maxilloturbinate and nasoturbinats and focally along the nasal septum in more anterior regions of the nose. At the final sacrifice, nasal lesions were evident in mal es and females of the 100 ppm and 400 ppm exposure groups characterised by inflammatory degeneration of nasal epithelium. The primary target tissue was the olfactory epithelium with degeneration and/or atrophy of neurogenic epithelium and submucosal (Bowman's) glands lining the dorsal meatus, hyperplasia ofbasal cells, replacement of olfactory epithelium with ciliate (respiratory like) epithelium (metaplasia), and inflammation of the mucosa and/or submucosa. The severity of the lesions varied from minimal to slight at 0.4 mg/l (equivalent to 100 ppm) to moderate at 1.7 mg/l (equivalent to 400 ppm). At 0.1 mg/l (equivalent to 25 ppm) no pathological effects on the olfactory epithelium were reported, representing the NOAEC for local effects on the respiratory tract. Slight to moderate changes in respiratory epithelium occurred at 1.7 mg/l (equivalent to 400 ppm) and were characterized as hyperplasia of submucosal glands and/or goblet cells in the anterior regions of the nasal cativy. In the respiratory epithelium, there was inflammation of the mucosa and/or submucosa in males and females exposed to 400 ppm.... The NOAEC for systemic effects was considered to be 100 ppm for female rats and 400 ppm for male rats.

 

The cancer studies of the National Institutes of Health (NTP, 1986) revealed toxicological effects regarding the respiratory tract in male and female rats and mice. Groups of 50 male F344 rats and 50 B6C3Fl mice of each sex were exposed 6 hours per day, 5 days per week to air containing methyl methacrylate at target concentrations of 0, 2.1 or 4.2 mg/l (equivalent to 500 or 1,000 ppm) for 102 weeks. Groups of 50 female rats were exposed at concentrations of 0, 1.0 or 2.1 mg/l (equivalent to 250 or 500 ppm) on the same schedule. Increased incidences of serous and suppurative inflammation of the nasal cavity were observed in male and female rats.

Degeneration of the olfactory sensory epithelium characterized by loss of neuroepithelial cells was also observed in male and female rats. In exposed male and female mice inflammation of the nasal cavity, epithelial hyperplasia in the nasal mucosa and degenerative changes of the olfactory sensory epithelium were reported. In addition methyl methacrylate caused interstitial inflammation of the lung in high dose male mice. The trachea and larynx were also included in the histopathology, but no compound-related effects on these tissues were reported for rats and mice of each dose and sex. A NOAEC could not be established either from rats or mice.” This is true for local effects. For systemic effects, the NOAEC is is the highest tested dose, i.e. 1000 ppm for mice and male rats and 500 ppm for female rats.

 

1,3-BD (primary alcohol metabolite of 1,3-BDDMA)

NTP (1996) stated as follows: “Sprague-Dawley rats (30 males and 30 females per group) received 1%, 3%, or 10% 1,3-BD in feed, and dogs (four males and four females per group) received 0.5%, 1%, or 3% 1,3-butanediol in feed for 2 years. Blood and urine samples were collected from rats at six time points and from dogs at eight time points during the study. Blood samples were evaluated for hematology parameters, and urine was analyzed for specific gravity, pH, glucose, protein, and porphyrins. After 1 year of chemical exposure, 10 rats and 2 dogs from each group were evaluated; after 2 years of chemical exposure, the surviving animals were evaluated. At necropsy, organ weights were taken and all major tissues were fixed and prepared for histopathologic examination. No adverse effects were observed during the study, and there were no gross or microscopic lesions attributable to chemical exposure (Scala and Paynter, 1967).”

 

Justification for classification or non-classification

Based on the available data, 1,3-BDDMA 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.