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Toxicological information

Carcinogenicity

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Description of key information

No carcinogenicity study is available for 1,4-BDDMA. For the alcohol metabolite 1,4 -Butanediol and the methacrylate metabolite methacrylic acid, data are available from the respective metabolite donor substances, namely Gamma-butyrolactone and methyl methacrylate. More details on the metabolism are available in the chapter Toxicokinetics and in the Category document.

Gamma-Butyrolactone:

Rats, oral, 2 yrs: negative (NTP 1992, NTP 1996)

Mice, oral, 2 yrs: females negative, males equivocal (NTP 1992, NTP 1996)

Methylmethacrylate

Rats, inhalation, 2 yrs: negative (NTP 1986)

Mice, inhalation, 2 yrs: negative (NTP 1986)

Rats, male inhalation, 2 yrs: negative (Lomax 1992)

 

Rats, oral (Borzelleca, 196, limited reliability)

 

In summary there is no evidence of carcinogenicity of the ester hydrolyses products of 1,4-BDDMA and therefore no carcinogenicity is expected for 1,4-BDDMA itself.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
carcinogenicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods
Justification for type of information:
Read across from the alcohol metabolite donor substance.
REPORTING FORMAT FOR THE ANALOGUE APPROACH
see attached category document

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
see attached category document, chapter 1.1ff

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
see attached category document, chapter 1

3. ANALOGUE APPROACH JUSTIFICATION
see attached category document, chapter 5 (Toxikokinetics) and endpoint specific chapters

4. DATA MATRIX
see attached category document, table in chapter 1.2 and endpoint specific chapters
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
other: NTP Protocol
GLP compliance:
yes
Remarks:
According to U.S. FDA regulations
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Frederick Cancer Research Facility (Frederick, MD)
- Age of male miceat study initiation: 55 days
- Age of female miceat study initiation: 62 days
- Weight at study initiation: At week 1, approx. 23.7 g (males) / 18.5 g (females)
- Fasting period before study: No
- Housing: 5 mice per cage (male mice were housed individually from 9th Feburary 1983 and
female mice were housed individually from 1st July 1983)
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum):ad libitum
- Acclimation period: 19 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16°-29° C
- Humidity (%): 25%-79%
- Air changes (per hr): minimum 15h
- Photoperiod (hrs dark / hrs light): 12h

IN-LIFE DATES: From: First dose-Nov 3, 1981 To: last dose-Oct 24th, 1983
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The dose formulations were prepared by mixing appropriate quantities of 7-butyrolactone and corn oil to give the required concentrations. Dose formulations were prepared weekly and discarded 2 weeks after the date of preparation.

