Eurobichons

Angel Glow and Angel Eyes Both contain exactly the same active ingredient, the stuff works and so far as I have read its completely safe to use daily for up to two years so to put minds at rest here is the reports .

TYLOSIN

First Draft prepared by
Dr.F.X.R. van Leeuwen
Toxicology Advisory Centre, National Institute of
Public Health and Environmental Protection
Bilthoven, The Netherlands

Toxicological Abbreviations
TYLOSIN (JECFA Evaluation)
Tylosin is a macrolide antibiotic produced by a strain of
Streptomyces fradiae. The compound is active against most
gram-positive bacteria, mycoplasma and certain gram-negative
bacteria. The antibiotic is used in animal feed and veterinary
medicine. The chemical structure of tylosin, and of certain of its
metabolites, is shown at Figure I.



Tylosin was evaluated at the 12th meeting of the Joint FAO/WHO
Expert Committee on Food Additives in 1968 (Annex 1, reference 17).
No ADI was established. It was concluded that tylosin used in animal
feed or in veterinary medicine should not give rise to detectable
residues in edible products of animal origin; when using the
recommended methods of analysis it will be possible to ensure that
residues in meat for human consumption not exceed 0.2 ppm. Since
that time additional data have become available which are summarized
and discussed in this monograph addendum (Annex 1, reference 17).

2. BIOLOGICAL DATA

2.1 Biochemical aspects

2.1.1 Absorption, distribution and excretion

Fasted rats received a single oral dose of 50 mg/kg b.w.
tylosin base or tylosin tartrate. Tylosin activity was assayed in
serum after 15 and 30 minutes and 1, 2, 4, 5, 7, and 24 hours after
treatment. Peak serum levels < 1.0 mg/l were seen after 1-2
hours. Within 7 hours serum levels decreased to less than the limit
of detection (i.e. 0.10 mg/l, microbiological assay). Four rats were
given i.p. 100 mg/kg b.w. tylosin base. Bile samples were collected
for 2 hours. The bile/serum concentration ratio ranged from 143-266
(Anderson et al., 1966).

Rabbits received i.m. 10 mg/kg b.w. tylosin base as a 5%
aqueous solution acidified with hydrochloric acid to pH 5.5. Serum
levels were determined after 1.5, 4, 7, and 24 hours. Peak serum
levels ranging from 0.57 to 0.88 mg/l were observed after 1.5 hours.
A similar study was carried out using tylosin tartrate in aqueous
(25 mg/kg b.w.) as well as in PEG-200 (10 mg/kg b.w.) solutions.
Peak serum levels at 1.0 hour were 4.7-7.2 and 0.96-1.25,
respectively. Within 24 hours serum levels were below the limits of
detection, which were 0.05 mg/l for tylosin hydrochloride and
0.10 mg/l for tylosin tartrate.

Two dogs given 25 mg/kg b.w. tylosin base orally in capsules
excreted 2% of the dose in the urine within 5 hours. Serum
concentrations were very low, < 0.05 and 3.3 mg/l at 2.5 hours
(microbiological assay). In another study groups of 8 dogs received
orally by capsule 1, 10, or 100 mg/kg b.w./day for 8 days. Blood
levels determined 2 hours after the last dose ranged from
< 0.15 mg/ml to 9.5 mg/ml mostly ranging with the dose. Two dogs
received 25 or 100 mg/kg b.w. tylosin base orally by capsule daily
during 29 days. Serum levels were determined 0, 1, 2, 3, 4, 5, 6,
and 7 hours after the 1st, 15th, and 29th dose. At 25 mg/kg b.w/day
peak serum levels (1.4-2.7 mg/l) were seen 2 hours after dosing and
at 100 mg/kg b.w./day the highest levels (2.7-4.6 mg/l) were seen
2-5 hours after dosing. No accumulation was observed. One dog given
i.v. 10 mg/kg b.w. tylosin base (dissolved in a minimal amount of
hydrochloric acid) excreted a total of 25.2% of the activity in the
urine. During 5 hours after dosing 13.7% of the dose was recovered
from bile. The bile/serum concentration ratio varied from 1230 to
3780. Four dogs were administered 10 mg/kg b.w tylosin base i.v. (as
an aqueous solution acidified with dilute hydrochloric acid). Blood
t´ was calculated as 48 min. Urinary recovery was 18.8% of the
dose during 6 hours after dosing (15.7% within 2 hours). Serum

levels of tylosin in 4 dogs receiving 25 mg tylosin base
intraduodenally at 0.25, 0.5, 1, 2, 3, 4, and 5 hours averaged 0.78,
1.98, 1.77, 1.94, 0.56, 0.29, and 0.13 mg/l, respectively. Urinary
recovery was 7.2% of the dose in 5 hours (Anderson, et al., 1966).

Thirty mg/kg b.w. tylosin tartrate was administered orally by
gavage or intravenously to groups of pigs (5/group, 30-days old). At
38 days of age the treatments were crossed over. Tylosin activity
was measured in blood samples taken at 10 intervals up to 24 hours
after treatment. After oral administration tylosin activity was
present in plasma 10 minutes after dosing with a peak concentration
of 2.4 mg/l at about 1.5 hours. By comparing the areas under the
curve of the tylosin concentration in blood following the 2 routes
of administration a biological availability of 22.5% was determined
(Shionogo &amp; Co. Ltd., 1981).

Tylosin at 110 mg/kg b.w. (as the granulated phosphate) was
orally administered to 3 male and 3 female pigs. Tylosin activity
was assayed in blood samples taken up to 24 hours after dosing.
Serum activity peaked 1 hour after dosing (average 17.81 mg/l); 24
hours after dosing tylosin was not detectable (< 0.1 mg/l) (Van
Duyn &amp; Kline, undated).

