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State of the Science Report for MBMBP
Exposure Assessment, Hazard Characterization and Risk Evaluation
Quantitative data upon which to base upper-bounding estimates of intake of MBMBP were not available for any environmental media in Canada or elsewhere. Estimated environmental concentrations were modelled for air, water and soil based upon the information provided in the Section 71 survey (Environment Canada, 2001). Children aged 0.5-4 years appear to be the subgroup (of the general population) most highly exposed to MBMBP in Canada, their maximum upper-bounding daily intake being 3.4 × 10-4 µg/kg-bw per day; this estimate is based on modelled environmental concentrations (see Table 1). Elevated exposure from drinking water may occur in populations close to point source releases of MBMBP to surface water. Due to the absence of monitoring data, upper-bounding estimates of daily intake associated with potential point source releases of MBMBP to surface water were estimated based on conservative modelled concentrations in drinking water.1 Estimated intakes ranged from 7.1 × 10-3 µg/kg-bw per day (12-19 years) to a maximum of 3.7 × 10-2 µg/kg-bw per day for the 0-6 months age group.
Confidence in the exposure database is considered to be very low to low, as it is based solely on modelled concentrations of MBMBP in air, soil and water and there is no indication of whether MBMBP is present in food. In view of MBMBP's high octanol/water partition coefficient, exposures through food and breast milk could occur. However, given the low concentrations predicted in water and soil and the fate of MBMBP in the environment, it is unlikely that exposures through foodstuffs and breast milk would exceed the conservative estimate presented here. MBMBP may also be present in residual amounts in consumer products, but no data were available as a basis to quantify this exposure, although it is expected to contribute minimally to total intake compared with soil.
Based on a screening-level evaluation of available toxicological data on MBMBP (see Table 2), the lowest Lowest-Observed-Effect Level (LOEL) identified was 6 mg/kg-bw per day in dogs exposed to MBMBP in the diet for 90 days (ACC, 1965b). At this dose, there was a significant difference in the change in plasma alkaline phosphatase activity from pre-exposure levels to those measured at weeks 12 and 17 in dogs exposed to MBMBP compared with controls, while histopathological changes in the liver were observed at the higher exposure levels (i.e., 10 mg/kg-bw per day or more). Results of the one limited chronic bioassay identified and the results of quantitative structure-activity relationship/structure-activity relationship modelling do not indicate that MBMBP is carcinogenic; similarly, the available limited data and model predictions do not suggest that the substance has a high potential for genotoxicity. The confidence in the database on health effects is considered to be moderate, based on the number of toxicity studies available addressing acute, repeated-dose, long-term genetic, reproductive and developmental toxicity endpoints.
Comparison of this conservative critical effect level with the upper-bounding modelled estimate of exposure for the highest exposed group (aged 0-6 months) living in the vicinity of a point source results in a margin of exposure of approximately 160 000.
Based on the level of confidence in the available database and the conservative nature of this evaluation, including the use of an upper-bounding exposure estimate based on modelled predictions and lowest reported effect level, the margin between estimated exposure levels of MBMBP and those causing health effects in experimental animals is considered adequate to account for the uncertainties in the database.
| Route of exposure | Estimated intake (µg/kg-bw per day) of MBMBP by various age groups | ||||||
|---|---|---|---|---|---|---|---|
| 0-6 months1,2,3 | 0.5-4 years4 | 5-11 years5 | 12-19 years6 | 20-59 years7 | 60+ years8 | ||
| Formula fed | Not formula fed | ||||||
| Air9 | 7.2 × 10-9 | 1.5 × 10-8 | 1.2 × 10-8 | 6.8 × 10-9 | 5.8 × 10-9 | 5.1 × 10-9 | |
| Drinking water10 | 6.4 × 10-6 | 2.4 × 10-6 | 2.7 × 10-6 | 2.1 × 10-6 | 1.2 × 10-6 | 1.3 × 10-6 | 1.3 × 10-6 |
| Food and beverages11 | NA12 | NA | NA | NA | NA | NA | |
| Soil13 | 2.1 × 10-4 | 3.4 × 10-4 | 1.1 × 10-4 | 2.6 × 10-5 | 2.2 × 10-5 | 2.2 × 10-5 | |
| Total intake | 2.2 × 10 -4 | 2.1 × 10 -4 | 3.4 × 10-4 | 1.1 × 10-4 | 2.8 × 10-5 | 2.3 × 10-5 | 2.3 × 10-5 |
1 No data were identified on concentrations of MBMBP
in breast milk.
2 Assumed to weigh 7.5 kg, to breathe 2.1 m3 of
air per day, to drink 0.8 L of water per day (formula fed) or 0.3
L/day (not formula fed), and to ingest 30 mg of soil per day (EHD,
1998).
3 For exclusively formula-fed infants, intake from water
is synonymous with intake from food. The concentration of MBMBP
in water used to reconstitute formula was based on modelling. No
data on concentrations of MBMBP in formula were identified for
Canada. For non-formula fed infants approximately 50% are introduced
to solid foods by 4 months of age and 90% by 6 months of age (NHW,
1990 in EHD, 1998).
4 Assumed to weigh 15.5 kg, to breathe 9.3 m3 of
air per day, to drink 0.7 L of water per day and to ingest 100
mg of soil per day (EHD, 1998).
5 Assumed to weigh 31.0 kg, to breathe 14.5 m3 of
air per day, to drink 1.1 L of water per day and to ingest 65 mg
of soil per day (EHD, 1998).