VEHICLE
- Amount of vehicle (if gavage): 10 ml
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Verification was performed by GC using a flame ionization detector (FID) and a nitrogen carrier gas at 35ml/min and chloroform as a solvent, with two systems:
(1) 20% SP-2100 / 0.1% Carbowax 1500 on 100/120 mesh Supelcoport, oven temperature program of 50° C for 5 minutes, then 50° to 170° C at 10° C/minute, and
(2) 10% Carbowax 20M-TPA on sO/l00 mesh Chromasorb W(AW), oven temperature program of 50° C for 5 minutes, then 50° to 200° C at 10° C/minute.
During the 2-year studies, the dose formulations were analyzed at least once every 8 weeks; 41 of 42 dose formulations for rats and 27 of 28 dose formulations for mice were within 10% of the target concentrations.
Duration of treatment / exposure:
103 weeks
Frequency of treatment:
5d/wk
Post exposure period:
1 week
Remarks:
Doses / Concentrations:
262, 525 mg/kg bw
Basis:
analytical conc.
male and female mice
No. of animals per sex per dose:
50
Control animals:
yes, concurrent vehicle
Details on study design:
Rationale for animal assignment (if not random): Animals were grouped by weight intervals, then groups were assigned to cages. A table of random numbers was used to assign cages to treatment groups.
Dose selection: Doses selected for 2yr study for mice were 262 and 525 mg/kg, which were based on the chemical related mortality observed in male mice (3/10) and in female mice (1/10) at 1,050 mg/kg in 13 week study.
Positive control:
no
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice/day
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: initailly once/ wk for 13 wks, once/month thereafter.
BODY WEIGHT: Yes
- Time schedule for examinations:initailly once/ wk for 13 wks, once/month thereafter.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as
g food/kg body weight/day: No data
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted
averages from the consumption and body weight gain data: No data
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
OPHTHALMOSCOPIC EXAMINATION: No data
HAEMATOLOGY: No data.
CLINICAL CHEMISTRY: No data
URINALYSIS: No data
NEUROBEHAVIOURAL EXAMINATION: yes
Other: The health of the animals was monitored during the course of the studies according to the
protocols of the NTP Sentinel Animal Program.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes.
At necropsy, all organs and tissues were examined for gross lesions, and all major tissues were fixed and preserved in 10% neutral buffered formalin, processed and trimmed, embedded in paraffin, sectioned, and stained with hematoxylin and eosin for microscopic examination.
HISTOPATHOLOGY: Yes
Complete histopathlogical examinations were performed on all control, all high-dose and low dose male mice. Selected tissues were examined from low-dose female mice. Histopathology examinations were performed on all grossly visible lesions in all dose groups. The tissues and tissue groups examined are listed in the formal report.
Statistics:
The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958). Animals found dead of other than natural causes or found missing were censored from the survival analyses; animals dying from natural causes were not censored. Statistical analyses for possible dose-related effects on survival used Cox’s (1972) method for testing two groups for equality and Tarone’s (1975) life table test to identify dose-related trends. All reported P values for the survival analyses are two sided. The incidences of neoplasms or nonneoplastic lesions were given as the numbers of animals bearing such lesions at a specific anatomic site to the numbers of animals with that site examined microscopically. Analysis of tumor incidence was performed using logistics regression analysis. Other tests used were life table test (Cox; 1972; Tarone, 1975), Fisher exact test and the Chochran-Armitage trend test (Armitage, 1971; Gart et. al., 1979). For analysis of continuous variables tests performed include Dunnett (1955) and
Williams (1971, 1972), and Jonckheere’s test (Jonckheere, 1954).
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
High dose (525 mg/kg) males and females were slightly lethargic after dosing.
Mortality:
mortality observed, treatment-related
Description (incidence):
High dose (525 mg/kg) males and females were slightly lethargic after dosing.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
High dose (525 mg/kg) females had reduced final mean body weights at the end of the study.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Low dose (262 mg/kg) males had statistically significant increased incidence of proliferative lesions, primarily hyperplasia, of the adrenal medulla.
Details on results:
CLINICAL SIGNS AND MORTALITY
High-dose mice were partially sedated or lethargic and inactive shortly after dosing;
There was a significantly lower survival of high-dose male mice. This was attributed partially to fighting during the first year of the study, when the animals were housed in groups of five. Survival of low- and high-dose female mice was similar to controls.
Survival rate for male mice: 35/50 (control), 30/50 (262 mg/kg) and 12/50 (525 mg/kg)
Survival rate for female mice: 38/50 (control), 34/50 (262mg/kg) and 38/50 (525 mg/kg)
BODY WEIGHT AND WEIGHT GAIN
In male mice mean body weights of both low- and high-dose animals were consistently lower than mean boy weights of the control. This was evident from 3rd week onward. The decrement in body weight gain continued to increase until week 66. In week 67 all mice were housed individually; thereafter, the difference between the mean body weights of dosed males and control mice decreased. By the end of the study, the final body weights of low-
and high-dose male mice were only 6% less than that of the controls In female mice mean body weights of both low- and high-dose animals were within 10% of the control group till week 27. After that weight gains of low- and high-dose female mice declined steadily compared to controls. The difference didn’t diminish after housing individually from week 87.
HISTOPATHOLOGY: NON-NEOPLASTIC
There were no nonneoplastic degenerative lesions associated with the administration of γ-butyrolactone. Decreases in a number of miscellaneous spontaneous legions in low- and high dose male mice were attributed to decreased survival and were not considered related to γ-butyrolactone. The
observed dose-related increases in several nonneoplastic lesions in male mice were considered to be associated with fighting or bite wounds.
HISTOPATHOLOGY: NEOPLASTIC (if applicable)
Adrenal medulla: Statistically significant increased incidences of proliferative lesions, primarily hyperplasia, of the adrenal medulla in low-dose male mice were associated with γ-butyrolactone administration (pheochromocytoma, benign or malignant: 2/48, 6/15, 1/50; hyperplasia: 2/48, 9/50, 4/50).
Liver: The incidence of hepatocellular neoplasms in both dose groups of male mice was lower than the incidence in the controls (hepatocellular adenoma or carcinoma: 24/50, 8/50, 9/50).
Harderian Gland: The incidences of harderian gland adenoma in the dosed groups of male mice were also significantly lower than the incidence in the controls.
Dose descriptor:
NOAEL
Effect level:
525 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Low dose males had marginally increased incidence of proliferative lesions, primarily hyperplasia, of the adrenal medulla. No dose-dependency observed.
Critical effects observed:
no
Conclusions:
Conclusions: Under the conditions of these 2-years gavage studies, there was no evidence of carcinogenic activity of γ-butyrolactone in female B6C3F1 mice given 262 or 525 mg/kg. There was equivocal evidence of carcinogenicity in low-dose in male B6C3F1 mice based on the
marginally increased incidences of adrenal medulla pheochromocytomas and hyperplasia.
Sensitivity of the study in male mice to detect a carcinogenic effect was reduced by the low survival of the high-dose group associated with fighting.
Executive summary:

Groups of 50 mice of each sex were administered gamma-butyrolactone in corn oil by gavage 5 days a week for up to 103 weeks.Mice of each sex received 0, 262, or 525 mg/kg of body weight.

Mice were quarantined 19 days and male mice were 55 days old, and female mice were 62 days old at study initiation. Mice were housed five per cage until week 67 (males) or week 87 (females); after this time mice were housed individually. Clinical observations were made twice daily; findings were recorded at the time of weighing. Animals were weighed at study initiation,

weekly for 13 weeks, and monthly thereafter. Necropsy was performed on all animals. At necropsy, all organs and tissues were examined for gross lesions, complete histopathlogical examinations were performed on all control, all high-dose and low dose male mice and selected tissues were examined from low-dose female mice. High-dose mice were partially sedated or lethargic and inactive shortly after dosing. There was a significantly lower survival of high-dose male mice. This was attributed partially to fighting during the first year of the study, when the animals were housed in groups of five. Survival of low- and high-dose female mice was similar to

controls. There were no nonneoplastic degenerative lesions associated with the administration of γ-butyrolactone. Statistically significant increased incidences of proliferative lesions, primarily hyperplasia, of the adrenal medulla in low-dose male mice were associated with γ-butyrolactone administration. The incidence of hepatocellular neoplasms in both dose groups of male mice was lower than the incidence in the controls. The incidences of harderian gland adenoma in the dosed groups of male mice were also significantly lower than the incidence in the controls.