Six pigs (weight 56 kg) were orally given 50 mg/kg b.w. tylosin
phosphate in water. Blood and tissue samples were taken at intervals
up to 24 hours. Tylosin levels were detected in serum from 10
minutes to 8 hours after dosing and peaked at 1 hour (8.53 mg/l).
Tylosin was widely distributed in the body with tissue
concentrations in liver and kidney peaking at 1 hour. No activity
was found in the brain or spinal cord. Highest activity was found in
bile and urine (Nakamura et al., 1969).

Young calves (weight range 44.4-59.0 kg) were injected with
10 mg/kg Tylan 200 either subcutaneously or intramuscularly. The
rate of tylosin absorption, time to peak concentration and decline
of serum concentrations were very similar via both routes of
administration (Thomson, undated a).

Groups of calves (average weight 60 kg) received 10 mg
tylosin/kg b.w. subcutaneously or intramuscularly {as formulations
of tylosin tartrate in water, tylosin tartrate in propylene glycol
and water and tylosin base in propylene glycol and water (Tylan 200
injection)}. Another group of calves received the same dose (as
Tylan 200 injection) intravenously. Tylosin activity in serum was
measured in blood samples taken at various intervals after
treatment. Absorption of the formulations containing tylosin
tartrate was faster after subcutaneous and intramuscular
administration than absorption of the formulation containing tylosin
base (Thomson, undated b).

Holstein calves (1-3 weeks, 38-56 kg) were given 1 or 1 to 5
daily intramuscular injections of 17.6 mg tylosin/kg b.w. (as Tylan
200). In all experiments tylosin levels in serum peaked 2 hours
after administration (average 2.0 mg/l) decreasing to about 0.1 mg/l
at 36 hours. Peak lung tissue levels were observed at 6 to 24 hours
post injection varying from 12.6 to 15.7 mg/l. Lung tissue levels
were greater than serum levels and still detectable (2.2 mg/l) at 48
hours after administration (microbiological assay) (Van Duyn &amp;
Folkerts, 1979; Van Duyn &amp; Johnson (undated a); Van Duyn &amp; Handy
(undated)).

A serum half-life of 1.62 hours was established in cows given a
single i.v. injection of 12.5 mg tylosin/kg b.w. (as Tylan 200). The
apparent specific volume of distribution was 1.10 l/kg indicating no
specific accumulation (Gingerich et al., 1977).

Neonatal holstein calves with a natural occuring pneumonia were
treated intramuscularly with 17.6 mg tylosin/kg b.w. (as Tylan 200)
daily for 3 consecutive days. Healthy calves were subjected to the
same treatment. Six hours following the last dose all the calves
were sacrificed and tylosin activity was measured in the lungs.
Tylosin distributed equally into both normal and pneumonic lung
tissue (Thomson, undated a).

Groups of neonatal healthy calves were fed a milk replacer
containing 1.0 g tylosin (as tylosin tartrate) for 4, 7, and 10
days. Serum samples were taken 4 hours after each dose; the animals
were killed after the final sample had been taken and lung tissues
were analyzed. Mean serum and lung tissue levels were 0.41, 0.37,
and 0.42 mg/l, and 1.76, 3.16, and 3.17 mg/l for the 4, 7, and
10-day treatment groups, respectively. Lung/serum tylosin ratios
were 7.24, 9.36, and 14.01, respectively (Buck et al., undated).

Groups of 4 calves (weight 250 kg) received intramuscular
injections with 10 mg tylosin/kg b.w. (as Tylan 200) for 5 days. The
calves were killed 2, 4, 6, 12, or 72 hours after the last
injection. Tylosin activity was measured in serum and lungs. Tylosin
activity in serum was highest at 4 hours after treatment (1.3 mg/l)
and was no longer detectable after 72 hours using a microbiological
assay whose detection limit was 0.05 mg/l. The mean tylosin activity
in the lungs was 5.9, 5.0, 6.6, 4.4, and 0.6 mg/l at 2, 4, 6, 12,
and 72 hours after treatment, respectively (Lilly, undated a).

Four broiler chickens (weight 720 g) were given a single dose
of 50 mg tylosin/bird (as tylosin tartrate) by stomach intubation.
Tylosin activity was detected in serum after 0.5 hours and peak
concentrations of 0.6-4.0 mg/l were found after 2 hours, declining
to negligible after 24 hours. Repeated oral doses of 50 mg tylosin
to chickens (weight 2 kg, dosed at 1, 2, and 3 hours) caused serum
peak levels at 4 hours (about 0.28 mg/l) declining to negligible at
24 hours (Lilly, undated b, undated c).

Groups of 6 chickens (5-7 weeks old, surgically prepared)
received orally 25, 100 or 250 mg tylosin/kg bw (as tartrate). Urine
and faeces were collected during 72 hours. Peak tylosin levels in
urine (< 100 mg/l at the 25 mg/kg dose and > 1400 mg/l at the
250 mg/kg dose) occurred 2-4 hours after dosing and declined rapidly
thereafter. Peak levels in faeces occurred at 8 hours and varied
from 300 to 2000 µg/g with the dose (Lilly, undated d)

2.1.2 Biotransformation

Four male rats, preconditioned on unlabelled tylosin (10 mg/kg
b.w.) for 3 days, received daily during 5 days by gavage 2 ml of a
solution containing 14C-labelled (in lactone ring) tylosin base.
The rats were killed 4 hours after the last dose; 99% of the
radioactivity was excreted in the faeces and 1% in the urine. The
greatest part of the excreted residues was found to be tylosin
factor A, tylosin factor D and dihydrodesmycosin. Less than
0.25 mg/kg total 14C-residue was found in liver and kidney (Sieck
et al., 1978b).

