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Tolerance Studies on Sulfaquinoxaline in Poultry
SULFAQUINOXALINE TOLERANCE
ACKNOWLEDGMENTS
The authors wish to express their appreciation to Mattox and Moore, Inc., Indianapolis, Indiana, for the diethylstil-
bestrol paste preparation used in this study. REFERENCES Akpinar, A. C , and C. S. Shaffner, 1953. Reproductive ability of chickens implanted at nine weeks of age with estrogen pellets. Poultry Sci. 32:119-122. Burrows, W. H., and H . W. Titus, 1939. Some observations on the semen production of the male fowl. Poultry Sci. 18:8-10. Hogue, R. L., and E. E. Schnetzler, 1937. Development of fertility in young Barred Plymouth Rock males. Poultry Sci. 16: 62-67. Jones, D. G., 1943. The relationships between development of the comb, body size, and reproductive capacity in White Leghorn males. Ph.D. Thesis submitted to Cornell University, Ithaca, N. Y., pp. 1-70. Kumaran, J. D. S., and C. W. Turner, 1949. The endocrinology of spermatogenesis in birds. I. Effect of estrogen and androgen. Poultry Sci. 28: 593-602. Nalbandov, A. V., and G. J. Baum, 1948. The use of stilbestrol inhibited males as test animals for gonadotropic hormones. Endocrinology, 43: 371379.
Tolerance Studies on Sulfaquinoxaline in Poultry ASHTON C. CUCKLER AND WALTHER H . OTT Merck Institute for Therapeutic Research, Rahway, New Jersey (Received for publication December 3, 1954)
S
ULFAQUINOXALINE has been widely and intensively used as an effective anticoccidial agent for poultry since its introduction in 1948. However, in spite of this wide acceptance, occasional reports have appeared which attribute intolerance to sulfaquinoxaline (Delaplane and Milliff, 1948; and Davies and Kendall, 1953). Because of the great diversity and variety of feeding and management practices with sulfaquinoxaline, we have studied a number of conditions and their effect on growth, survival, feed and water intake, hematological effects and sulfaquinoxaline plasma
concentrations in poultry. These studies, which are reported here, have shown that sulfaquinoxaline is well-tolerated by normal chickens, turkeys and ducks in amounts greatly exceeding the recommended and effective dosages. MATERIALS AND METHODS All birds used in these studies were obtained from commercial hatcheries when 1 day old. In most experiments the groups were initially balanced for number, weight, and sex. The birds in the laboratory experiments were kept in all-metal, wire-floored battery brooders. The ex-
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ent from the controls in regard to the three characters studied. The subduing effect of the paste treatment seemed to last approximately five weeks after which the incidence of fighting began to increase. The subcutaneous implantation of a pellet containing 12 mgs. of diethylstilbestrol lengthened the time necessary for males to reach maximum fertility. After reaching a plateau in fertility, the treated males were only slightly less fertile than the controls. The most noticeable effect of this treatment was the marked reduction in volume of semen. This reduction was of a greater magnitude than the reduction in fertility and was not accompanied by decreased testis size.
867
868
A . C . CUCKXER AND W . H . OxT TABLE 1.—Composition of open-formula chick and turkey rations Ration Chick Starters
Ingredients
L
%
58.38
— — —
30.0
— —
5.0
—
2.0
— — — —
2.0
—
1.5 0.5 0.02 0.4 0.2
— — — — — — *
%
Broiler C-3
%
42.7 5.0 11.25
57.5
— —
5.0 15.0 5.0 2.0 5.0
—
3.0 2.0 3.0
25.0 2.0 1.5 2.0 3.0
3.0 2.0 0.2
'—
— —
Turkey Starter C-4
%
21.48 5.0 14.0
—
35.0
—
—
8.0 3.0 3.0 3.0 2.0 3.0
— —
0.4
0.75
—
— —
1.0 1.0 0.25 0.019
1.5 0.25 0.019
1.5 0.25 0.019
— — —
— — —
— —
0.05 0.05
— — — —
—
0.05
0.15 0.1
—
0.1
— —
0.017 40 gm./ton
0.08
—
•
—
—
* The vitamin mixture for 1 kg. of ration L was as follows: 20 mg. niacin, 15 mg. calcium pantothenate, 5 mg. pyridoxine, 5 mg. riboflavin, 2.5 mg. thiamine, 0.5 mg. menadione, 0.125 mg. biotin and 0.05 mg. vitamin Bl2.
periments in floor pens were conducted under practical conditions in broiler houses with shredded cane as litter and allowing 1 square foot per bird. The water and feed were provided ad libitum. The rations used (Table 1) were an open-formula laboratory ration (L) composed of natural feed stuffs and supplemented with all known required vitamins, an open-formula commercial chick starter ration (C-1), a closed-formula commercial chick starter ration (C-2), and an open-formula broiler ration (C-3). Crystalline sulfaquinoxaline was thoroughly and evenly mixed into the ration when administered in the feed or sus-
pended in 10% gum acacia for individual oral dosing. Solutions of sulfaquinoxaline, buffered, or in excess sodium hydroxide, were used for administration of the drug in the drinking water. Blood clotting time was determined by quickly withdrawing 2 cc. of blood from the jugular vein with a syringe and placing 1 cc. amounts in serological tubes in a 40°C. water bath. The time required for complete clotting was recorded to the nearest 0.1 minute. The prothrombin determinations were performed by Mushett's (1954) modification of the original one-stage procedure of Quick (1938), employing acetone-dehydrated chicken
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Yellow corn meal Ground oats Ground wheat Wheat flour middlings Soybean oil meal Corn gluten meal Meat scrap Fish meal Homogenized cond. fish Alfalfa meal Brewers' dried yeast Dried whey product Dried corn dist. solubles Riboflavin supplement Steamed bonemeal Dicalcium phosphate Ground limestone Iodized salt Manganese sulfate Choline chloride (25% dry mix) Viadex (4,000A, 750 D/gm.) Vitamin A Oil (4,500 A/gm.) " D " Activated sterol (1,500 D/gm.) Vitamin Bi2 and antibiotic feed supplement (2 mg. B12, 3 gm. antibiotic/lb.) Antibiotic feed supplement (5 gm./lb.) Vitamin E supplement Niacin Vitamin mixture
C-1
869
SULFAQUINOXALINE TOLERANCE
TOLERANCE I N CHICKENS
Single Oral Doses. The acute effects of graded oral doses of sulfaquinoxaline were determined for 2-week-old White Leghorn cockerels fed ration C-2 and dosed individually with sulfaquinoxaline. In order to administer a larger dose than the suspension permitted, the crystalline sulfaquinoxaline was placed in gelatin capsules and given at a dosage of 10.5 gm./ kg. All chicks were sacrificed 2 weeks after dosage and the viscera were examined grossly for pathological lesions but none were found. The results in Table 2 indicate that sulfaquinoxaline in a single dose of 4 gm./kg. has no significant toxic or other effects on chickens. A dose of 10.5 gm./kg. produces an initial loss in weight and subsequent growth retardation and may cause some mortality. Repeated Oral Doses. Sulfaquinoxaline was administered once daily for 2 weeks to TABLE 2.—Effect of single oral doses of sulfaquinoxaline on 2-week-old White Leghorn chicks Mean bodj' weight in grams Dosage, gm./kg.
chicks
None 0.1 0.5 1.0 2.0 4.0 10.5
25 5 5 25 30 30 5
i Death on 5th day.
Initial
After 1 week
78 70 71 81 78 78 71
130 133 130 130 122 120 104
Percent mortalAfter ity 2 weeks 209 209 212 218 204 196 168
0 0 0 0 0 0 201
TABLE 3.—Effect of 14 daily oral doses of sulfaquinoxaline on 2-week-old White Leghorn chicks
Daily dosage, gm./kg.
Total dosage, gm./kg.
None 0.0062 0.025 0.1 0.4
None 0.06 0.27 1.4 5.6
No.