Endpoint:
carcinogenicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods
Remarks:
NTP protocol
Justification for type of information:
Read across from the alcohol metabolite donor substance.
REPORTING FORMAT FOR THE ANALOGUE APPROACH
see attached category document

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
see attached category document, chapter 1.1ff

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
see attached category document, chapter 1

3. ANALOGUE APPROACH JUSTIFICATION
see attached category document, chapter 5 (Toxikokinetics) and endpoint specific chapters

4. DATA MATRIX
see attached category document, table in chapter 1.2 and endpoint specific chapters
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
other: NTP Protocol
GLP compliance:
yes
Remarks:
According to U.S. FDA regulations
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Frederick Cancer Research Facility (Frederick, MD)
- Age at study initiation: 61 days
- Weight at study initiation: At week 1, approx. 190 g (males) / 138 g (females)
- Fasting period before study: No
- Housing: 5 rats per cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum):ad libitum
- Acclimation period: 18 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16°-29° C
- Humidity (%): 31%-79%
- Air changes (per hr): minimum 15h
- Photoperiod (hrs dark / hrs light): 12h
IN-LIFE DATES: From: First dose-Nov 10, 1981 To: last dose-Oct 31st, 1983

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The dose formulations were prepared by mixing appropriate quantities of gamma-butyrolactone and corn oil to give the required concentrations.Dose formulations were prepared weekly and discarded 2 weeks after the date of preparation.
VEHICLE
- Amount of vehicle (if gavage): 5 ml
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Verification was performed by GC using a flame ionization detector (FID) and a nitrogen carrier gas at 35ml/min and chloroform as a solvent, with two systems:
(1) 20% SP-2100 / 0.1% Carbowax 1500 on 100/120 mesh Supelcoport, oven temperature program of 50° C for 5 minutes, then 50° to 170° C at 10° C/minute, and
(2) 10% Carbowax 20M-TPA on sO/l00 mesh Chromasorb W(AW), oven temperature program of 50° C for 5 minutes, then 50° to 200° C at 10° C/minute.
During the 2-year studies, the dose formulations were analyzed at least once every 8 weeks; 41 of 42 dose formulations for rats and 27 of 28 dose formulations for mice were within 10% of the target concentrations.
Duration of treatment / exposure:
103 weeks
Frequency of treatment:
5d/wk
Post exposure period:
1 week
Remarks:
Doses / Concentrations:
0, 112 or 225 mg/kg bw
Basis:
analytical conc.
in male rats
Remarks:
Doses / Concentrations:
0, 225, 450 mg/kg bw
Basis:
analytical conc.
in female rats
No. of animals per sex per dose:
50
Control animals:
yes, concurrent vehicle
Details on study design:
Rationale for animal assignment (if not random): Animals were grouped by weight intervals, then groups were assigned to cages. A table of random numbers was used to assign cages to treatment groups.
Dose selection: Doses selected for 2yr study for male rats were 112 and 225 mg/kg, which were based on the chemical related mortality observed in male rats (10/10) at 900 mg/kg and reduction in weight gain in male rats given 450 mg/kg in 13 week study. Doses selected for 2yr study for female rats were 225 and 450 mg/kg, which were based on the chemical related mortality observed in female rats (1/10) and no reduction in weight gain in female rats given ) at 900 mg/kg in 13 week study.
Positive control:
no
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice/day
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: initailly once/ wk for 13 wks, once/month thereafter.
BODY WEIGHT: Yes
- Time schedule for examinations:initailly once/ wk for 13 wks, once/month thereafter.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as
g food/kg body weight/day: No data
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted
averages from the consumption and body weight gain data: No data
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
OPHTHALMOSCOPIC EXAMINATION: No data
HAEMATOLOGY: No data.
CLINICAL CHEMISTRY: No data
URINALYSIS: No data
NEUROBEHAVIOURAL EXAMINATION: No data
Other:The health of the animals was monitored during the course of the studies according to the
protocols of the NTP Sentinel Animal Program.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes.
At necropsy, all organs and tissues were examined for gross lesions, and all major tissues were fixed and preserved in 10% neutral buffered formalin, processed and trimmed, embedded in paraffin, sectioned, and stained with hematoxylin and eosin for microscopic examination.
HISTOPATHOLOGY: Yes
Complete histopathological examinations were performed on rats that died or were killed moribund prior to day 637, on all control and high-dose rats. Selected tissues were examined from all low-dose rats. Histopathology examinations were performed on all grossly visible lesions in all dose groups. The tissues and tissue groups examined are listed in the formal report.
Statistics:
The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958). Animals found dead of other than natural causes or found missing were censored from the survival analyses; animals dying from natural causes were not censored. Statistical analyses for possible dose-related effects on survival used Cox’s (1972) method for testing two groups for equality and Tarone’s (1975) life table test to identify dose-related trends. All reported P values for the survival analyses are two sided. The incidences of neoplasms or nonneoplastic lesions were given as the numbers of animals bearing such lesions at a specific anatomic site to the numbers of animals with that site examined microscopically. Analysis of tumor incidence was performed using logistics regression analysis. Other tests used were life table test (Cox; 1972; Tarone, 1975), Fisher exact test and the Chochran-Armitage trend test (Armitage, 1971; Gart et. al., 1979). For analysis of continuous variables tests performed include Dunnett (1955) and
Williams (1971, 1972), and Jonckheere’s test (Jonckheere, 1954).
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
There was a marginal increase in survival of high-dose males. This was attributed to a marginal decrease in mononuclear cell leukemia in the high-dose males.
Mortality:
mortality observed, treatment-related
Description (incidence):
There was a marginal increase in survival of high-dose males. This was attributed to a marginal decrease in mononuclear cell leukemia in the high-dose males.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
In female rats reduction in bodyweight gain at 450 mg/kg-day from week 6 to end of the study. Mean body weight of high dose females was within 10% of the mean body weight of the controls until until week 58; and by the end of 2-year studies 20 % lower.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
There were no clinical findings attributed to γ-butyrolactone.
There was no adverse effect of the test substance on survival in male or female. There was a marginal increase in survival of high-dose males. This was attributed to a marginal decrease in mononuclear cell leukemia in the high-dose males.
Survival rate for male rats: 24/50 (control), 27/50 (112mg/kg) and 32/50 (225 mg/kg)
Survival rate for female rats: 28/50 (control), 27/50 (225mg/kg) and 28/50 (450 mg/kg)

