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Effects
EUROPEAN COMMISSION.
Final addendum to the Draft Assessment Report (DAR)
- public version -
Initial risk assessment provided by the rapporteur Member State
Finland for the existing active substance
TOLYLFLUANID
of the second stage of the review programme referred to in Article
8(2) of Council Directive 91/414/EEC
February 2005
Excerpts
| B.6.8.1.1
Subacute and subchronic studies
Table
6.8-1. Determination of fluoride in ashes from canine bone
sections of dogs in a 52 week subchronic study by the oral
route (Wetzig and Schilde, 1997). page
74 |
| Tolyfluanid
(mg/kg bw/day) |
Milligram
fluoride / g ash |
| Male
dogs |
Female
dogs |
| 0 |
0.974
± 0.245 |
0.879
± 0.092 |
| 5 |
1.062
± 0.229 |
0.955
± 0.169 |
| 20 |
1.133
± 0.075 |
1.111
± 0.154 * |
| 80 |
1.838
± 0.162 * |
1.587
± 0.191 * |
| *
p < 0.05 (Mann-Whitney U test) |
| B.6.8.1.1
Subacute and subchronic studies
Table
6.8-2. Determination of fluoride in ashes from canine teeth
of dogs in a 52 week subchronic study by the oral route
(Wetzig and Schilde, 1997). page
74 |
| Tolyfluanid
(mg/kg bw/day) |
Milligram
fluoride / g ash |
| Male
dogs |
Female
dogs |
| 0 |
0.444
± 0.076 |
0.358
± 0.091 |
| 5 |
0.464
± 0.082 |
0.589
± 0.155 * |
| 20 |
0.519
± 0.027 |
0.517
± 0.085 |
| 80 |
0.771
± 0.068 * |
0.670
± 0.099 * |
| *
p < 0.05 (Mann-Whitney U test) |
| 2-year
rat study (Leser et al., 1996)
Table
6.8-3. Determination of fluoride in ashes from bone and
teeth of rats in a 2-year chronic study by dietary administration
(Leser et al. , 1996). Results after 53 weeks of administration
of tolylfluanid. page 75 |
| Tolyfluanid
(ppm) |
Milligram
fluoride / g ash in bone |
| Males |
Females |
| 0 |
0.414 |
0.648
|
| 60 |
0.529
|
0.761 |
| 300 |
0.886
|
1.223 |
| 1500 |
2.389*
|
3.148* |
| 7500 |
4.721*
|
7.693* |
| |
Milligram
fluoride / g ash in teeth |
| Males |
Females |
| 0 |
0.123
|
0.146 |
| 60 |
0.168 |
0.192 |
| 300 |
0.335* |
0.393 |
| 1500 |
0.745* |
0.952* |
| 7500 |
2.706*
|
3.557* |
| *
p < 0.05 (Mann-Whitney U test) |
| 2-year
rat study (Leser et al., 1996)
Table
6.8-4. Determination of fluoride in ashes from bone and
teeth of rats in a 2-year chronic study by dietary administration
(Leser et al. , 1996). Results after 105 - 107 weeks of
administration of tolylfluanid. page 75 |
| Tolyfluanid
(ppm and mg/kg bw/day) |
Milligram
fluoride / g ash in bone |
| Males |
Females |
| 0 |
0.683 |
0.805
|
| 60 (3.6)
|
0.833
|
0.935
|
| 300 (18.1)
|
1.326*
|
1.360*
|
| 1500
(90.1) |
3.289*
|
3.506*
|
| 7500
(504.2) |
9.698*
|
10.899*
|
| |
Milligram
fluoride / g ash in teeth |
| Males |
Females |
| 0 |
0.309
|
0.328
|
| 60 (4.2)
|
0.252 |
0.277
|
| 300 (21.1) |
0.450 |
0.430
|
| 1500
(105.2) |
1.097*
|
1.098*
|
| 7500
(584.4) |
3.456*
|
3.822*
|
| *
p < 0.05 (Mann-Whitney U test) |
| 2-year
mouse study (Leser and Ruehl-Fehlert, 1996)
Table
6.8-7. Determination of fluoride in ashes from bone and
teeth of mice in a 2-year chronic study by dietary administration
(Leser and Ruehl-Fehlert, 1996). Results after 54 weeks
of administration of tolylfluanid. page
76
|
| Tolyfluanid
(ppm) |
Milligram
fluoride / g ash in bone |
| Males |
Females |
| 0 |
1.107
|
0.926 |
| 60 |
1.200
|
1.089 |
| 300 |
1.777* |
1.702* |
| 1500 |
3.971* |
3.167* |
| 7500 |
9.936*
|
9.398* |
| |
Milligram
fluoride / g ash in teeth |
| Males |
Females |
| 0 |
0.258 |
0.250 |
| 60 |
0.312
|
0.292 |
| 300 |
0.517* |
0.515 |
| 1500 |
1.205*
|
1.131* |
| 7500 |
3.275*
|
3.595* |
| *
p < 0.05 (Mann-Whitney U test) |
| 2-year
mouse study (Leser and Ruehl-Fehlert, 1996)
Table
6.8-8. Determination of fluoride in ashes from bone and
teeth of mice in a 2-year chronic study by dietary administration
(Leser and Ruehl-Fehlert, 1996). Results after 106 weeks
of administration of tolylfluanid. page
77
|
| Tolyfluanid
(ppm and mg/kg bw/day) |
Milligram
fluoride / g ash in bone |
| Males |
Females |
| 0 |
1.421
|
1.244
|
| 60 (15.3)
|
1.708
|
1.529*
|
| 300 (76.3)
|
2.465
|
2.427*
|
| 1500
(375.8) |
5.492*
|
5.630*
|
| 7500
(2307.6) |
10.862*
|
12.599*
|
| |
Milligram
fluoride / g ash in teeth |
| Males |
Females |
| 0 |
0.398
|
0.452 |
| 60 (24.5)
|
0.513
|
0.498 |
| 300 (123.9)
|
1.004*
|
0.699
|
| 1500
(610.8) |
1.860*
|
1.731*
|
| 7500
(2962.8) |
5.192*
|
6.159*
|
| *
p < 0.05 (Mann-Whitney U test) |
Intake of fluoride at exposure
to tolylfluanid
Tolylfluanid contains about 6% fluorine as part of the molecule.