30 10 10 10 10
Mean body weight in grams Initial
After 1 week
After 2 weeks
128 121 126 126 121
203 196 210 195 191
281 257 271 295 273
Percent mortality 0 0 0 0 10'
i This bird was severely pecked.
determine the effect on 2-week-old White Leghorn cockerels fed ration C-2. The data in Table 3 indicate that repeated doses of 400 mg./kg. are non-toxic. Although 1 chick was severely pecked and died, this death was not considered as due to toxicity. These data demonstrate that sulfaquinoxaline is well-tolerated by young chicks when given in relatively large doses for 2 weeks. Oral Doses—Effect of Age. The effect of sulfquinoxaline on 2-week-old White Leghorn chicks and on Barred Rock pullets about 20 weeks of age was determined by administering 10 daily oral doses in a period of 2 weeks. From data summarized in Table 4, it is evident that young chicks and mature chickens tolerate sulfaquinoxaline equally satisfactorily. Although young pullets may show a slight loss in weight from administration of sulfaquinoxaline in a total dosage of 16 gm./kg., there was no evidence of gross pathological TABLE 4.—Comparative effect of sulfaquinoxaline on young and old chickens when administered orally in 10 daily doses during a 2-week period Age Daily Total in dosage, dosage, weeks gm./kg. gm./kg. 2 2 2 2 20 20 20
None 0.1 0.4 1.6 None 0.1 0.4 1.6
None •1.0 4.0 16.0 None 1.0 4.0 16.0
Mean body weight in grams Initial
After 1 week
After 2 weeks
No. dead/ total
102 102 102 102 1,633 1,643 1,473 1,655
182 176 178 174 1,817 1,673 1,760 1,600
253 244 232 235 1,958 1,782 1,788 1,597
0/5 0/5 0/5 1/5 0/3 0/3 0/3 0/3
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brain as the source of thromboplastin. Plasma was obtained by the centrifugation of blood taken in tubes containing a dry oxalate mixture (1.2 mg. ammonium oxalate plus 0.8 mg. potassium oxalate per cc. blood). The sulfaquinoxaline plasma concentrations were determined by the method described by Bratton and Marshall (1939). The blood samples were obtained from the jugular vein in 1 to 5 cc. quantities and pooled or assayed individually.
870
A . C . CUCKLER AND W . H . O T T TABLE 5 .—Effect of
continuous administration of isulfaquinoxaline '• in the feed for 2 to 3 weeks to 3-week-old New Hampshire chicks Mean body weight in ,grams
Percent in feed
1 2 3 Avg. 1 2 3 Avg. 1 2 3 Avg. 1 2 3 Avg. 1 2 3 Avg.
After 2 weeks
Initial 14
C-2
L
C-2
234 209 216 220 225 191 222 213 212 220 225 219 222 222 226 223 214 235 235 228
211 218 222 217 247 217 217 227 220 233 219 224 212 228 226 222 221 223 224 223
426 389 427 414 437 378 426 414 413 383 421 406 426 363 414 401 381 365 402 383
405 395 398 399 457 409 400 422 403 409 401 404 359 376 403 379 363 363 361 362
After 3 weeks
Percent rrlortaiity
C-2
L
C-2
—
—
552 556 554
555 541 548
0 0 0
0 0 0
0 0 0
0 0 5
—
0 0 0
0 10 0
—
0 0 0
0 0 0
—
0 0 0
0 0 5
L
—
541 517 529
—
534 563 548
—
500 513 506
—
519 541 530
—
•
570 530 550 557 526 542 530 536 533 512 469 490
* Expt. 1 and 2 had 10 chicks/group; expt. 3 had 20/group. f L=Laboratory ration; C-2 = commercial ration.
lesions in any of the visceral organs. Continuous Feeding for 3 Weeks. The short-term effect of sulfaquinoxaline on 3-week-old New Hampshire chicks was determined by feeding higher than recommended use concentrations for 2 to 3 weeks. Sulfaquinoxaline-medicated feeds, in graded levels from 0.025% to 0.2%, were prepared in the laboratory ration and in a commercial feed (C-2). The results are summarized in Table 5 and, except for slight growth retardation with 0.2% sulfaquinoxaline in the commercial ration, there is no other evidence of any adverse effects. A total of 3 chicks died and all were on the commercial ration. In the case of 2 of the birds, the deaths were probably due to pecking or cannibalism. In the other instance, the chick was in good physical condition and there was no gross pathology recognized. There were no indications of hemorrhages in the subcutaneous tissues, muscles or
viscera, or of other lesions described as occurring in "sulfonamide poisoning." Continuous Feeding of Excessive Levels for 4 Weeks. Three-week-old New Hampshire cockerels (mean weight 231 grams) were fed graded levels of 0.05% to 1.6% sulfaquinoxaline in three commercial rations for 4 weeks to observe the effect of excessively high levels of drug on the growth of the birds. Although feed intake at the highest dosage (1.6%) was reduced one-third, the total consumption of sulfaquinoxaline in the 4-week period was 15 to 17 grams per bird. The feed intake at the lowest dosage (0.05%) was essentially normal and provided 0.7 to 0.8 grams of sulfaquinoxaline per bird. The average weight was depressed about 30 grams each time the sulfaquinoxaline level was doubled beginning with 0.05% of the drug (Figure 1) and there were no indications of differences between the three rationSi These re-
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None None None None 0.025 0.025 0.025 0.025 0.05 0.05 0.05 0.05 0.1 0.1 0.1 0.1 0.2 0.2 0.2 0.2
Expt. No.*
871
SULFAQUINOXALINE TOLERANCE
co
1000
UJ UJ
900 -
CO
< cr o
700-
o UJ
5 z < u 2
600-
500
o Rotion C-l • Ration C-2 with arsenical x Ration C-2 with arsenical and a coccidiostot
•-As 025 •
•
0.05
0.1
0.2
0.4
0.8
1.6
PERCENT SULFAQUINOXALINE ADDED TO THE RATION FIG. 1. Effect of feeding excessive concentrations of sulfaquinoxaline to 3-week old New Hampshire cockerels for a period of 4 weeks. Each point represents the mean weight of a group of 5 chicks. The sloping solid line is the mean dosage-response curve for the graded levels of sulfaquinoxaline, and the broken lines represent the confidence limits at 0.01 probability.
suits indicate that the continuous feeding of 0.05% sulfaquinoxaline for 4 weeks is the minimal dosage having a barely detectable effect on growth. No evidence of hemorrhages was noted in the live birds during the test and when the chicks were autopsied at the end of the test only agonal hemorrhages were observed. All sulfaquinoxaline treated birds appeared normal except for size. One chick died after 2\ weeks on 0.1% and another died after 3J weeks on 1.6% sulfaquinoxaline. When autopsied some internal hemorrhages were found in the first bird, which had been trampled and peeked, but the other one appeared normal, except for being the smallest in the group. Continuous Administration in Feed or Water for 12 Weeks. Graded levels of sulfaquinoxaline were given continu-
ously in the feed or water to groups of 2-week-old White Leghorn cockerels until 14 weeks of age. The data summarized in Table 6 indicate that feeds medicated with 0.05% sulfaquinoxaline have no detrimental effect on growth of chickens when given for 12 weeks. Similarly, water medicated with 0.025% sulfaquinoxaline may be given to TABLE 6.—Effect of continuous administration of sulfaquinoxaline in feed or water to 2-weekold White Leghorn chicks for 1Z weeks % in feed or water None 0.025 in feed 0.05 in feed 0.1 in feed 0.2 in feed 0.4 in feed 0.0125 in water 0.025 in water 0.05 in water 0.1 in water
Mean body weight in grams PerNo. cent chickAfter After After morens Initial 4 12 8 tality weeks weeks weeks 70 10 20 30 20 20 10 10 20 10
112 123 85 113 120 120 123 98 110 98
538 525 479 386 436 361 569 497 447 228
1,045 1,501 1,063 1,570 1,023 1,554 836 1,219 888 1,310 775 1,145 1,050 1,360 1,053 1,507 949 1,351 910 604
0 0 0 0 10 10 0 0 10 10
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I
800-
872
A. C. CUCKLER AND W. H. OTT TABLE 7.—Comparison of continuous and, intermittent administration of sulfaguinoxaline solutions to 2-week-old White Leghorn chicks for a 15-day period
Percent in water None 0.025 0.02S 0.04 0.04
Schedule
Continuous Intermittent Continuous Intermittent
No. chicks
Mean dailyfluid consumption cc./chick
IS 10 10 10 10
44 43 42 32 42
Mean body weight in grams Initial
After 1 week
After 2 weeks
116 116 116 116 116
189 197 194 176 197
299 290 294 247 300
Percent mortality 0 0 0 0* 0
* One accidental death—chick badly pecked. indicate t h a t 0.025% sulfaquinoxaline administered continuously or intermittently in the water is highly palatable and has no adverse effects on growth or viability of young chicks. The recommended intermittent administration of 0.04% sulfaquinoxaline in the water likewise has no detectable adverse effects, although the continuous administration of 0.04% sulfaquinoxaline is somewhat unpalatable and retards growth slightly. Daily examinations revealed no evidence of hemorrhages. Intermittent Feeding for 3 Weeks in Floor Pens. Tolerance to intermittent feeding of sulfaquinoxaline was tested
TABLE 8.—Comparative effect of intermittent and continuous administration of 0.05% sulfaquinoxaline in the feed of New Hampshire chicks beginning at 3 weeks of age Schedule of administration Ration
None
Age in weeks Exp. 1
C-3 C-2 C-l
3 3 3
C-3 C-2 C-l C-3 C-2 C-l C-3 C-2 C-l
3 3 3 7-8* 7-8* 7-8* 9 9 9
195 166
Exp. 2 Number of Chicks 153
—
Exp. 1
Exp. 2
Exp. 1
293 170
307
115 74
154 Mean Body Weight in Pounds 0.50 0.45 0.48 0.42 0.44 — 0.45 — — 1.66(1.3) 1.90(0.7) 1.82(1.0)f 1.69(1.2) 1.65(0) — 1.47(0) — — 2.30(0.3) 2.33(0) 2.54(1.3) 2.17(0) 2.10(2.4) — 2.25(0) — —
—
Continuous
Intermittent
* Expt. 1--8 weeks; expt. 2--7 weeks. t Percent non-coccidial mortality is givenL in parenthesis.