BODY WEIGHT AND WEIGHT GAIN
In male rats there was no body weight change associated with administration of 112 or 225 mg/kg-day test material. In female rats there was no body weight change associated with administration of the low dose (225 mg/kg-day). In female rats there was a reduction in bodyweight gain associated
with administration of the high-dose (450 mg/kg-day) from week 6 to end of the study. The mean body weight of high dose females was within 10% of the mean body weight of the controls until week 58; by the end of 2-year studies the mean body weight was 20% lower than that of the controls.

GROSS PATHOLOGY
There were no significant gross pathological effects reported.
HISTOPATHOLOGY: NON-NEOPLASTIC
There were no significant non-neoplastic lesions reported.
HISTOPATHOLOGY: NEOPLASTIC (if applicable)
Skin: Several morphological types of epithelial neoplasm were noted in male rats compared to controls. However, they were principally benign. The incidence of keratocanthoma was marginally increased in both low and high dose males, but, was not significantly greater than the incidence
in controls. In addition, the incidences were within the range for historical controls and all keratoacanthomas occurred in animals killed at 2 years, therefore, it is likely that the apparent increase in this neoplasm was due to increased survival in the high dose group relative to control
group. Therefore, increased incidence of keratocanthoma is not considered related to γ-butyrolactone. Basel cell adenomas were noted in four low-dose male rats; and none in highdose and control group animals. The basel cell adenomas were not considered related to γ-butyrolactone because they did not occur at a significantly increased incidence in low-dose group and did not occur with an increased incidence in the high-dose group.
Mesothelium; Mesotheliomas were noted in four high-dose and one low-dose male rat but none in control group. The historical data shows incidence of mesotheliomas.in corn oil control male rat is 26/770 with a range of 0% to 10%. Therefore, increased incidence reflects the low incidence
in control males and is not considered related to γ-butyrolactone. Mammary Gland: In female rats the incidence of fibroadenomas was noted with a statistically significant (P<0.0l) negative trend. The incidence in the high-dose group was significantly lower than that of the controls (22/50, 14/50, 6/50). The overall historical control incidence for fibroadenomas in female rats is 298/770 (38.7%) with a range of 18% to 56%. The decreased
incidence of fibro-adenomas in low- and high-dose female rats was considered related to γ-butyrolactone administration. The incidence of mammary gland cysts (markedly dilated ducts or glands lined by a single layer of epithelium) also showed a statistically significant (P<0.01) negative trend (42/50, 35/50, 23/50).
Pituitary Gland. A statistically significant (P<0.01) decrease in the incidence of cysts in the pars distalis was noted in high-dose female rats (25/49, 13/37, 11/48). A decreased incidence of adenomas in high-dose females was not statistically significant (22/49, 24/37, 16/48).
Hematopoietic System: The incidence of mononuclear cell leukemia in male rats occurred with a significant negative trend, and the incidence in the high-dose males was significantly less than controls (16/50, 15/50, 9/50). Mononuclear cell leukemia is a common neoplasm in male F344/
N rats with an overall historical control incidence of 164/770 (21.3%) and a range of 4% to 38%
Dose descriptor:
NOAEL
Effect level:
225 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: decreased incidences of mammary gland fibroadenomas and cysts and pituitary cysts in female rats which were associated with the administration of y-butyrolactone
Remarks on result:
other:
Remarks:
no carcinogenicity observed
Dose descriptor:
NOAEL
Effect level:
450 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects in males (highest dose) and statistically significant decreases in weight gain and mean body weight in females from the sixth week until the end of the study at 450 mg/kg-bw/day.
Remarks on result:
other:
Remarks:
no carcinogenicity observed
Critical effects observed:
no
Conclusions:
Under the conditions of these 2-years gavage studies, there was no evidence of carcinogenic activity of γ-butyrolactone in male F344/N rats given 112 or 225 mg/kg or in female F344/N rats 225 or 450 mg/kg in corn oil. There was a decreased incidences of mammary gland fibroadenomas and cysts and pituitary cysts in female rats which were associated with the administration of y-butyrolactone.
Executive summary:

Groups of 50 rats of each sex were administered gamma-butyrolactone in corn oil by gavage 5 days a week for up to 103 weeks. Male rats received 0, 112, or 225 mg/kg, female received 0, 225, or 450 mg/kg of body weight. Rats were quarantined 18 days and were about 61 days old at study initiation. Clinical observations were made twice daily; findings were recorded at the time of weighing. Animals were weighed at study initiation, weekly for 13 weeks, and monthly thereafter. Necropsy was performed on all animals. At necropsy, all organs and tissues were examined for gross lesions, Complete histopathologic examinations were performed on rats that died or were killed moribund prior to day 637, on all control and high-dose rats.

Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of γ-butyrolactone in male F344/N rats given 112 or 225 mg/kg or in female F344/N rats 225 or 450 mg/kg in corn oil. There was a decreased incidences of mammary gland fibroadenomas and cysts and pituitary cysts in female rats which were associated with the administration of y-butyrolactone.

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via inhalation route

Link to relevant study records

Referenceopen allclose all

Endpoint:
carcinogenicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Method and results sufficient described, similar to OECD-guideline 451, NTP-study.
Justification for type of information:
Read across from the methacrylic metabolite donor substance.
REPORTING FORMAT FOR THE ANALOGUE APPROACH
see attached category document

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
see attached category document, chapter 1.1ff

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
see attached category document, chapter 1

3. ANALOGUE APPROACH JUSTIFICATION
see attached category document, chapter 5 (Toxikokinetics) and endpoint specific chapters

4. DATA MATRIX
see attached category document, table in chapter 1.2 and endpoint specific chapters
Reason / purpose for cross-reference:
read-across source
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
Principles of method if other than guideline:
- Principle of test: 2 year study, inhalation
- Short description of test conditions: groups of 50 mice of each sex were exposed for 5 days per week, target conc. of 0, 500 and 1000 ppm
- Parameters analyzed/observed: survival, body weight, clinical signs, pituitary gland, prepuital gland, nasal cavity and olfactory sensory epithelium, lung, uterus, liver.
GLP compliance:
not specified
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: 8-9 weeks
- Weight at study initiation: males 21.8-23.8 g; females 16.6-20.0 (mean weights per treatment group)
- Housing: individually in stainless steel cages within the exposure chambers
- Acclimation period: 3 weeks
- Feed and water: both freely avaiable except during exposre period, when only water wa available
Route of administration:
inhalation
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
All animals were exposed to MMA vapors via whole body inhalation. MMA was vaporized at 50 ºC diluted with air and introduced into the chambers.  GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
Methyl methacrylate was pumped from a stainless steel reservoir to a vaporizer by a stable micrometering pump with adjustable drift-free pump rates. The vaporizer was heated to 50° ± 2° C, and the study material vapor, along with an air stream, entered the test chamber.

TEST ATMOSPHERE
- Brief description of analytical method used: Methyl methacrylate concentrations were monitored on-line twice during each exposure hour, initially by a photoionization detector and later by gas chromatographic analysis

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Uniformity of the vapor concentration in the chambers was measured periodically throughout the studies. The mean concentrations in the chambers over the two-year study were 499 ± 17 and 984 ± 36 for the 500 and 1000 ppm exposure groups, respectively.
Duration of treatment / exposure:
2 years (102 weeks)
Frequency of treatment:
6 hours per day, 5 days per week
Post exposure period:
no
Dose / conc.:
2.05 mg/L air (nominal)
Remarks:
male/female(corresponding to 500ppm
Dose / conc.:
4.1 mg/L air (nominal)
Remarks:
male/female(corresponding to 1000ppm
No. of animals per sex per dose:
50
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: Based on the results of the subchronic study
Positive control:
no
Observations and examinations performed and frequency:
Observations: Animals were observed twice daily for mortality and morbidity. Body weights were measured prior to study initiation, weekly or the first 13 weeks and monthly thereafter. A more detailed clinical observation was performed on each animal at the time of body weight measurement.
Sacrifice and pathology:
Necropsy: All animals were subjected to a gross necropsy, unless they were excessively autolyzed or cannibalized, missexed, or found missing.
A histological evaluation was performed with the following tissues: gross lesions and tissue masses, regional lymph nodes, mandibular lymph nodes, sternebrae including marrow, thyroid glands, parathyroids, small intestine, rectum, colon, liver, mammary gland, prostate, testes, epididymis, or ovaries/uterus, lungs and mainstem bronchi, nasal cavity and turbinates, skin , heart, esophagus, stomach, salivary gland, brain, thymus, trachea, pancreas, spleen, kidneys, adrenal glands, urinary bladder, pituitary gland, preputial or clitoral gland and tracheobronchial lymph nodes.
Statistics:
Data analysis: Survival probability was estimated using the product limit procedure of Kaplan and Meier (1958). Statistical analysis of survival was completed according to Cox (1972) and to Tarone's life table test (1975). P values for the survival analysis were two-sided and the analysis of the tumor incidence was evaluated using Mantel and Haenszel (1959). In addition the Fisher Exact Test for pairwise comparisons and the Cochran-Armitage linear trend test were conducted.
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
No significant differences were observed in mortality for any of the exposure groups when compared to that of the controls.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean body weights of both male and female mice at both concentrations were lower than those of the controls throughout most of the study (males: up to 16% lower mean body weight; females: up to 17%).
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Acute and chronic inflammation, epithelial hyperplasia, cytoplasmic inclusions in the epithelial cells, and degeneration of the olfactory epithelium in the nasal cavity occurred at increased incidences in male and female mice exposed to the test substance. Accumulation of homogeneous, eosinophilic material in the cytoplasm of cells, primarily of the respiratory epithelium (cytoplasmic inclusions) was significantly increased in treated animals when compared to that of the controls.
Uterine adenocarcinomas were reduced in animals from both of the treatment groups, but statistical significance was not observed.
In the lungs, interstitial inflammation was increased in the male mice from the high-group, while alveolar/bronchiolar adenomas and alveolar/bronchiolar adenomas and carcinomas (combined) were significantly reduced in the male mice exposed to 500 and 1000 ppm. Pituitary gland adenomas and adenomas and adenocarcinomas (combined) were significantly reduced in the female mice in each of the treatment groups. Hepatocellular adenomas and hepatocellular adenomas and carcinomas (combined) were significantly reduced in males and female mice exposed to the test substance relative to the controls.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
No treatment-related tumors were observed
Dose descriptor:
NOAEC
Effect level:
>= 4.1 mg/L air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects observed; corresponding to 1000 ppm
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Dose descriptor:
NOAEC
Effect level:
>= 4.1 mg/L air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no biologically relevant adverse systemic effects observed; corresponding to 1000 ppm
Remarks on result:
other:
Remarks:
Effect type: other: systemic toxicity (migrated information)
Dose descriptor:
LOAEC
Effect level:
ca. 2.05 mg/L air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: inflammation, epithelial hyperplasia, cytoplasmic inclusions in the epithelial cells, and degeneration of the olfactory epithelium in the nasal cavity; corresponding to 500 ppm
Remarks on result:
other:
Remarks:
Effect type: other: local toxicity (migrated information)