A male pig, preconditioned on feed containing 110 mg/kg
unlabelled tylosin for 2 weeks, received for 3 days feed with
110 mg/kg of feed tylosin base 14C-labelled in the lactone ring.
Four hours after the last dose the pig was killed. The radioactivity
was excreted 99% in the faeces and 1% in the urine. The majority of
the excreted residues (15% of the radioactivity in faeces was not
extractable) was found to be tylosin factor D (33%), tylosin factor
A (6%) and dihydrodesmycosin. At least 10 minor metabolites (< 5%
of activity) were present in the excreta. In liver and kidneys
< 0.25 mg/kg tylosin was found. At least 4 different metabolites
(of which one was detected as dihydrodesmycosin) were detected in
liver and kidneys (Sieck et al., 1978b).

Three pigs received twice daily for 4 days a ration containing
110 mg tylosin base/kg of feed 14C-labelled in the lactone ring. A
control pig received the basal diet throughout the experiment. Pigs
were sacrificed within 4 hours after the last dose. Total
14C-residues in liver and kidney were < 0.28 mg/kg and in
muscle and < 0.04 mg/kg in fat. Investigations by TLC of liver
residues revealed 5 or 6 metabolites. Two of the metabolites could
be identified as tylosin factor A and dihydrodesmycosin, each
representing about 5% of the total extractable liver residue. Mass
spectrometer analysis of the faeces identified 3 metabolites as
tylosin factor A, tylosin factor D and dihydrodesmycosin (Sieck
et al., 1978a; Sieck et al., 1980).

2.2. Toxicological studies

2.2.1 Acute toxicity

The acute toxicity of tylosin formulations and of tylosin are
given in Tables 1 and 2, respectively.

Table 1. The acute toxicity of tylosin formulations


Species Sex Route LD50 LC50 Reference
(mg/kg b.w) (mg/l)


rat M&amp;F oral > 5001 Gries et al.,
1985a
M&amp;F oral > 0.52 > 1.054 Gries et al.,
1 hr > 0.65 1985b
M&amp;F inhal Gries et al.
M&amp;F inhal 1985c

rabbit M&amp;F dermal > 20001 Gries et al.,
1985a
M&amp;F dermal > 20003 Gries et al.,
1985c
M&amp;F dermal > 2.02 Gries et al.,
1985b


1. administered as granulated tylosin concentrate, a formulation
containing 26.7% of tylosin base activity as the phosphate salt
2. ml/kg b.w. administered as undiluted tylan 200 injection
3. administered as tylan soluble, a dry granular formulation, also
known as tylosin tartrate
4. liquid droplet aerosol of tylan 200/injection formulation at
1.05 mg/litre for 1 hour
5. solid particulate aerosol of tylan soluble at 0.6 mg/litre.

Table 2. The acute toxicity of tylosin


Species Sex Route LD50 Reference
(mg/kg b.w.)


mouse F oral > 62001 Anderson &amp; Worth,
- oral > 50002 undated
- oral > 62005
- i.p. 492.51
- i.p. 594.12
- s.c. 13545
- s.c. 784.11
- s.c. > 25002 Gries et al.,
- i.v. 385.71 1983
- i.v. 581.73
- i.v. 588.84
- i.v. 588.95
F i.v. approx 3216

rat M oral > 62001 Anderson &amp; Worth,
- oral > 50002 undated
- oral > 62005
- i.p. 10011
- i.p. > 25005
- i.v. 6955 Gries et al.,
- s.c. 40831 1985c
- s.c. > 30005
M&amp;F oral > 5005

dog M&amp;F oral > 8002 Anderson &amp; Worth,
undated


1. administered as tylosin phosphate
2. administered as tylosin base
3. administered as tylosin hydrochloride
4. administered as tylosin lactate.
5. administered as tylosin tartrate.
6. administered as 20 mg tylosin/ml of acidified sterile water for
injection, USP (2.0%)


After oral administration no deaths were recorded at the
highest dose used; dogs vomited at 800 mg/kg b.w. but not at
400 mg/kg b.w.; at both these doses the dogs salivated and
defecated. Intravenous and intraperitoneal administration caused
depression, prostration, convulsions and death or recovery within 24
hours.

2.2.2 Short-term studies

2.2.2.1 Rats

Groups of rats (Harlan strain, 5 females/group) received daily
s.c. injections of 10, 20, 50 or 100 mg/kg b.w. tylosin base as a
suspension in 5% acacia gum for 1 month. No effects were seen on
food intake, body weight gain, adrenal weight and terminal blood
cell counts. Macroscopy and microscopy did not show abnormalities
(Anderson et al., 1966; study R2-58). Remark: Summary only.

Groups of rats (Harlan strain, 6/sex/group) received daily s.c.
injections of 100, 250, 500, or 1000 mg/kg b.w. tylosin tartrate or
2.5 ml/kg b.w. saline for 1 month. At doses > 250 mg/kg b.w.
diarrhoea was seen during the first week, regressing to soft stools
(occasionally seen at 100 mg/kg b.w. too) during the remainder of
the study. At doses > 250 mg/kg b.w. scarring and scabbing at the
injection site was seen (occasionally at 100 mg/kg b.w.). No effects
were observed on growth, haematology, organ weight, macroscopy and
microscopy (Anderson et al., 1966; study R19-59). Remark: Summary
only.