—
•
—
155 0.47
—
0.48 1.61(2.0)
— 0.50 0.47
—
—
2.03(1.7) 1.95(1.4)
—
2.41(0.9) 2.34(0)
1.55(2.0) 2.38(1.3) 2.28(0.6)
—
—
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chickens for 12 weeks without deleterious effects. Higher dosages for this long period depress the growth rate of chickens and some mortality may occur. Comparison of Continuous and Intermittent Administration. T h e effect of sulfaquinoxaline ( 2 5 % sulfaquinoxaline solubilized powder) given continuously or intermittently in the drinking water (2 days on medication, 3 days off, followed by 2 days on, etc.) for 15 days was studied in 2-week-old White Leghorn cockerels. The fluid intake was recorded and fresh solutions were prepared daily. T h e results shown in Table 7 clearly
873
SULFAQUINOXALINE TOLERANCE
TABLE 10.—Effect of continuous administration of sulfaquinoxaline in the water to turkeys from 1 day to 10 weeks of age
TABLE 9.—Effect of continuous administration of sidfaquinoxaline to New Hampshire chicks from 1 day to 11 weeks of age Percent in feed
No. chicks
Mean body weight M ,. atllwks.,inlbs. M e e e a d n per Males Females
None 2,790 3.39 0.0125 1,395 3.42 0.025 1,395 3.40 Least difference between] means for significance a t [ 0 . 1 1
0.05 probability
2.64 2.67 2.67
J
IK iD
-
g„„;„ aln
Percent ?rtalltv
(noncoccidial)
3.47 3.45 3.38
2.8 2.9 2.5
0.12
1.2
Percent in water
No. poults
Initial
None 0.006 0.012 0.025
40 20 20 20
53 53 53 53
After After After 4 8 10 weeks weeks weeks 2,016 1,857 1,950 1,811
1,518 440 428 . 1,428 1,461 430 1,321 387
The results (Table 9) of these broiler trials show that 0.0125% and 0.025% sulfaquinoxaline-medicated rations do not interfere with growth, feed conversion and viability. TOLERANCE IN TURKEYS AND DUCKS
Continuous Administration to Turkeys. The effect of administering graded amount of sulfaquinoxaline in the water continuously to turkeys from 1 day to 10 weeks of age was determined. Approximately equal numbers of straight-run White Holland and Beltsville White turkeys were randomly distributed into groups of 20 each (2 groups of controls). The poults were fed a closed-formula commercial turkey starting mash to 6 weeks of age and a commercial turkey growing mash for the remainder of the experiment. The medicated solutions were prepared fresh daily (from 25% sulfaquinoxaline solubilized powder) and the
of continuous administration of sulfaquinoxaline in the water to turkeys from 1 day to 10 weeks of age Mean daily consumption/poult
Percent in water
None 0.006 0.012 0.025
No. poults
40 20 20 20
4th week Feed, g-
Water, cc.
13 14 14 12
50 51 54 46
8th week
10th week
Feed, g-
Water, cc.
Feed, g-
Water, cc.
Feed, g-
Water, cc.
55 52 55 55
172 148 161 114
116 118 HI 114
332 349 275 289
134 122 130 125
369 279 312 263
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with straight run New Hampshire chicks reared from 1 day to 9 weeks of age. The medication was begun at 3 weeks of age with the schedule of intermittent feeding being 0.05% sulfaquinoxaline in the feed for 3 days followed by 2 days on nonmedicated feed, and this schedule was repeated 6 times. No disease outbreak nor unusual mortality occurred during these experiments and there was no detrimental effect on growth from the intermittent feeding of 0.05% sulfaquinoxaline in the ration (Table 8). These results show that this intermittent feeding of sulfaquinoxaline is well-tolerated for a period of 4 to 5 weeks. Continuous Feeding for 11 Weeks in Floor Pens. Sulfaquinoxaline was fed continuously at 0.0125% and 0.025% in the ration (C-1) of straight run New Hampshire chicks from 1 day to 11 weeks of age. Two control groups and the 2 levels of sulfaquinoxaline were replicated in a total of 9 experiments started at intervals of 3 to 9 weeks throughout 1 year. TABLE 11.—Effect
Mean body weight in grams
m
874
A . C . CUCKXER AND W . H . OTT TABLE 12.—Effect
% Sulfaquinoxahne m water
N o
. f««'«>
Age in weeks
consump^ ^ o n ^ J r poult
Mean body weight in grams Iw+;„i mtml
After 1 week
Af ter 2 weeks
FV^A eed
g-
>
Water, cc.