Effects on body weight gain

Reduced body weights of the high dosed animals by maximum 17% are considered as secondary effects following the inflammatory effects in the URT and therefore not relevant for the assessment of a systemic NOAEC.

Conclusions:
In a two years inhalation toxicology and carcinogenesis study (NTP) in B6CF31 mice methyl methacrylate did not induce neoplasms in the highest doses testd (1000 ppm/males and females)
Executive summary:

In a two years inhalation toxicology and carcinogenesis study (NTP) in B6CF31 mice with methyl methacrylate50 males and 50 females of each species male and female mice were exposed to 0, 500, or 1,000 ppm methyl methacrylate by inhalation.

 

Animals were exposed 6 hld, 5 d/wk for 102 wk. Animals were observed twice per day, weighed once per week for the first 13 wk and monthly thereafter; individual clinical examinations were made at weighing.

 

Necropsy and histologic examination performed on all animals . The following tissues were examined: gross lesions and tissue masses, regional lymph nodes, mandibular lymph node, sternebrae including marrow, thyroid gland, parathyroids, small intestine, rectum, colon, liver, mammary gland, prostate/testes/epididymis or ovaries/uterus, lungs and mainstem bronchi, nasal cavity and turbinates, skin, heart, esophagus, stomach, salivary gland, brain, thymus, trachea, pancreas, spleen, kidneys, adrenal glands, urinary bladder, pituitary gland, preputial or clitoral gland, and tracheobronchial lymph nodes

 

In this study methyl methacrylate did not induce neoplasms in mice in the highest doses tested (1000 ppm, males and females)

Endpoint:
carcinogenicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Method and results sufficient described, similar to OECD-guideline 451, NTP-study.
Justification for type of information:
Read across from the methacrylic metabolite donor substance.
REPORTING FORMAT FOR THE ANALOGUE APPROACH
see attached category document

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
see attached category document, chapter 1.1ff

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
see attached category document, chapter 1

3. ANALOGUE APPROACH JUSTIFICATION
see attached category document, chapter 5 (Toxikokinetics) and endpoint specific chapters

4. DATA MATRIX
see attached category document, table in chapter 1.2 and endpoint specific chapters
Reason / purpose for cross-reference:
read-across source
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
Principles of method if other than guideline:
- Principle of test: 2 year study, inhalation
- Short description of test conditions: groups of 50 males were exposed for 5 days per week, target conc. of 0, 500 and 1000 ppm, groups of 50 females were exposed for 5 days per week, target conc. 0, 250 and 500 ppm,
- Parameters analyzed/observed: survival, body weight, clinical signs, hematopoietic system, pituitary gland, prepuital gland, nasal cavity and olfactory sensory epithelium, lung
GLP compliance:
not specified
Species:
rat
Strain:
Fischer 344
Details on species / strain selection:
- Source: Charles River Breeding Laboratories
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS

- Age at study initiation: 7-8 weeks
- Weight at study initiation: males 151-155g; females 117-119g (mean weights per treatment group)
- Housing: individually in stainless steel cages within the exposure chambers
- Acclimation period: 3 weeks
- Feed and water: both freely avaiable except during exposre period, when only water wa available
Route of administration:
inhalation
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
All animals were exposed to MMA vapors via whole body inhalation. MMA was vaporized at 50 ºC diluted with air and introduced into the chambers.  GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
Methyl methacrylate was pumped from a stainless steel reservoir to a vaporizer by a stable micrometering pump with adjustable drift-free pump rates. The vaporizer was heated to 50° ± 2° C, and the study material vapor, along with an air stream, entered the test chamber.