Groups of rats (Harlan Wistar, 15/sex/group, F1a offspring
from parents fed the same amount of tylosin base for about 10 weeks
prior to mating and during gestation and lactation) were fed diets
containing 0, 0.1, 0.5 or 1.0% tylosin base for 1 year. No
treatment-related effects were observed on mortality, growth, food
consumption, ophthalmoscopy, organ weights, macroscopy and
histopathology. Treated rats appeared moderately hyperirritable and
hyperactive after 7 to 12 months of treatment. An increase in
lymphocytes and a corresponding reduction in neutrophils were
observed in both sexes (significantly in females) at 0.5 and 1.0%. A
trend towards a slightly more alkaline urine occurred in females at
0.5% and 1.0%. The authors concluded that the NOEL was 1.0% tylosin
base, equivalent to 500 mg/kg b.w. However, the Committee concluded
that the NOEL in this study was 0.1% tylosin base, equivalent to
50 mg/kg b.w. (Broddle et al., 1978a).

2.2.2.2 Dogs

Groups of 8 dogs (2/sex mongrel dogs and 2/sex beagle dogs)
received orally by gelatin capsule during 2 years 0, 1, 10 or 100 mg
tylosin base/kg b.w./day. Groups of mongrel dogs (2/sex/group) given
200 or 400 mg tylosin base/kg b.w./day in capsules for 2 years or
longer were subsequently added. Salivation, vomiting and diarrhoea
were observed at 200 and 400 mg/kg b.w./day (at 100 mg/kg b.w./day 1
dog vomited once). Haematology, urinalysis and relative organ
weights did not reveal abnormalities. No changes were observed in
faecal microbiological flora. Liver and kidney function tests
revealed two dogs at 100 mg/kg b.w./day and 1 dog at 400 mg/kg

b.w./day with a transient increased BSP retention time. Macroscopy
and microscopy did not show compound-related changes except for mild
pyelonephritis seen in 1/4 dogs at 200 mg/kg b.w./day and bilateral
nephrosis, mild chronic pyelonephritis and mild cystitis seen in 1/4
dogs at 400 mg/kg b.w./day. Terminal bone-marrow counts were normal
(only measured in normal study). At dose levels > 10 mg/kg
b.w./day serum tylosin levels in blood could be detected. The NOEL
in this study was 100 mg/kg b.w./day (Anderson et al., 1966; study
D4-59). Remark: The limited details provided and the poor reporting
of the study made proper interpretation difficult.

2.2.3 Long-term/carcinogenicity studies

2.2.3.1 Rats

In a limited study rats (3/sex/group) were fed diets containing
0, 0.1, 0.3, or 1.0% tylosin base for 17 months. In the 0.3% group 1
female died due to malnutrition. No effects on growth or on terminal
haematological parameters were seen. Relative organ weights revealed
changes in weights of ovaries and uteri due to thickening in uteri
and a decrease in size of the ovaries in 1/3, 3/3, 2/3, and 2/3
female rats at the 0, 0.1, 0.3, and 1.0% levels, respectively.
Macroscopy and microscopic examination revealed squamous metaplasia
of the uterine glands in 2 female rats at the highest dose (Anderson
et al., 1966; Study R9-58). Remark: Incomplete report.

Groups of about 25 male and female Harlan rats (total 213)
received 0, 0.001, 0.01 or 0.1 % tylosin base in their diet for 2
years. Survival was better in tylosin treated groups than in control
rats (54% and 30% respectively). No effects were seen on growth,
haematology, or relative organ weights. Macroscopy and microscopy
revealed an increased number of animals with fatty changes in livers
and kidney at all dose groups and a slight increased incidence of
bile duct proliferation at the 0.1 and 0.01% levels, but neither was
dose-related (Anderson et al., 1966; Study R10-58). Remark:
Incomplete reports of growth and haematology; limited
histopathology.

In another 2-year study groups of Harlan rats (30/sex/group)
were fed diets containg 0, 0.01, or 1.0% tylosin base. Survival was
better in rats fed tylosin than in control rats (57% and 29%
survival in high dose and control rats, respectively). No effects
were seen on growth, haematology, urinalysis, organ weights,
macroscopy and microscopy. A dose-unrelated increase of fatty
changes in liver and kidney was observed. (Anderson et al., 1966;
R3-59). Remark: Incomplete reports of growth, haematology and
urinalysis.

In a very limited study groups of 10 male and 10 female rats
were fed diets containing 0, 2, 5, 10, or 20% tylosin base for up to
2 years. No effects on food consumption, growth and haematology were
observed on rats at 2% and 5%. At the 10% level, growth and food
consumption were slightly reduced. At the highest dose food
consumption and growth were markedly reduced followed by death
(Anderson et al., 1966; R6-60). Remark: Incomplete reports.

Two replicate 2-year studies were carried out with Wistar rats
(40/sex/group in each study derived from F1a offspring from
parents fed diets containing tylosin from 10 weeks prior to mating
up to the time of weaning). The control groups (60/sex/group in each
replicate study) were derived from parents fed untreated diet.
Treated groups were fed diets containing 0.1, 0.5, or 1.0% tylosin
base. Observations included clinical signs, mortality, food
consumption, food efficiency, body weight, terminal haematology and
biochemistry, urinalysis, organ weights, macroscopy, and
histopathology. There were trends towards improved survival in
males, although overall survival was low (20% and 28% for the
control and treated groups, respectively), and increased food
consumption and body weight gain in both males and females in all
treated groups. At histopathology an increased incidence of
pituitary adenomas in males (but not in females) was observed. The
combined incidence of pituitary adenomas in males for both
replicates was 6/120 (5%) in the control group, 9/80 (11%) in the
low dose (0.1% tylosin) group, 18/80 (22.5%) in the mid dose (0.5%)
group, and 20/80 (25%) in the high dose (1.0%) group. The authors
concluded that the increase in pituitary tumours was an indirect
result of the ability of tylosin to increase survival and weight
gain. The incidence of malignant tumours was unaffected in males or
in females (Gries, 1980)