6 Assumed to weigh 59.4 kg, to breathe 15.8 m3 of
air per day, to drink 1.2 L of water per day and to ingest 30 mg
of soil per day (EHD, 1998).
7 Assumed to weigh 70.9 kg, to breathe 16.2 m3 of
air per day, to drink 1.5 L of water per day and to ingest 30 mg
of soil per day (EHD, 1998).
8 Assumed to weigh 72.0 kg, to breathe 14.3 m3 of
air per day, to drink 1.6 L of water per day and to ingest 30 mg
of soil per day (EHD, 1998).
9 Modelling using ChemCAN 4.0 (Mackay et al., 1996)
indicated that the highest concentration of MBMBP in ambient air
was 2.56 x 10 -8 μg/m3. Ambient air was assumed to
be representative of exposure to indoor air since there is no indication
of additional sources of MBMBP in indoor environments. No measured
data were identified.
10 It was assumed that 0.65% of the maximum estimated
quantity of MBMBP imported into Canada was released via waste water
(OECD, 2003) and that 92.97% of those emissions would be removed
during waste water treatment prior to release into the environment
(U.S. EPA, 2003). It was also assumed that there was no further
biodegradation following the release of MBMBP to the environment
(i.e., half lives were assumed to be negligible). Modelling using
ChemCAN 4.0 (Mackay et al., 1996) indicated that the highest concentration
of MBMBP in water was 6.0 x 10-5 μg/L. For formula-fed
infants, the concentration of MBMBP in the water used to reconstitute
formula accounts for the intake of MBMBP from food. No measured
data were identified.
11 No measured data were identified.
12 NA = not available
13 It was assumed that 1.0% of the maximum estimated
quantity of MBMBP imported into Canada was released via solid waste
which would be sent to landfill and released to soil. It was also
assumed that there was no biodegradation in the environment (i.e.,
half lives were assumed to be negligible). Modelling using ChemCAN
4.0 (Mackay et al., 1996) indicated that the highest concentration
of MBMBP in soil was 52.2 μg/kg. No measured data were identified.
| Endpoint | Lowest effect levels1/Results |
|---|---|
| Acute toxicity | Lowest oral LD50(mouse) = 3200 mg/kg-bw (Ashland Oil Inc., 1992) [Additional studies: Hagan, 1952; Stasenkova et al., 1977; Sumitomo Chemical Co., 1977a; ACC, 1988; Bayer AG, 1988; Takagi et al., 1994; NLM, 1998] Lowest dermal LD50(rabbit) >10 000 mg/kg-bw (ACC, 1988) |
| Short-term repeated-dose toxicity | Lowest oral (gavage) LOEL (rat) = 50 mg/kg-bw per day: prolongation of prothrombin time, increased liver weight, degeneration of spermatids and vacuolation of Sertoli cells (28- and 53-day studies) (MHW, 1996, 1999) [Additional studies: Hagan, 1952; Takahashi and Hiraga, 1981a, 1981b; Ashland Oil Inc., 1992] |
| Subchronic toxicity | Lowest oral (diet) LOEL (dog) = 6 mg/kg-bw per day: change in alkaline phosphatase activity (90-day study) (ACC, 1965b) [Additional studies: ACC, 1965a; Takagi et al., 1994] |
| Chronic toxicity/ carcinogenicity | Lowest non-neoplastic oral (diet) LOEL (rat) = 12.7 mg/kg-bw per day: increased relative liver weight (18-month study); no increases in tumour incidence observed in rats exposed to up to 42.3 mg/kg-bw per day for 18 months (Takagi et al., 1994) |
| Genotoxicity and related endpoints: in vitro | Negative : Mutagenicity in Salmonella typhimurium TA98, TA100, TA1535 and TA1537 and Escherichia coli (Sumitomo Chemical Co., 1977b; Yamaguchi et al., 1991; MHW, 1996), chromosomal aberrations in Chinese hamster lung cells (MHW, 1996), DNA damage in Bacillus subtilis (Sumitomo Chemical Co., 1977b) Positive : Cell transformation in BALB/c3T3 cells and promotion in Chinese hamster V79 lung fibroblasts (Tsuchiya et al., 1995) |
| Developmental toxicity | Lowest oral (gavage) LOEL (fetal rat) = 375 mg/kg-bw per day: increase in fetal deaths; LOEL (maternal) = 187 mg/kg-bw per day: decreased body weight gain (exposure during gestation days 7-17) (Tanaka et al., 1990) [Additional studies: Telford et al., 1962; MHW, 1999] |
| Reproductive toxicity | Lowest oral (diet) LOEL (male rat) = 42.3 mg/kg-bw per day: decreased absolute and relative testis weights, testis tubule atrophy and decreased spermatogenesis (18-month study) (Takagi et al., 1994) [Additional studies: MHW, 1996, 1999] |
1 LD50 = median lethal dose; LOEL = lowest-observed-effect level.
1For the point source release scenario, it was assumed that 0.65% of the maximum estimated quantity of MBMBP imported into Canada was released into wastewater at one location (OECD, 2003b) and that the plant operated 300 days/year (European Communities, 2003). Removal of MBMBP during wastewater treatment was modelled (U.S. EPA, 2003) and subtracted from the amount released, and it was assumed that there was no further biodegradation in the environment (i.e., half-lives were assumed to be negligible). Modelling indicated that water concentrations were estimated to be 0.35 µg/L. For formula-fed infants, the concentration of MBMBP in the water used to reconstitute formula accounts for the intake of MBMBP from food. No measured data were identified.