TEST ATMOSPHERE
- Brief description of analytical method used: Methyl methacrylate concentrations were monitored on-line twice during each exposure hour, initially by a photoionization detector and later by gas chromatographic analysis

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Uniformity of the vapor concentration in the chambers was measured periodically throughout the studies. The mean concentrations in the chambers over the two-year study were 249 ± 1, 499 ± 17 and 984 ± 36 ppm for the 250, 500 and 1000 ppm exposure groups, respectively.
Duration of treatment / exposure:
2 years (102 weeks)
Frequency of treatment:
6 hours/day, 5 days/week
Post exposure period:
no
Dose / conc.:
1.03 mg/L air (nominal)
Remarks:
females, corresponding to 250 ppm
Dose / conc.:
2.05 mg/L air (nominal)
Remarks:
males and females, corresponding to 500 ppm
Dose / conc.:
4.1 mg/L air (nominal)
Remarks:
males, corresponding to 1000 ppm
No. of animals per sex per dose:
50
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: based on the results of the subchronic study
Positive control:
no
Observations and examinations performed and frequency:
Observations: Animals were observed twice daily for mortality and morbidity. Body weights were measured prior to study initiation, weekly for the first 13 weeks and monthly thereafter. A more detailed clinical observation was performed on each animal at the time of body weight measurement.
Sacrifice and pathology:
Necropsy: All animals were subjected to a gross necropsy, unless they were excessively autolyzed or cannibalized, missexed, or found missing.
A histological evaluation was performed with the following tissues: gross  lesions and tissue masses, regional lymph nodes, mandibular lymph nodes, sternebrae including marrow, thyroid glands, parathyroids, small  intestine, rectum, colon, liver, mammary gland, prostate, testes,  epididymis, or ovaries/uterus, lungs and mainstem bronchi, nasal cavity  and turbinates, skin , heart, esophagus, stomach, salivary gland, brain,  thymus, trachea, pancreas, spleen, kidneys, adrenal glands, urinary  bladder, pituitary gland, preputial or clitoral gland and tracheobronchial lymph nodes.  
Statistics:
Data analysis: Survival probability was estimated using the product limit procedure of Kaplan and Meier (1958). Statistical analysis of survival was completed according to Cox (1972) and to Tarone's life table test (1975). P values for the survival analysis were two-sided and the analysis of the tumor incidence  was evaluated using Mantel and Haenszel (1959). In addition the Fisher Exact Test for pairwise comparisons and the Cochran-Armitage linear trend test was conducted.
Clinical signs:
not specified
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
No significant differences were observed for mortality in any of the exposure groups when compared to that of the controls.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Mean body weights of the males in the 1000-ppm group were 5 - 10% reduced from that of the control group after week 81 and the mean body weights of the females in the 500-ppm group decreased by 6 - 11% from that of the controls after week 73.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
A statistically significant positive trend in the incidence of mononuclear cell leukemia occurred in female rats exposed to 500-ppm (incidence of 22%, 26% and 40% for the control, 250 ppm and 500 ppm groups, respectively). However, life table analysis, which can be regarded as more appropriate for life-threatening lesions, showed no difference. The incidence of mononuclear cell leukemia in the three groups of male rats was not statistically different by life table analysis.
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Pituitary and preputial gland adenomas were significantly reduced in the male rats exposed to 1000 ppm test substance.
Serious and suppurative inflammation and degeneration of the olfactory epithelium in the nasal cavity was observed at an increased incidence in the treated rats when compared to the controls. Although alveolar macrophages were observed at an increased incidence treated rats, the severity was considered minimal. An increased incidence of focal or multifocal fibrosis was observed females exposed to 500 ppm of the test substance.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
No treatment-related tumors were observed.
Relevance of carcinogenic effects / potential:
no
Dose descriptor:
NOAEC
Effect level:
>= 2.05 mg/L air (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: no effects observed; corresponding to 500 ppm
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Dose descriptor:
NOAEC
Effect level:
>= 4.1 mg/L air (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: no effects observed; corresponding to 1000 ppm
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Dose descriptor:
NOAEC
Effect level:
>= 2.05 mg/L air (nominal)
Sex:
male/female
Basis for effect level:
other: no biologically relevant adverse systemic effects observed; corresponding to 500 ppm
Remarks on result:
other:
Remarks:
Effect type: other: systemic toxicity (migrated information)
Dose descriptor:
LOAEC
Effect level:
ca. 1.03 mg/L air (nominal)
Sex:
male/female
Basis for effect level:
other: Inflammation and degeneration of the olfactory epithelium in the nasal cavity; corresponding to 250 ppm
Remarks on result:
other:
Remarks:
Effect type: other: local toxicity (migrated information)

Effects on body weight gain

Reduced body weights of the high dosed animals by maximum 11% are considered as secondary effects following the inflammatory effects in the URT and therefore not relevant for the assessment of a systemic NOAEC.

Hematological effects

Mononuclear cell leukemia has a high spontaneous incidence in Fischer 344 rats. Based on the lack of statistical significance and the normal occurrence of this 

neoplasm, the increased incidence was not considered biologically significant. In support of this conclusion, a classification of the leukemia into three 

stages of severity showed that there were no differences in the characteristics of the leukemia between the exposed and control females, and, further, there 

was no increase in this neoplasm in males exposed to 1000 ppm MMA.



Conclusions:
In a two years inhalation toxicology and carcinogenesis study (NTP) in F344 rats methyl methacrylate did not induce neoplasms in the highest doses testd (500 ppm /females, 1000 ppm/males)
Executive summary:

In a two years inhalation toxicology and carcinogenesis study (NTP) in F344 rats with methyl methacrylate50 males and 50 females of each species male rats were exposed to 0, 500, or 1,000 ppm methyl methacrylate by inhalation and female rats were exposed to -0, 250, or 500 ppm methyl methacrylate by inhalation.

Animals were exposed 6 hld, 5 d/wk for 102 wk. Animals were observed twice per day, weighed once per week for the first 13 wk and monthly thereafter; individual clinical examinations were made at weighing.