Toxicological Abbreviations
TYLOSIN (JECFA Evaluation)
[/code]

2.2.4 Reproduction studies

2.2.4.1 Mice

Groups of 7-8 male and 14-17 female ICR mice were fed diets
containing 0, 0.1, or 1.0% tylosin (composition unknown) for two
succesive generations with 2 litters/generation. Some of the mice
were maintained on an ordinary diet, but all the mice received the
experimental diet prior to delivery of the offspring. No
treatment-related effects were observed on reproductive performance
(sexual maturation, number of pups or weaning of pups) (Tsubura
et al., undated). Remark: Only a few summary tables were available.

2.2.4.2 Rats

A 3-generation reproduction study was performed with 2 groups
of 5 male and 10 female Harlan rats/group receiving 0 or 1.0%
tylosin base in their diet. Fertility, viability, gestation and
lactation indices in the F0 generation rats did not reveal any

abnormality. Growth was equal in all generations for both control
and treated rats. In each succeeding generation the capability for
reproduction and perpetuation was unaffected (Anderson et al., 1966;
R3-59). Remark: Incomplete report.

In a special study weanling Wistar rats (25/sex/group, 6-7
weeks old) were fed diets containing 0.1, 0.5, or 1.0% tylosin base
for 10 weeks prior to mating and thereafter for about 6 months
total. A control group consisted of 35 rats/sex. Only one litter was
bred. No effects were observed on parental body weight, food
consumption, reproductive indices (male or female fertility,
gestation length, number of live fetuses, mean litter weight or
offspring survival) or biochemistry. High dose male rats revealed
significantly decreased white blood cells at termination. Sera
collected from parental rats (approx. 150 days on experimental
diets) did not contain detectable levels of tylosin (< 0.1 mg/l).
Offspring were physically normal and were assigned to the one year
toxicity study with tylosin (see Section 2.2.2.1) (Broddle, et al.,
1978b). Remark: Only summarized data given on reproductive indices.

2.2.5 Special studies on embryotoxicity and teratogenicity

2.2.5.1. Mice

Groups of 10 pregnant mice (2 strains, CBA and A/Jax) received
orally 100, 500, or 1000 mg/kg b.w./day tylosin (composition not
given) in 0.1 ml water from days 7-12 of gestation. Two control
groups of 3 and 5 mice received saline or remained untreated,
respectively. Females were killed on day 18 of pregnancy. No effects
were observed on number of corpora lutea, number of implantations,
number of early and late deaths, number of embryos alive, or fetal
development (Tsuchikawa &amp; Akabori, undated).

Four groups of mice given 0 or 500 mg/kg b.w. and a further 2
pregnant females (A/Jax x male CBA) per group, receiving orally 0 or
1000 mg tylosin/kg b.w./day during days 7-12 of gestation, were
allowed to deliver and rear their young for 4 weeks. No effects were
observed in growth, survival, or genital system of all mice born
determined up to 9 weeks. At 8 weeks after birth rearing ability,
hearing ability and kinetic functions were not effected. At the 9th
week the mice were killed and visceral and skeletal examinations
were performed. No abnormalities were seen (Tsuchikawa &amp; Akabori,
undated).

2.2.5.2 Rats

Groups of 15 Wistar rats were fed diets containing 0.1, 1.0, or
10.0% tylosin (composition not given; equal to 60.5, 725, or
4800 mg/kg b.w./day, respectively) in their diet during days 1-20 of
gestation. A control group consisted of 10 rats. Females were killed

on day 20 of gestation. Observations included number of resorptions
and live and dead fetuses, sex ratio, fetal weight and external,
visceral and skeletal abnormalities. Fetus weight at the highest
dose was slightly decreased (Terashima, undated).

In another study 3 groups of 15 Wistar rats received 0, 1.0, or
10.0% tylosin (composition not given, equal to 0, 725, or 4800 mg/kg
b.w.) during days 1-20 of gestation. Normal delivery was allowed.
Number of fetuses, sex ratio, external abnormalities and growth
during the weaning period (3 weeks) were determined. Motor functions
and senses were examined. The weanlings were killed and visceral and
skeletal examinations were performed. A slightly reduced growth was
observed in weanlings at the highest dose (Terashima, undated).

2.2.6 Special studies on genotoxicity

Tylosin was tested for genotoxicity in an in vitro
chromosomal assay with Chinese hamster ovary cells, a mouse lymphoma
assay and an in vivo assay for cytogenetic damage. The results are
summarized in Table 3.

2.2.7 Special studies on microbiological activity

The anti-microbial activity of tylosin has been described in
the published literature. Tylosin is markedly active in vitro
against gram-positive bacteria, certain gram-negative bacteria and
mycobacteria; it is inactive against Enterobacteriaceae (McGuire
et al., 1961).