6 6 6 10 10
944 848 892 1,666 1,689
1,204 1,067 1,043 1,780 1,862
1,538 1,360 1,423 2,074 2,120
113 107 110 132 136
299 252 266 334 285
6 6
813 800
1,087 1,036
1,321 1,297
108 114
257 237
unused portions were measured and discarded. The data in Table 10 indicate that 0.025% sulfaquinoxaline slightly retarded the growth of turkeys while 0.006% and 0.012% sulfaquinoxaline had little, if any, effect. The feed and water consumption records (Table 11) indicate that the sulfaquinoxaline treated turkeys eat as much feed, but none drink as much water, as the unmedicated controls. Intermittent Administration to Turkeys. The effect of intermittent administration of sulfaquinoxaline solutions on the growth of young turkeys was determined. The studies were conducted in 6- and 10week-old turkeys in approximately balanced groups composed of mixed sexes and equal numbers of White Holland and Beltsville White varieties. The sulfaquinoxaline (25% sulfaquinoxaline solubilized powder) solutions were given at 0.025% and 0.04% concentrations on an intermittent schedule of 2 or 3 days on the medicated solution followed by 3 days administration of water, etc., for a period of 15 days. The fluid consumption was determined and the unused portions were discarded. The data in Table 12 indicate that intermittent administration of 0.025% and 0.04% sulfaquinoxaline solutions does not adversely affect the growth of young tur-
keys. These dosages of sulfaquinoxaline do not cause any toxic manifestations during or after administration. The feed consumption is not affected although the fluid intake is decreased during the administration of the medicated solutions. Continuous Feeding for 11 Weeks to Turkeys in Floor Pens. Sulfaquinoxaline was fed continuously at 0.005% to 0.02% in an open-formula turkey starting ration (C-4) to Bronze and White Holland turkey poults from 1 day t o l l weeks of age. Two experiments were conducted with 90 poults in each pen. The results in Table 13 show that turkeys tolerate these levels of sulfaquinoxaline in the feed without noticeable effect on body weight, feed efficiency or viabilityContinuous Administration to Ducks. The effect of feeding sulfaquinoxaline to White Pekin ducklings was determined. TABLE 13.—Effect of continuous administration of sulfaquinoxaline to turkey poults from 1 day to 11 weeks of age Percent in feed
No. poults
Mean body w „ _15n . Percent weight at fjff-"! ,!; mortality rlb 11 weeks, f e e gd „K ' (nonam in lbs. coccidial)
None 360 0.005 270 0.010 270 0.015 270 0.020 270 Least difference between) means for significance a t [ 0.05 probability J
5.86 5.92 5.85 5.88 5.79
2.60 2.64 2.61 2.64 2.62
2.8 3.0 3.7 4.4 1.5
0.26
0.05
3.1
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Schedule: 2—3—2—3—2--3 None 39 0.025 14 0.04 14 None 5 0.025 5 Schedule: 3—3—3—3—3 0.025 14 0.04 14
of intermittent administration 0} sulfaquinoxaline to young turkeys
875
SULFAQUINOXALINE TOLERANCE TABLE 14.—Effect of continuous administration of sulfaquinoxaline to 2-week-old Pekin ducks
TABLE 16.—Effect of continuous administration of sulfaquinoxaline for 3-13 weeks on plasma prothrombin times in chickens
Mean body weight in grams Percent in feed
15 ducks/group — Initial After 5 Weeks
None 0.0125 0.025 0.05 0.1
1,838 1,929 1,891 1,801 1,781
344 344 343 343 340
%
8 ducks/group After 5 weeks
After 9 weeks
1,853 1,913 1,866 1,792 1,762
2,495 2,460 2,548 2,507 2,390
TABLE 15.—Effect % sulfaquinoxaline
Ration
Plasma prothrombin times—Seconds time3—Seconds Mean
Range
None 0.1 0.2
5 5 10
5 5 5
14 17 18
13-15 15-22 14-24
None 0.1 0.4
10 10 10
5 5 5
11 12 23
9-12 10-15 14-31
None 0.1
10 10
9 9
11 15
9-12 12-19
None 0.4
10 10
10 10
15 17
13-18 14-22
10 20 16 18
15 15 14 14
16 13 15 21
14-18 10-17 10-28 15-28
None 0.1 0.2 0.4
13 12 12
verse effects on the growth of ducks. There was no mortality attributable to sulfaquinoxaline. The data suggest that
of sulfaquinoxaline medication: on whole blood cloth'ng times in chickens
Schedule
No. weeks adm.
No. chicks
Age in weeks
Clotting time—Minutes Mean
Range
None 0.025—water 0.04 —water 0.025—water
L L L L
Intermittent Intermittent Continuous
2 2 2 2
15 10 10 10
4 4 4 4
6.2* 5.7* 4 2* 7 >
3.33.12.02.5-
8.6 10.0 8.0 23.0
None 0.025—feed 0.2 —feed
L L L
Continuous Continuous
3 3 3
10 10 10
6 6 6
4.8 4.3 5.3
3.42.72.9-
6.4 6.8 7.9
None 0.025—feed 0.2 —feed
C-l C-l C-l
Continuous Continuous
3 3 3
10 10 10
6 6 6
4.9 4.1 6.0
2.72.24.0-
5.7 5.8 9.4
None—feed 0.025—feed 0.1 —feed 0.4 —feed
C-2 C-2 C-2 C-2
Continuous Continuous Continuous
3 3 3 3
20 10 10 10
6 6 6 6
4.7 4.4 3.9 >25.4
None—feed 0.1 —feed 0.04 —water
C-2 C-2 C-2
Continuous Continuous
2 2 2
10 10 10
8 8 8
3.6 3.9 4.0
1.92.02.5-
4.9 8.7 5.2
None 0.015—feed
C-2 C-2
Continuous
11 11
20 10
11 11
5.1 5.5
3.23.5-
8.5 8.5
2.38.8 2.85.6 1.95.2 4.3->30.0
* These clotting times were determined at room temperature (approx. 25°C.) instead of 40°C.
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The ducks were fed a commercial starting ration until 2 weeks of age, at which time groups of 15 ducklings were given the sulfaquinoxaline medicated feed or only the basal feed. At the end of the 5th week, the number of ducks in each group was reduced from 15 to 8 by retaining alternate band-numbered animals. The results given in Table 14 indicate that sulfaquinoxaline in concentrations of 0.0125% to 0.1% has no detectable ad-
sulfaNo. j ^ Age quinoxa- weeks •, • V in cmcKS line in adm. weeks feed (C-l)
876
A. C. CUCKLER AND W. H. OTT
TABLE 17.—Concentrations of sulfaquinoxaline in plasma of chickens after 3 to 13 weeks administration of medicated feed or water
%
uinoxaline
Schedule
No. weeks adm.
No. chicks
Age in weeks
Sulfaquinoxaline plasma concentration, mg. % Mean
Range
—'
Continuous Continuous Continuous
3 6 12
5 5 5
5 8 14
3.2 1.6 1.6
0.025 in feed 0.025 in feed 0.025 in feed
Continuous Contmuous Continuous
3 6 12
5 5 5
5 8 14
4.5 2.2 2.6
—1
0.05 0.05 0.05
in feed in feed in feed
Continuous Continuous Continuous
3 6 9
5 10 6
4 7 10
4.3 5.0 3.5
Ei
0.05 0.05 0.05
in feed in feed in feed
Intermittent Intermittent Intermittent
3 6 9
5 10 6
4 7 10
3.5 3.2 4.0
—'
0.05 0.05 0.05
in water in water in water
Continuous Continuous Continuous
3 6 12
5 5 5
5 8 14
14.2 8.4 12.3
0.1 0.1 0.1 0.1 0.1
in in in in in
Continuous Continuous Continuous Continuous Continuous
3 6 9 12 13
20 10 6 5 20
5 8 11 14 15
9.8 10.6 10.1 11.4 9.4
8.0-12.9
0.1 0.1 0.1
in feed in feed in feed
Intermittent Intermittent Intermittent
3 6 9
5 10 6
4 7 10
6.2 7.3 7.4
—1
0.2 0.2 0.2
in water in water in feed
Continuous Continuous Continuous
3 6 12
5 5 18
5 8 14
45.6 38.2 18.1
12.1-21.2
0.4 0.4 0.4
in feed in feed in feed
Continuous Continuous Continuous
3 8 12
10 9 18
5 10 14
18.9 22.6 21.0
15.2-23.1 19.0-26.5 13.4-24.5
feed feed feed feed feed
—>
6.5-13.6 2
1 2
Pooled sample. The values were 0.3-4.2 (1.3) and 0-1.8 (0.3) 48 and 72 hours, respectively, after withdrawal of medicated feed.
0.0125% to 0.1% sulfaquinoxaline-medicated feeds might be used safely for the control of diseases in ducks caused by sulfaquinoxaline-sensitive organisms. HEMATOLOGICAL EFFECTS
Effect on Blood Clotting. Studies were performed on the effect of various dosages of sulfaquinoxaline on the whole blood clotting times of chickens. The sulfaquinoxaline was administered in the feed
or water to groups of 10 to 20 White Leghorn or New Hampshire chickens for 2 to 11 weeks. The data summarized in Table 15 demonstrate that sulfaquinoxaline may be given continuously for 2 or 3 weeks in a cencentration of 0.2% without effect on whole blood clotting times. The recommended continuous use concentration of 0.015% may be given for 11 weeks without having effect on blood clotting time
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0.0125 in water 0.0125 in water 0.0125 in water
877
SULFAQTJINOXALINE TOLERANCE
TABLE 18—Concentrations of sulfaquinoxaline in plasma, of turkeys and ducks after 2 to 10 weeks administration of medicated feed or water
Animal
%
No. animals
Age in weeks
Sulfaquinoxaline plasma concentration, mg. %
sulfaquinoxaline
Schedule
No. weeks adm.