 

Necropsy and histologic examination performed on all animals . The following tissues were examined: gross lesions and tissue masses, regional lymph nodes, mandibular lymph node, sternebrae including marrow, thyroid gland, parathyroids, small intestine, rectum, colon, liver, mammary gland, prostate/testes/epididymis or ovaries/uterus, lungs and mainstem bronchi, nasal cavity and turbinates, skin, heart, esophagus, stomach, salivary gland, brain, thymus, trachea, pancreas, spleen, kidneys, adrenal glands, urinary bladder, pituitary gland, preputial or clitoral gland, and tracheobronchial lymph nodes

 

In this study methyl methacrylate did not induce neoplasms in rats in the highest doses tested (500 ppm /females, 1000 ppm/males).

 

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

The available data give no concern on carcinogenic properties of the test substance. Thus, classification of 1,4 -BDDMA as carcinogenic is not required according to GHS Regulation EC No 1272/2008 and therefore labelling is not necessary.

Additional information

No carcinogenicity study is available for 1,4-BDDMA. For the alcohol metabolite 1,4 -Butanediol and the methacrylate metabolite methacrylic acid, data are available from the respective metabolite donor substances, namely Gamma-butyrolactone and methyl methacrylate. More details on the metabolism are available in the chapter Toxicokinetics and in the Category document.

Gamma-Butyrolactone:

Rats, oral

Groups of 50 rats of each sex were administered γ-butyrolactonein corn oil by gavage 5 days a week for up to 103 weeks. Male rats received 0, 112, or 225 mg/kg, female received 0, 225, or 450 mg/kg of body weight.

There was no evidence of carcinogenic activity of γ-butyrolactonein male F344/N rats given 112 or 225 mg/kg or in female F344/N rats 225 or 450 mg/kg in corn oil. There was a decreased incidence of mammary gland fibroadenomasand cysts and pituitary cysts in female rats which were associated with the administration of y-butyrolactone.

Mice, oral

Groups of 50 mice of each sex were administered gamma-butyrolactone in corn oil by gavage 5 days a week for up to 103 weeks. Mice of each sex received 0, 262, or 525 mg/kg of body weight.

There were nononneoplasticdegenerative lesions associated with the administration of γ-butyrolactone. Statistically significant increased incidences of proliferative lesions, primarily hyperplasia, of the adrenal medulla in low-dose male mice were associated with γ-butyrolactoneadministration. The incidence of hepatocellular neoplasms in both dose groups of male mice was lower than the incidence in the controls. The incidences of harderian gland adenoma in the dosed groups of male mice were also significantly lower than the incidence in the controls.

Methylmethacrylate

Rats, inhalation

Groups of 50 male F344/N rats were exposed to methyl methacrylate (purity >99%; containing 0.04 mg/1 equivalent to 10 ppm monomethylethylether of hydroquinone as an inhibitor of polymerization) by inhalation at ca. 0, 2.05 and 4.1 mg/L (equivalent to 500 or 1000 ppm), female F344/N rats at ca. 0, 1.03 or 2.05 mg/L (equivalent to 250 or 500 ppm) and male and female B6C3F1 mice at ca. 2.05 or 4.1 mg/L (equivalent to 500 or 1000 ppm), 6 hours a day, 5 days a week for 102 weeks (NTP, 1986).

No significant differences of the survival rates were observed between any groups of rats and mice. Reductions in mean body weights of high dosed animals were considered as secondary effects based on the observed inflammations and degenerations of the olfactory epithelium in all MMA treatments. The marginal increase in the incidence of mononuclear-cellleukaemiaobserved in female rats (control 11/50; low-dose 13/50; high-dose 20/50) fell within the range of values seen in historical controls. Both in mice and rats no treatment-relatedtumourswere observed.

The combined chronic toxicity and carcinogenicity study on methyl methacrylate of Rohm and Haas (1979a, re-evaluated by Lomax, 1992; Lomax et al. 1997) did not reveal any significant incidence of tumours or increase of tumour incidence. One male each out of a total of 49, respectively 47 males exposed to 100 and 400 ppm methyl methacrylate had a small solitary polypoid mass attached to the lateral wall of one side of the anterior nasal cavity. Both masses were composed of well differentiated pseudoglandular structures arising from respiratory epithelium diagnosed as adenomas. Both animals had chronic inflammation of the respiratory epithelial region. An association of the nasal adenomas to methyl methacrylate inhalation were considered to be unlikely, because the incidence was not significantly increased in comparison to controls without any nasal tumour and the findings were not confirmed by other studies. However, historical data show that adenomas from respiratory epithelium are very rare tumours in rats with a spontaneous rate of 0-0.1 % for F344 male and female rats.

 

Rats, oral

An early 2-year chronic study on rats treated orally with MMA revealed no adverse effect other than slightly elevated kidney weights in high-dose female rats (Borzelleca et al., 1964).

 

In summary there is no evidence of carcinogenicity of the ester hydrolyses products of 1,4-BDDMA and therefore no carcinogenicity is expected for 1,4-BDDMA itself.

There is no concern for mutagenicity or genotoxicity at physiologically relevant levels. Although in single in vitro mutagenicity assays there was some evidence of mutagenicity, the substance was non-mutagenic in vivo.

In the available repeated-dose toxicity study there are no indications of non-specific organ damage or chronic inflammation. Available data give no concern on carcinogenic properties of the test substance. Carcinogenicity in humans is not expected.

 Justification for selection of carcinogenicity via oral route endpoint:
No carcinogenicity study is required. There is no concern for mutagenicity or genotoxicity at physiologically relevant levels. In the available repeated-dose toxicity study there are no indications of non-specific organ damage or chronic inflammation. Available data give no concern on carcinogenic properties of the test substance.

Compliance to REACh requirements