Table 3: Results of genotoxicity assays on Tylosin


Test system Test Concentration Purity Results Reference
object of substance
tested


Chromosome Chinese 500-1000 99.3 - Gries,
aberration hamster µg/ml2, 1990a
assay1 ovary 250-750
cells µg/ml3, both
in DMSO

Lymphoma Mouse 10-1000 µg/ml2 99.3 +5 Gries,
assay L5178Y 10-1000 µg/ml3 1990b
TK+/- (1000 µg/ml
cells toxic) both in
DMSO

Micronucleus ICR 2 daily doses 966 - Gries,
mice of 1250, 2500 1990c
or 5000 mg/kg4


1. Mitomycin C and cyclophosphamide, used as positive controls, yielded
positive results
2. without metabolic activation
3. with metabolic activation
4. the positive control cyclophosphamide yielded positive results.
5. positive at cytotoxic dose
6. administered as tylosin base

In recent studies the minimal inhibitory concentration (MIC) of
tylosin has been determined for bacterial pathogens isolated from
target animal species of European and North American origin since
1984. Additional information on sensitivity of bacterial isolates to
tylosin was obtained from literature published since 1980. Tylosin
was active against most Gram-positive bacteria and mycoplasmas
tested in vitro. Activity against Gram-negative bacteria was
generally lower. Tylosin was also found to be active against
isolates of Chlamydia psittaci. MIC values for streptocci,
enterococci and staphylococci are given in Table 4 (Herd, 1990).

Table 4. MIC1 values for tylosin against some Gram-positive bacteria


Organism MIC range Total No.
(mg/1) of isolates


Streptococcus pyogenes 0-1 - 0.2 5
Streptococcus pneumoniae 0.2 - 0.4 4
Streptococcus dysgalactiae 0.06 - 128 50
Streptococcus agalactiae 0.125 - 0.5 51
Streptococcus suis 0.125 - > 128 42
Streptococcus uberis 0.125 - > 128 53
Enterococcus faecalis 0.25 - > 128 31
Staphylococcus aureus2 0.125 - > 128 98
Staphylococcus Spp.3 0.78 - 1.0 7

The active ingredient in both ANGEL GLOW an ANGEL EYES IS TYLOSIN TARTRATE .

Tylosin

The reason I posted this was to ensure that all users of both Angel Glow and Angel Eyes knew that despite what some may say it is safe.

The overdose rate that is or should I say has been tolerated in dogs is extremely high at 800mg, in a single dose.

Tylosin tartrate is the active macro ingredient, its a wide spectrum mini antibotic used for all animals.

What I would advise is that you dont use any product daily forever, the pharmocopeia results indicate that up to two years daily use is ok and has NO KNOWN SIDE EFFECTS.

What a vet would notice if liver functon tests were carried out is a possible raised ALT , this is a false positive and you should tell the vet that you use AG or AE and the active ingredient is Tylosin as tartrate.

Diagnosing Liver Disease in Dogs: What do the Tests Really Mean?


Liver disease can be frustrating to diagnose. Although in the dog (in contrast to the cat), it is uncommon for a patient to have normal clinical pathology values in the presence of significant liver disease, enzymology and other clinical pathology tests rarely indicate the type of liver pathology present. In addition, even liver “specific” enzymes such as ALT can be increased in non-primary hepatic disease and care must be taken in interpreting slight or even moderate increases. This lecture will focus on the tests that may be utilised in the diagnosis of liver disease and the non-hepatic causes for changes in these tests that the clinician should be aware of when interpreting clinical pathology results.

Diagnostic tests

Liver enzymology

Alanine aminotransferase (ALT, formerly SGPT). ALT is a liver specific enzyme in the dog and cat. The highest cellular concentrations occur in the cytosol therefore the enzyme is released following severe, acute and diffuse hepatocellular necrosis. In general, serum levels are not regarded as significant unless they are two to three times above normal. Mild-moderate increases in ALT (up to four to five times normal) may occur with non-hepatic disorders such as inflammatory GI disease, cardiac failure and haemolytic anaemia.

The serum half-life of ALT is less than 24 hours. Levels peak two to three days after hepatic insult and return to normal in one to three weeks if hepatic insult resolves. A persistent increase indicates continuing hepatocellular insult. ALT levels may also be moderately increased in animals on anticonvulsant therapy and glucocorticoids and with biliary stasis.

Alkaline phosphatase (ALP). ALP is bound to membranes of bile canaliculi and bile ducts. Values are increased by any condition causing cholestasis, either intra- or extra-hepatic. Cholestasis results in increased synthesis and regurgitation of the enzyme from the biliary system into the serum.

Isoenzymes. Other isoenzymes of ALP are also found in bone, intestine, kidney tubules and the placenta. However, the half-life of the intestinal, renal and placental isoenzymes are so short (two to six minutes) that serum elevations of ALP would rarely occur from these organs. Usually an elevation in ALP is due to hepatic or bone isoenzymes. However, exogenous and endogenous glucocorticoids can induce a specific isoenzyme and thus result in elevated serum levels in the dog (but not in the cat). The value in measuring the ALP isoenzyme in the diagnosis of hyperadrenocorticism is highly questionable as the isoenzyme is increased by hepatic pathology as well as hyperadrenocorticism.

ALP levels will be increased in young growing animals (bone isoenzyme) and in destructive bone disease. ALP is also increased in certain carcinomas and mammary gland tumours, and with anticonvulsant therapy in dogs, but not cats.

ALT vs. ALP—does their relative increases help determine the location of liver pathology (intra- or extra-hepatic)?

Serum enzymology is not particularly helpful in determining whether an animal has hepatic or post-hepatic disease. Post-hepatic obstruction of the biliary tract almost invariably causes secondary hepatocellular damage and hence both ALT and ALP will be elevated. ALP is elevated by both intra- and extra-hepatic cholestasis thus is increased in hepatic and post-hepatic disease.

The relative degree of increase of each enzyme is also not helpful; in fact, if ALP is substantially increased and ALT normal or only slightly increased, non-hepatic disease such as hyperadrenocorticism or exogenous corticosteroid administration is more likely to be present.