in in in in in
Continuous Continuous Continuous Intermittent Intermittent
10 10 10 2 2
10 10 10 7 7
10 10 10 8 8
1.2 2.7 6.4 4.6* 3.7
water water water water water
0.006 0.012 0.02S 0.025 0.04
Duck Duck Duck
0.0125> in feed 0.0125 in feed 0.0125> in feed
Continuous Continuous Continuous
3 7 9
15 8 8
5 9 11
0.6 0.3 0.4
Duck Duck Duck
0.025 in feed 0.025 in feed 0.025 in feed
Continuous Continuous Continuous
3 7 9
15 8 8
5 9 11
2.0 1.0 0.9
Duck Duck Duck
0.05 0.05 0.05
in feed in feed in feed
Continuous Continuous Continuous
3 7 9
15 8 8
5 9 11
4.0 "^ 2.7 3.3
Duck Duck Duck
0.1 0.1 0.1
in feed in feed in feed
Continuous Continuous Continuous
3 7 9
15 8 8
5 9 11
7.4 5.3 4.8
* The values were 3.1, 2.6 and 0.4 mg. % 24, 48 and 72 hours, respectively, after withdrawal of medicated water.
while administration of 0.4% sulfaquinoxaline for 3 weeks will produce prolonged clotting times. Effect on Plasma Prothrombin Time. Similar studies have been conducted on the effect of sulfaquinoxaline on the plasma prothrombin times in White Leghorn chickens. The results summarized in Table 16 indicate that sulfaquinoxaline may be fed continuously for 3 to 13 weeks in a concentration of 0.2% without having detectable effect on plasma prothrombin times. However, a concentration of 0.4% sulfaquinoxaline in the feed will produce a slight prolongation of prothrombin clotting times when fed for 3 to 12 weeks. Sulfaquinoxaline Concentrations in Plasma. The results obtained from the analysis of the plasma of chickens, turkeys and ducks for sulfaquinoxaline at various intervals and dosages have been summarized in Tables 17 to 18.
The data indicate that about twice as much sulfaquinoxaline is required in the feed as in the water to obtain a comparable plasma concentration. There is no indication that sulfaquinoxaline accumulates in the blood with continued longterm administration. Furthermore, the plasma concentrations are of similar order of magnitude for the same dosages administered continuously or intermittently. Although turkeys seem to absorb sulfaquinoxaline equally as well as chickens and have similar concentrations in plasma, ducks given the same dosages in the feed do not have plasma concentrations as high as chickens. DISCUSSION Extensive data have been presented on the effect of sulfaquinoxaline on normal poultry. The results have demonstrated that single oral doses of 4 gm./kg. are well-
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Turkey Turkey Turkey Turkey Turkey
878
<
A. C. CUCKLER AND W. H. OXT
0.025% sulfaquinoxaline solution to turkeys retards the growth slightly, but there is no mortality or other adverse effects. Sulfaquinoxaline medicated solutions are less palatable than water and this may be the cause of growth retardation. However, the intermittent administration of 0.04% sulfaquinoxaline in the water has no effect on growth of young turkeys. Likewise, the continuous use of 0.005% to 0.02% sulfaquinoxaline in the feed has been well-tolerated and there are no adverse effects on growth, feed conversion or viability. Ducks tolerate up to 0.1% sulfaquinoxaline in the feed for 9 weeks without growth retardation or mortality. Since sulfonamides and other anticoccidial agents have been considered as possible factors in hemorrhagic conditions in chickens, studies were conducted to determine the effect of sulfaquinoxaline medication on the whole blood clotting and prothrombin times. The intermittent or continuous administration of 0.025% and 0.04% sulfaquinoxaline solutions for 2 to 3 weeks does not alter the clotting times of chicken blood. The feeding of 0.1% and 0.2% sulfaquinoxaline in the ration for 2 to 3 weeks or 0.015% for 11 weeks also has no detectable effect on blood clotting. However, the administration of 0.4% sulfaquinoxaline continuously for 3 weeks greatly increased the clotting time. Studies on the prothrombin times of chicken blood have indicated that 0.1% and 0.2% sulfaquinoxaline-medicated feeds have not affected this component of the blood clotting system of chickens. The determinations on blood from chickens fed 0.4% sulfaquinoxaline for 3 to 12 weeks indicated a slight prolongation of prothrombin times. These observations, therefore, tend to confirm the effect noted on whole blood clotting by 0.4% sulfaquinoxaline, a concentration greatly in ex-
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tolerated by chickens. Even an extremely large and almost practically impossible dose of 10.5 gm./kg. has only slight growth-retarding effect. Furthermore, the data indicate that chickens satisfactorily tolerate repeated daily administration of sulfaquinoxaline in a total dosage of 4 to 16 gm./kg. during a period of 2 weeks. Under these conditions of administration, there are no significant differences in the response of young chicks and mature hens to sulfaquinoxaline. When sulfaquinoxaline is fed to chickens for relatively short periods in dosages which are as high as 64 times the recommended concentration for use under severe conditions, the only significant effect observed is the retardation of growth. There is no evidence that variations in feeds have an effect since the chickens responded similarly when fed 4 different rations. The chickens were observed for indications of so-called "sulfonamide poisoning," i.e., hemorrhages beneath the skin, in the muscles, fluid in the peritoneal cavity, etc., but none were found. However, small agonal hemorrhages were seen in the birds at autopsy, and these occurred as frequently and as abundantly in the nonmedicated controls as in the sulfaquinoxaline-treated chickens. The continuous administration of 0.05% sulfaquinoxaline in the feed or of 0.025% in water for as long as 12 weeks had no adverse effects on chickens. Similarly, there was no evidence that the intermittent administration of sulfaquinoxaline at 0.05% in the feed or at 0.025% in the water for 2 to 5 weeks has any deleterious effects. The recommended intermittent administration of 0.04% sulfaquinoxaline in the water is tolerated satisfactorily, but the continuous administration of this dosage has a growth retarding effect. The continuous administration of
879
NEWS AND NOTES
cess of that commercially recommended. Analyses of the blood of chickens, turkeys and ducks given sulfaquinoxaline have indicated that chickens and turkeys have comparable plasma concentrations, while ducks maintain lower blood concentrations after receiving similar dosages. There is no suggestion that the drug accumulates in the blood after long-term administration.
The results have been presented of extensive studies on the effect of sulfaquinoxaline medication on normal chickens, turkeys and ducks. The data demonstrate that under both battery- and penrearing conditions sulfaquinoxaline is extremely well-tolerated by poultry. When up to 64 times the recommended use concentration of sulfaquinoxaline is fed to young chickens, the only significant effect is retardation of growth. Comparative studies with 4 different poultry rations have indicated that these sulfaquinoxaline medicated feeds are equally well-tolerated by chickens. There was no evidence of
REFERENCES Bratton, A. C , and E. K. Marshall, Jr., 1939. A new coupling component for sulfanilamide determination. J. Biol. Chem. 128: 537-550. Davies, S. F. M., and S. B. Kendall, 1953. Toxicity of sulphaquinoxaline (2-sulphanilamidoquinoxaline) for chickens. Vet. Rec. 65: 85-88. Delaplane, J. P., and J. H. Milliff, 1948. The grossand micropathology of sulfaquinoxaline poisoning in chickens. Am. J. Vet. Res. 9:92-96. Mushett, C. W., 1954. Personal communication. Quick, A. J., 1938. The nature of the bleeding in jaundice. J. Am. Med. Assoc. 110: 1658-1662.
NEWS AND NOTES {Continued from page 850) husbandry, genetics, nutrition, pathology and physiology. He explored and developed the multiple testing procedure for controlling pullorum disease. He helped to organize the North Carolina Hatchery Association and the North Carolina Poultry Council. Recognizing his services to them, the Hatchery Association presented a portrait of him to the College. It hangs in Scott Hall. He has served on the Southern States Cooperative College Feed Conference Board, and as a representative to the American Feed Manufacturers Association. He is a member of the Poultry Science Association, having been an Associate Editor of Poultry Science from 1933 to 1936, the American Association for the Advancement of Science, Sigma Xi, Phi Kappa Phi, and an Associate member of Alpha Zeta.