If the ADI is set at 0.2 mg/kg bw/day, based on the 2-year dietary
study in rat with a NOAEL of 18.1 – 21.1 mg/kg bw/day (SF
= 100), then the highest acceptable amount of fluoride released
from the molecule is about 0.012 mg/kg bw/day. Table 6.8-11 presents
a calculation of the intake of tolylfluanid based on the currently
supported MRL:s for commodities in the European diet (Heimann,
2002). page
74
The TMDI for tolylfluanid in the european diet is 0.017721
mg/kg bw/day. Assuming that the release of fluoride is
6% of the mass of tolylfluanid, then the expected intake of fluoride
from tolylfluanid treated food commodities is about 0.0011 mg/kg
bw/day. In assessing the extent of exposure to fluoride released
from tolylfluanid in consumers, all possible exposure sources
must be considered. The main source for fluoride in most countries
is direct consumption of drinking water. Food commodities are
also a major source for fluoride intake in consumers. The WHO
guideline for a maximum level of fluoride in water is 1.5 mg/litre
(WHO, 1994). The UK Medical Research Council (MRC, 2002) has concluded
that there is a risk for dental fluorosis in children at drinking
water fluoride levels ≥2 mg/l. In areas where the natural
levels of fluoride in water are low, the recommended maximum addition
of fluoride in the form of tablets to prevent dental caries is
1.5 mg per day. Provided that the maximum allowable daily intake
of fluoride from all sources should not exceed 1.5 mg per person,
to avoid fluorosis, the allowable intakes as mg/kg bw/day for
different age groups (addults 70 kg and children 20 kg bw) vary
between 0.02 and 0.08 mg/kg bw/day. If the total recommendable
intake of fluoride in humans from all sources should not exceed
0.02 mg/kg bw/day, the addition of fluoride from tolylfluanid
in the diet would contribute at most to about 5% of the total
amount fluoride that can be safely ingested per day. page
79
Summary of possible health effects of fluoride released
from tolylfluanid
In rats, at life-time ingestion of tolylfluanid, fluoride levels
in bone increased from 0.683 – 0.805 mg/g ash in controls
to about 1.3 mg/g ash at a dose of about 20 mg/kg bw/day of tolylfluanid.
In mice fluoride levels in bone increased from 1.244 – 1.421
mg/g ash in controls to 1.529 – 1.708 mg/g ash at a dose
of >15 mg/kg bw/day. There is surprisingly little information
about levels of fluoride in bones of humans in relation to ingested
amounts, considering that the controversy over the benefits of
fluoride supplementation of the diet has been going on now for
at least 40 years. Weatherell (1966) reported that the amount
of fluoride in bones of humans, in areas where drinking water
contains less than 0.5 mg/l fluoride, increases with age. In the
age group 20 – 30 years the range of fluoride concentrations
in bone varied between 0.2 and 0.8 mg/g ash, and in the age group
70 – 80 years from 1.0 to 2.5 mg/g ash. A direct comparison
with animal data is difficult, but at the highest recommended
level of fluoride in water (1.5 mg/l) the concentrations of fluoride
in bones of humans in these aereas may expected to be higher than
0.6 mg/g ash and even higher than 5.0 mg/g ash in different age
groups. Skeletal anomalies in rats and mice occurred clearly at
feeding levels higher than 100 mg/kg bw/day tolylfluanid, when
concentrations of fluoride in bones were usually over 3.0 mg/g
ash. The dietary intake assessment for tolylfluanid and the fluoride
released from it show that the tolylfluanid residues in food contributes
little to the total amount of fluoride ingested per day. Based
on the animal studies and what is known about effects of fluoride
in humans, the overall NOAEL:s for the 2-year rat study (about
20 mg/kg bw/day) and the 2-year mouse study (about 15 mg/kg bw/day)
are approporiate also from the point of view of fluoride release
from tolylfluanid and the likelyhood of fluorosis in humans at
intake levels close to the ADI:s possibly set from these values.
pages 79-80
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