It is important to be aware that serum enzymes are not liver function tests and there is no correlation between the magnitude of the enzyme increase and the severity or reversibility of the condition. Occasionally, cases of severe liver dysfunction, e.g., biliary cirrhosis, neoplasia or portacaval shunt, may be associated with minimal or no increases in serum enzymes.

Gamma glutamyl transpeptidase (GGT). GGT levels are increased in most conditions that cause elevation in ALP, i.e., cholestasis, glucocorticoid therapy, hyperadrenocorticism. However, unlike ALP, GGT is not elevated with increased osteoblastic activity (e.g., growing dogs) and may not be elevated in dogs on anticonvulsant medication. ALP is slightly more sensitive than GGT for detection of cholestatic disease in dogs

Serum protein

Serum albumin. Albumin is synthesised only in the liver. A loss of greater than 70% of liver function is required before hypoalbuminaemia occurs. Hypoalbuminaemia most commonly occurs in cirrhosis and portosystemic encephalopathy but will also occur in severe diffuse necrosis. Albumin concentrations may also be decreased in renal and gut disease, severe cutaneous burns, protein malnutrition, in the presence of acute phase reactants, and in patients with exudative effusions (which cause sequestration of albumin).

Serum globulins. Increased serum globulin levels may occur in inflammatory hepatic disease or when the hepatic reticuloendothelial system is compromised. Decreased levels will often occur in portosystemic encephalopathy as a large proportion of globulins are synthesised in the liver.

Bilirubinaemia and bilirubinuria

Dogs (males more than females) have a low resorptive threshold for bilirubin. They also have renal enzyme systems that produce and conjugate bilirubin to a limited extent. Therefore, mild bilirubinuria (up to 2+) can occur in normal dog urine of greater than 1.025 specific gravity.

Slight bilirubinuria may occur in starvation and febrile states and mild bilirubinaemia and bilirubinuria can also occurs with sepsis. Bilirubinuria will develop well before overt jaundice in dogs due to the low renal threshold.

Is the relative ratio of conjugated vs. unconjugated bilirubinaemia helpful in determining whether hepatic pathology is intra- or extra-hepatic?

While an animal with only conjugated bilirubinaemia would most likely have post-hepatic jaundice (due to biliary tract or pancreatic disease most commonly), the majority of animals with hepatic or post-hepatic jaundice will have both unconjugated and conjugated bilirubinaemia. Post-hepatic obstruction will cause secondary hepatocellular damage and, as previously mentioned, bilirubin excretion is the first process to become disordered in primary hepatocellular disease.

Cholesterol

Very low serum cholesterol concentrations may occur in patients with congenital or acquired portosystemic shunts and fulminant hepatic failure. Increased serum cholesterol in a jaundiced patient usually indicates major bile duct occlusion particularly in cats. However, cholesterol concentrations are also increased in non-hepatic diseases such as pancreatitis, diabetes mellitus, hyperadrenocorticism and hypothyroidism which if present concurrently can confuse interpretation.

Bile acids

Serum bile acids are a sensitive and specific measure of hepatobiliary function in the cat and dog. They should be considered when other routine clinical pathology results do not permit an unequivocal diagnosis of liver disease to be made. It is not necessary to do the test if the patient is jaundiced and not anaemic, nor if liver enzyme changes permit an unequivocal diagnosis of liver disease to be made.

Bile acids are useful as a screening test for hepatic encephalopathy (except in Maltese Terriers). Their major advantage in this context is the lack of stringent requirements for sample collection and processing in contrast to blood ammonia determination.

Occasionally, bile acids can be normal in patients with hepatic disease. We have observed this in some cases of hepatic neoplasia. The level of serum bile acid increase roughly correlates with the severity of the hepatobiliary disorder but the level gives no indication of reversibility or the type of the lesion and hence prognosis.

Serum bile acid concentrations are usually not affected by steroid administration but occasionally can be markedly altered due to alteration of hepatic architecture as a result of hepatic glycogen accumulation. Serum bile acids are therefore useful but not infallible for differentiating elevated ALP values due to steroids (endogenous or exogenous) or hepatobiliary disease.

Other diagnostic procedures

Radiology

Plain radiographs may be helpful in confirming hepatomegaly, the presence of a small liver, or asymmetric enlargement of a liver lobe. However, although the liver is the largest solid organ in the body, its plain film evaluation is unreliable. Contrast radiography is primarily indicated in diagnosing portacaval shunts.

Ultrasound

Ultrasound examination of the liver may assist in differentiating homogeneous enlargement from cellular infiltration and in differentiating hepatic from post-hepatic cholestasis.

Biopsy

Hepatic biopsy is usually the only method by which the type of hepatic pathology can be characterised. Hepatic biopsy (via exploratory laparotomy or ultrasound guided) should be considered in all dogs with obstructive jaundice and in those with evidence of chronic hepatocellular disease.

The pretenders

A number of diseases may be confused with hepatic disease because of clinical signs or clinicopathological abnormalities. Increased liver enzymes, ALT, and ALP may occur in pancreatitis, diabetes mellitus, and hyperthyroidism. Moderately increased bilirubin can occur in a variety of non-hepatic diseases as well as in conditions such as prolonged anorexia, catabolic states, and infection. Mild increases in ALT may be observed in animals with cardiac pathology. Substantial increases in ALP with moderate increases in ALT will occur in most dogs with hyperadrenocorticism.

Causes of hepatic disease in dogs






Chronic hepatitis

Chronic progressive hepatitis-idiopathic, immune mediated?