Dr. Edward W. Glazener succeeds Professor Dearstyne as Head of the Department. He was born in Raleigh in 1922 and graduated from Brevard Junior College in 1941. In 1943 he obtained a B.S. degree at North Carolina State College, a M.S. degree, specializing in genetics and physiology, in 1945 at the University of Maryland, and a Ph.D. degree at that University in 1949, specializing in genetics. He was Assistant County Agent in Chatham County in 1944, Assistant Professor of Genetics in the Poultry Department of the University of Maryland in 1945, and was appointed Associate Professor of Poultry Genetics at North Carolina State College in 1946, becoming Professor in 1949. Dr. Glazener was the research leader in develop-
{Continued on page 890)
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SUMMARY
"sulfonamide poisoning," but agonal hemorrhages were found as frequently in control as in sulfaquinoxaline-medicated chickens. Excessive dosage (0.4%) of sulfaquinoxaline was required to produce a prolongation in blood clotting time, but this dosage produced only a slight increase in prothrombin time. Under the conditions of our studies, gross pathological effects were not found. Turkeys and ducks appear to tolerate sulfaquinoxaline equally as well as chickens. Studies on plasma concentrations indicate that sulfaquinoxaline does not accumulate in the blood after long-continued administration.
ACKNOWLEDGMENTS
The authors wish to express their appreciation to Mattox and Moore, Inc., Indianapolis, Indiana, for the diethylstil-
bestrol paste preparation used in this study. REFERENCES Akpinar, A. C , and C. S. Shaffner, 1953. Reproductive ability of chickens implanted at nine weeks of age with estrogen pellets. Poultry Sci. 32:119-122. Burrows, W. H., and H . W. Titus, 1939. Some observations on the semen production of the male fowl. Poultry Sci. 18:8-10. Hogue, R. L., and E. E. Schnetzler, 1937. Development of fertility in young Barred Plymouth Rock males. Poultry Sci. 16: 62-67. Jones, D. G., 1943. The relationships between development of the comb, body size, and reproductive capacity in White Leghorn males. Ph.D. Thesis submitted to Cornell University, Ithaca, N. Y., pp. 1-70. Kumaran, J. D. S., and C. W. Turner, 1949. The endocrinology of spermatogenesis in birds. I. Effect of estrogen and androgen. Poultry Sci. 28: 593-602. Nalbandov, A. V., and G. J. Baum, 1948. The use of stilbestrol inhibited males as test animals for gonadotropic hormones. Endocrinology, 43: 371379.
Tolerance Studies on Sulfaquinoxaline in Poultry ASHTON C. CUCKLER AND WALTHER H . OTT Merck Institute for Therapeutic Research, Rahway, New Jersey (Received for publication December 3, 1954)
S
ULFAQUINOXALINE has been widely and intensively used as an effective anticoccidial agent for poultry since its introduction in 1948. However, in spite of this wide acceptance, occasional reports have appeared which attribute intolerance to sulfaquinoxaline (Delaplane and Milliff, 1948; and Davies and Kendall, 1953). Because of the great diversity and variety of feeding and management practices with sulfaquinoxaline, we have studied a number of conditions and their effect on growth, survival, feed and water intake, hematological effects and sulfaquinoxaline plasma
concentrations in poultry. These studies, which are reported here, have shown that sulfaquinoxaline is well-tolerated by normal chickens, turkeys and ducks in amounts greatly exceeding the recommended and effective dosages. MATERIALS AND METHODS All birds used in these studies were obtained from commercial hatcheries when 1 day old. In most experiments the groups were initially balanced for number, weight, and sex. The birds in the laboratory experiments were kept in all-metal, wire-floored battery brooders. The ex-
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ent from the controls in regard to the three characters studied. The subduing effect of the paste treatment seemed to last approximately five weeks after which the incidence of fighting began to increase. The subcutaneous implantation of a pellet containing 12 mgs. of diethylstilbestrol lengthened the time necessary for males to reach maximum fertility. After reaching a plateau in fertility, the treated males were only slightly less fertile than the controls. The most noticeable effect of this treatment was the marked reduction in volume of semen. This reduction was of a greater magnitude than the reduction in fertility and was not accompanied by decreased testis size.
867
868
A . C . CUCKXER AND W . H . OxT TABLE 1.—Composition of open-formula chick and turkey rations Ration Chick Starters
Ingredients
L
%
58.38
— — —
30.0
— —
5.0
—
2.0
— — — —
2.0
—
1.5 0.5 0.02 0.4 0.2
— — — — — — *
%
Broiler C-3
%
42.7 5.0 11.25
57.5
— —
5.0 15.0 5.0 2.0 5.0
—
3.0 2.0 3.0
25.0 2.0 1.5 2.0 3.0
3.0 2.0 0.2
'—
— —
Turkey Starter C-4
%
21.48 5.0 14.0
—
35.0
—
—
8.0 3.0 3.0 3.0 2.0 3.0
— —
0.4
0.75
—
— —
1.0 1.0 0.25 0.019
1.5 0.25 0.019
1.5 0.25 0.019
— — —
— — —
— —
0.05 0.05
— — — —
—
0.05
0.15 0.1
—
0.1
— —
0.017 40 gm./ton
0.08
—
•
—
—
* The vitamin mixture for 1 kg. of ration L was as follows: 20 mg. niacin, 15 mg. calcium pantothenate, 5 mg. pyridoxine, 5 mg. riboflavin, 2.5 mg. thiamine, 0.5 mg. menadione, 0.125 mg. biotin and 0.05 mg. vitamin Bl2.
periments in floor pens were conducted under practical conditions in broiler houses with shredded cane as litter and allowing 1 square foot per bird. The water and feed were provided ad libitum. The rations used (Table 1) were an open-formula laboratory ration (L) composed of natural feed stuffs and supplemented with all known required vitamins, an open-formula commercial chick starter ration (C-1), a closed-formula commercial chick starter ration (C-2), and an open-formula broiler ration (C-3). Crystalline sulfaquinoxaline was thoroughly and evenly mixed into the ration when administered in the feed or sus-
pended in 10% gum acacia for individual oral dosing. Solutions of sulfaquinoxaline, buffered, or in excess sodium hydroxide, were used for administration of the drug in the drinking water. Blood clotting time was determined by quickly withdrawing 2 cc. of blood from the jugular vein with a syringe and placing 1 cc. amounts in serological tubes in a 40°C. water bath. The time required for complete clotting was recorded to the nearest 0.1 minute. The prothrombin determinations were performed by Mushett's (1954) modification of the original one-stage procedure of Quick (1938), employing acetone-dehydrated chicken
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Yellow corn meal Ground oats Ground wheat Wheat flour middlings Soybean oil meal Corn gluten meal Meat scrap Fish meal Homogenized cond. fish Alfalfa meal Brewers' dried yeast Dried whey product Dried corn dist. solubles Riboflavin supplement Steamed bonemeal Dicalcium phosphate Ground limestone Iodized salt Manganese sulfate Choline chloride (25% dry mix) Viadex (4,000A, 750 D/gm.) Vitamin A Oil (4,500 A/gm.) " D " Activated sterol (1,500 D/gm.) Vitamin Bi2 and antibiotic feed supplement (2 mg. B12, 3 gm. antibiotic/lb.) Antibiotic feed supplement (5 gm./lb.) Vitamin E supplement Niacin Vitamin mixture
C-1
869
SULFAQUINOXALINE TOLERANCE
TOLERANCE I N CHICKENS
Single Oral Doses. The acute effects of graded oral doses of sulfaquinoxaline were determined for 2-week-old White Leghorn cockerels fed ration C-2 and dosed individually with sulfaquinoxaline. In order to administer a larger dose than the suspension permitted, the crystalline sulfaquinoxaline was placed in gelatin capsules and given at a dosage of 10.5 gm./ kg. All chicks were sacrificed 2 weeks after dosage and the viscera were examined grossly for pathological lesions but none were found. The results in Table 2 indicate that sulfaquinoxaline in a single dose of 4 gm./kg. has no significant toxic or other effects on chickens. A dose of 10.5 gm./kg. produces an initial loss in weight and subsequent growth retardation and may cause some mortality. Repeated Oral Doses. Sulfaquinoxaline was administered once daily for 2 weeks to TABLE 2.—Effect of single oral doses of sulfaquinoxaline on 2-week-old White Leghorn chicks Mean bodj' weight in grams Dosage, gm./kg.
chicks
None 0.1 0.5 1.0 2.0 4.0 10.5
25 5 5 25 30 30 5
i Death on 5th day.