Bedlington Terriers, WHW Terriers—copper toxicity

Lobular dissecting hepatitis

Leptospirosis

Viral—adenovirus

Drug induced- primidone, phenytoin

Suppurative cholangiohepatitis

Non-suppurative (lymphocytic) cholangiohepatitis

Acute hepatitis

Toxins e.g., thiacetarsamide, anticonvulsants

Aflatoxin, bacterial endotoxin, blue green algae

Bacterial- Leptospira, Salmonella, Clostridia

Viral- adenovirus I (ICH), canine herpes

Toxoplasmosis

Dirofilariasis—caval syndrome

Acute pancreatitis

Acute haemolytic anaemia

Heat stroke

Surgical hypotension or hypoxia

Trauma


Cirrhosis

End-stage fibrosis of many inflammatory hepatic diseases. Aetiology undetermined in majority of cases.

Glucocorticoid hepatopathy

The canine liver is uniquely sensitive to the effects of exogenous or endogenous corticosteroids.

Neoplasia

The liver is a frequent site for both primary and metastatic neoplasia.

Primary neoplasms

Hepatocellular carcinoma

Hepatoma

Cholangiocarcinoma

Fibroma/fibrosarcoma

Haemangioma/haemangiosarcoma

Lymphosarcoma (may also be multi-focal)

Portosystemic or hepatic encephalopathy

Kaz, that's 800mg per kilogram, so the overdose rate of a 2.5 kg puppy (Freya) would be 2 grams and I don't feed her anything like that amount of Angel Glow, she wouldn't tolerate the taste, for a start. After the first couple of weeks, she didn't need it daily, either, she gets a tiny dose once every 2-3 weeks so I won't worry about her.

Did you know that you can even die from drinking too much water?
google "Water intoxication", for some reason my computer won't copy and paste today

Yes Judes too much water is the reason people die from taking ecstacy, gives them water on the brain and they then drown as the lungs fill up etc, rather lke encephalitis.
Judes with AG and AE its ok for daily use for up to 2 years.

This is not a dangerous product, its effective for daily use up to 2 years, what is dangerous is a bichon breeder that wants her home made product to sell again . She profiteers and I would want to know what is in her product before I put it on my dogs. Some show breeders hey, all they care about is profit, I noted today that her partner after seeing our site updated her site too, originality they lack, shows how uneducated they actually are.I call them the gruesome 2some or S and M

Karen (no tea for me )
I have to correct you here, you know yourself that all drugs can be dangerous, however it is how the risk in taking them set against not taking them is given precedence.
Let me explain, a macrolide antibiotic isnt dangerous per se,(for dogs) providing the risk assessment has been carried out to see if the animal actually needs that or another form of treatment.
Here I think the debate is centered on the owner diagnosing the problem with tear staining.
Much debate should be centered around breeding this out from the gene pool, but that takes time and effort, for most show breeders , that just isnt likely to happen, its a rapid change over for them, they just dont have the facilities or the finances to wait!
The product we put together acts as an antioxidant which assist in cell regeneration and thus will (under most circumstances ) control tear production that then attracts bacteria.

I agree , with you.

Kaz, that's 800mg per kilogram, so the overdose rate of a 2.5 kg puppy (Freya) would be 2 grams and I don't feed her anything like that amount of Angel Glow, she wouldn't tolerate the taste, for a start. After the first couple of weeks, she didn't need it daily, either, she gets a tiny dose once every 2-3 weeks so I won't worry about her.



Surely 20g grams of AG/AE is the equiv of 2g of tylosin (assuming 10% of tylosin by weight of AE/AG)

my understanding of AE/AG is that they are safe but not legal simply because of the way that the way that regulations work.

btw are they actually legal in the States???

I dont do the math , but it is legal to use in the USA as its licenced as a grooming aid, I have given the actual FDA ruling here somewhere, the reason its illegal to buy in the UK is due to the medicines act which governs all medicines both human and veterinary.
If this was actually given by your vet it would be legal.
Vets wont give this out as they are worried about antibiotic resistance.
This whole situation was commenced because 1 bichon breeder repeatedly contacted DEFRA over thsi product. That person is now back tracking .

I dont think the tylosin is that high within the composed product, I feel at that rate it would be too expensive to produce, its more likey to be 0.01 % , especially considering the time it takes to work.

so a breeder's hissy fit is denying 1000s of owners the opportunity to use a tried and tested product.

name'n'shame? ;)

on what grounds is he/she back tracking???

It would be wrong for me to name her but there is a clue its a she AND MARRIED .

Bit of an old hag really with ideas above her station .
Saying she didnt make contact with them but her own admissions state that she did as do members of her circle.

would the curtain twitching hag by any chance be called m**reen???

just something i saw in a post about AE/AG in the bichon banter forum

To be fair I cannot say, I have never met her, but she does like to set gossip about(that is from one of her longtime associates)
IMO she is a dotty old bag with a big mouth and limited intelligence.She likes to TELL owners not advise and that shows arrogance.She doesnt have any qualifications but likes tp profess her experience, which if all goes wrong would leave her liable to prosecution as an expert.

How do you get your dogs to take Angel Eyes?

Lulu just won't eat it!

I think I am right in saying that Angel Eyes is no longer available in this country but if I'm wrong someone will correct me. You are probably referring to Angels Delight. This is sprinkled over the dogs food. I personally use the Angels Delight paste as Chloe can be a really fussy eater. I purchased it from The Bichon Hotel (link on the left of the forums) The paste is simply applied by using a small brush (a toothbrush is ideal) waiting for it to dry and then brushed out. It really is such a brilliant product and does exactly what it says it does.

Mix with some ardennes pate , mine eat it normally but have been the guinea pigs for the product and having a pack tends to improve eating habits.

when sprinkled on you need to mix with the food not leave on top because its main ingredient is sterilised bone meal and spirulina and they smell simple as. The dogs can smell that and think sod that !