Initial
After 1 week
78 70 71 81 78 78 71
130 133 130 130 122 120 104
Percent mortalAfter ity 2 weeks 209 209 212 218 204 196 168
0 0 0 0 0 0 201
TABLE 3.—Effect of 14 daily oral doses of sulfaquinoxaline on 2-week-old White Leghorn chicks
Daily dosage, gm./kg.
Total dosage, gm./kg.
None 0.0062 0.025 0.1 0.4
None 0.06 0.27 1.4 5.6
No.
30 10 10 10 10
Mean body weight in grams Initial
After 1 week
After 2 weeks
128 121 126 126 121
203 196 210 195 191
281 257 271 295 273
Percent mortality 0 0 0 0 10'
i This bird was severely pecked.
determine the effect on 2-week-old White Leghorn cockerels fed ration C-2. The data in Table 3 indicate that repeated doses of 400 mg./kg. are non-toxic. Although 1 chick was severely pecked and died, this death was not considered as due to toxicity. These data demonstrate that sulfaquinoxaline is well-tolerated by young chicks when given in relatively large doses for 2 weeks. Oral Doses—Effect of Age. The effect of sulfquinoxaline on 2-week-old White Leghorn chicks and on Barred Rock pullets about 20 weeks of age was determined by administering 10 daily oral doses in a period of 2 weeks. From data summarized in Table 4, it is evident that young chicks and mature chickens tolerate sulfaquinoxaline equally satisfactorily. Although young pullets may show a slight loss in weight from administration of sulfaquinoxaline in a total dosage of 16 gm./kg., there was no evidence of gross pathological TABLE 4.—Comparative effect of sulfaquinoxaline on young and old chickens when administered orally in 10 daily doses during a 2-week period Age Daily Total in dosage, dosage, weeks gm./kg. gm./kg. 2 2 2 2 20 20 20
None 0.1 0.4 1.6 None 0.1 0.4 1.6
None •1.0 4.0 16.0 None 1.0 4.0 16.0
Mean body weight in grams Initial
After 1 week
After 2 weeks
No. dead/ total
102 102 102 102 1,633 1,643 1,473 1,655
182 176 178 174 1,817 1,673 1,760 1,600
253 244 232 235 1,958 1,782 1,788 1,597
0/5 0/5 0/5 1/5 0/3 0/3 0/3 0/3
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brain as the source of thromboplastin. Plasma was obtained by the centrifugation of blood taken in tubes containing a dry oxalate mixture (1.2 mg. ammonium oxalate plus 0.8 mg. potassium oxalate per cc. blood). The sulfaquinoxaline plasma concentrations were determined by the method described by Bratton and Marshall (1939). The blood samples were obtained from the jugular vein in 1 to 5 cc. quantities and pooled or assayed individually.
870
A . C . CUCKLER AND W . H . O T T TABLE 5 .—Effect of
continuous administration of isulfaquinoxaline '• in the feed for 2 to 3 weeks to 3-week-old New Hampshire chicks Mean body weight in ,grams
Percent in feed
1 2 3 Avg. 1 2 3 Avg. 1 2 3 Avg. 1 2 3 Avg. 1 2 3 Avg.
After 2 weeks
Initial 14
C-2
L
C-2
234 209 216 220 225 191 222 213 212 220 225 219 222 222 226 223 214 235 235 228
211 218 222 217 247 217 217 227 220 233 219 224 212 228 226 222 221 223 224 223
426 389 427 414 437 378 426 414 413 383 421 406 426 363 414 401 381 365 402 383
405 395 398 399 457 409 400 422 403 409 401 404 359 376 403 379 363 363 361 362
After 3 weeks
Percent rrlortaiity
C-2
L
C-2
—
—
552 556 554
555 541 548
0 0 0
0 0 0
0 0 0
0 0 5
—
0 0 0
0 10 0
—
0 0 0
0 0 0
—
0 0 0
0 0 5
L
—
541 517 529
—
534 563 548
—
500 513 506
—
519 541 530
—
•
570 530 550 557 526 542 530 536 533 512 469 490
* Expt. 1 and 2 had 10 chicks/group; expt. 3 had 20/group. f L=Laboratory ration; C-2 = commercial ration.
lesions in any of the visceral organs. Continuous Feeding for 3 Weeks. The short-term effect of sulfaquinoxaline on 3-week-old New Hampshire chicks was determined by feeding higher than recommended use concentrations for 2 to 3 weeks. Sulfaquinoxaline-medicated feeds, in graded levels from 0.025% to 0.2%, were prepared in the laboratory ration and in a commercial feed (C-2). The results are summarized in Table 5 and, except for slight growth retardation with 0.2% sulfaquinoxaline in the commercial ration, there is no other evidence of any adverse effects. A total of 3 chicks died and all were on the commercial ration. In the case of 2 of the birds, the deaths were probably due to pecking or cannibalism. In the other instance, the chick was in good physical condition and there was no gross pathology recognized. There were no indications of hemorrhages in the subcutaneous tissues, muscles or
viscera, or of other lesions described as occurring in "sulfonamide poisoning." Continuous Feeding of Excessive Levels for 4 Weeks. Three-week-old New Hampshire cockerels (mean weight 231 grams) were fed graded levels of 0.05% to 1.6% sulfaquinoxaline in three commercial rations for 4 weeks to observe the effect of excessively high levels of drug on the growth of the birds. Although feed intake at the highest dosage (1.6%) was reduced one-third, the total consumption of sulfaquinoxaline in the 4-week period was 15 to 17 grams per bird. The feed intake at the lowest dosage (0.05%) was essentially normal and provided 0.7 to 0.8 grams of sulfaquinoxaline per bird. The average weight was depressed about 30 grams each time the sulfaquinoxaline level was doubled beginning with 0.05% of the drug (Figure 1) and there were no indications of differences between the three rationSi These re-
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None None None None 0.025 0.025 0.025 0.025 0.05 0.05 0.05 0.05 0.1 0.1 0.1 0.1 0.2 0.2 0.2 0.2
Expt. No.*
871
SULFAQUINOXALINE TOLERANCE
co
1000
UJ UJ
900 -
CO
< cr o
700-
o UJ
5 z < u 2
600-
500
o Rotion C-l • Ration C-2 with arsenical x Ration C-2 with arsenical and a coccidiostot
•-As 025 •
•
0.05
0.1
0.2
0.4
0.8
1.6
PERCENT SULFAQUINOXALINE ADDED TO THE RATION FIG. 1. Effect of feeding excessive concentrations of sulfaquinoxaline to 3-week old New Hampshire cockerels for a period of 4 weeks. Each point represents the mean weight of a group of 5 chicks. The sloping solid line is the mean dosage-response curve for the graded levels of sulfaquinoxaline, and the broken lines represent the confidence limits at 0.01 probability.
suits indicate that the continuous feeding of 0.05% sulfaquinoxaline for 4 weeks is the minimal dosage having a barely detectable effect on growth. No evidence of hemorrhages was noted in the live birds during the test and when the chicks were autopsied at the end of the test only agonal hemorrhages were observed. All sulfaquinoxaline treated birds appeared normal except for size. One chick died after 2\ weeks on 0.1% and another died after 3J weeks on 1.6% sulfaquinoxaline. When autopsied some internal hemorrhages were found in the first bird, which had been trampled and peeked, but the other one appeared normal, except for being the smallest in the group. Continuous Administration in Feed or Water for 12 Weeks. Graded levels of sulfaquinoxaline were given continu-
ously in the feed or water to groups of 2-week-old White Leghorn cockerels until 14 weeks of age. The data summarized in Table 6 indicate that feeds medicated with 0.05% sulfaquinoxaline have no detrimental effect on growth of chickens when given for 12 weeks. Similarly, water medicated with 0.025% sulfaquinoxaline may be given to TABLE 6.—Effect of continuous administration of sulfaquinoxaline in feed or water to 2-weekold White Leghorn chicks for 1Z weeks % in feed or water None 0.025 in feed 0.05 in feed 0.1 in feed 0.2 in feed 0.4 in feed 0.0125 in water 0.025 in water 0.05 in water 0.1 in water
Mean body weight in grams PerNo. cent chickAfter After After morens Initial 4 12 8 tality weeks weeks weeks 70 10 20 30 20 20 10 10 20 10
112 123 85 113 120 120 123 98 110 98
538 525 479 386 436 361 569 497 447 228
1,045 1,501 1,063 1,570 1,023 1,554 836 1,219 888 1,310 775 1,145 1,050 1,360 1,053 1,507 949 1,351 910 604
0 0 0 0 10 10 0 0 10 10
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I
800-
872
A. C. CUCKLER AND W. H. OTT TABLE 7.—Comparison of continuous and, intermittent administration of sulfaguinoxaline solutions to 2-week-old White Leghorn chicks for a 15-day period
Percent in water None 0.025 0.02S 0.04 0.04
Schedule
Continuous Intermittent Continuous Intermittent
No. chicks
Mean dailyfluid consumption cc./chick
IS 10 10 10 10
44 43 42 32 42
Mean body weight in grams Initial
After 1 week
After 2 weeks
116 116 116 116 116
189 197 194 176 197
299 290 294 247 300
Percent mortality 0 0 0 0* 0
* One accidental death—chick badly pecked. indicate t h a t 0.025% sulfaquinoxaline administered continuously or intermittently in the water is highly palatable and has no adverse effects on growth or viability of young chicks. The recommended intermittent administration of 0.04% sulfaquinoxaline in the water likewise has no detectable adverse effects, although the continuous administration of 0.04% sulfaquinoxaline is somewhat unpalatable and retards growth slightly. Daily examinations revealed no evidence of hemorrhages. Intermittent Feeding for 3 Weeks in Floor Pens. Tolerance to intermittent feeding of sulfaquinoxaline was tested
TABLE 8.—Comparative effect of intermittent and continuous administration of 0.05% sulfaquinoxaline in the feed of New Hampshire chicks beginning at 3 weeks of age Schedule of administration Ration
None
Age in weeks Exp. 1
C-3 C-2 C-l
3 3 3
C-3 C-2 C-l C-3 C-2 C-l C-3 C-2 C-l
3 3 3 7-8* 7-8* 7-8* 9 9 9
195 166
Exp. 2 Number of Chicks 153
—
Exp. 1
Exp. 2
Exp. 1
293 170
307
115 74
154 Mean Body Weight in Pounds 0.50 0.45 0.48 0.42 0.44 — 0.45 — — 1.66(1.3) 1.90(0.7) 1.82(1.0)f 1.69(1.2) 1.65(0) — 1.47(0) — — 2.30(0.3) 2.33(0) 2.54(1.3) 2.17(0) 2.10(2.4) — 2.25(0) — —
—
Continuous
Intermittent
* Expt. 1--8 weeks; expt. 2--7 weeks. t Percent non-coccidial mortality is givenL in parenthesis.
—
•
—
155 0.47
—
0.48 1.61(2.0)
— 0.50 0.47
—
—
2.03(1.7) 1.95(1.4)
—
2.41(0.9) 2.34(0)
1.55(2.0) 2.38(1.3) 2.28(0.6)
—
—
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chickens for 12 weeks without deleterious effects. Higher dosages for this long period depress the growth rate of chickens and some mortality may occur. Comparison of Continuous and Intermittent Administration. T h e effect of sulfaquinoxaline ( 2 5 % sulfaquinoxaline solubilized powder) given continuously or intermittently in the drinking water (2 days on medication, 3 days off, followed by 2 days on, etc.) for 15 days was studied in 2-week-old White Leghorn cockerels. The fluid intake was recorded and fresh solutions were prepared daily. T h e results shown in Table 7 clearly
873
SULFAQUINOXALINE TOLERANCE
TABLE 10.—Effect of continuous administration of sulfaquinoxaline in the water to turkeys from 1 day to 10 weeks of age
TABLE 9.—Effect of continuous administration of sidfaquinoxaline to New Hampshire chicks from 1 day to 11 weeks of age Percent in feed
No. chicks
Mean body weight M ,. atllwks.,inlbs. M e e e a d n per Males Females
None 2,790 3.39 0.0125 1,395 3.42 0.025 1,395 3.40 Least difference between] means for significance a t [ 0 . 1 1
0.05 probability
2.64 2.67 2.67
J
IK iD
-
g„„;„ aln
Percent ?rtalltv
(noncoccidial)
3.47 3.45 3.38
2.8 2.9 2.5
0.12
1.2
Percent in water
No. poults
Initial
None 0.006 0.012 0.025
40 20 20 20
53 53 53 53
After After After 4 8 10 weeks weeks weeks 2,016 1,857 1,950 1,811
1,518 440 428 . 1,428 1,461 430 1,321 387
The results (Table 9) of these broiler trials show that 0.0125% and 0.025% sulfaquinoxaline-medicated rations do not interfere with growth, feed conversion and viability. TOLERANCE IN TURKEYS AND DUCKS
Continuous Administration to Turkeys. The effect of administering graded amount of sulfaquinoxaline in the water continuously to turkeys from 1 day to 10 weeks of age was determined. Approximately equal numbers of straight-run White Holland and Beltsville White turkeys were randomly distributed into groups of 20 each (2 groups of controls). The poults were fed a closed-formula commercial turkey starting mash to 6 weeks of age and a commercial turkey growing mash for the remainder of the experiment. The medicated solutions were prepared fresh daily (from 25% sulfaquinoxaline solubilized powder) and the
of continuous administration of sulfaquinoxaline in the water to turkeys from 1 day to 10 weeks of age Mean daily consumption/poult
Percent in water
None 0.006 0.012 0.025
No. poults
40 20 20 20
4th week Feed, g-
Water, cc.
13 14 14 12
50 51 54 46
8th week
10th week
Feed, g-
Water, cc.
Feed, g-
Water, cc.
Feed, g-
Water, cc.
55 52 55 55
172 148 161 114
116 118 HI 114
332 349 275 289
134 122 130 125
369 279 312 263
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with straight run New Hampshire chicks reared from 1 day to 9 weeks of age. The medication was begun at 3 weeks of age with the schedule of intermittent feeding being 0.05% sulfaquinoxaline in the feed for 3 days followed by 2 days on nonmedicated feed, and this schedule was repeated 6 times. No disease outbreak nor unusual mortality occurred during these experiments and there was no detrimental effect on growth from the intermittent feeding of 0.05% sulfaquinoxaline in the ration (Table 8). These results show that this intermittent feeding of sulfaquinoxaline is well-tolerated for a period of 4 to 5 weeks. Continuous Feeding for 11 Weeks in Floor Pens. Sulfaquinoxaline was fed continuously at 0.0125% and 0.025% in the ration (C-1) of straight run New Hampshire chicks from 1 day to 11 weeks of age. Two control groups and the 2 levels of sulfaquinoxaline were replicated in a total of 9 experiments started at intervals of 3 to 9 weeks throughout 1 year. TABLE 11.—Effect
Mean body weight in grams
m
874
A . C . CUCKXER AND W . H . OTT TABLE 12.—Effect
% Sulfaquinoxahne m water
N o
. f««'«>
Age in weeks
consump^ ^ o n ^ J r poult
Mean body weight in grams Iw+;„i mtml
After 1 week
Af ter 2 weeks
FV^A eed
g-
>
Water, cc.
6 6 6 10 10
944 848 892 1,666 1,689
1,204 1,067 1,043 1,780 1,862
1,538 1,360 1,423 2,074 2,120
113 107 110 132 136
299 252 266 334 285
6 6
813 800
1,087 1,036
1,321 1,297
108 114
257 237
unused portions were measured and discarded. The data in Table 10 indicate that 0.025% sulfaquinoxaline slightly retarded the growth of turkeys while 0.006% and 0.012% sulfaquinoxaline had little, if any, effect. The feed and water consumption records (Table 11) indicate that the sulfaquinoxaline treated turkeys eat as much feed, but none drink as much water, as the unmedicated controls. Intermittent Administration to Turkeys. The effect of intermittent administration of sulfaquinoxaline solutions on the growth of young turkeys was determined. The studies were conducted in 6- and 10week-old turkeys in approximately balanced groups composed of mixed sexes and equal numbers of White Holland and Beltsville White varieties. The sulfaquinoxaline (25% sulfaquinoxaline solubilized powder) solutions were given at 0.025% and 0.04% concentrations on an intermittent schedule of 2 or 3 days on the medicated solution followed by 3 days administration of water, etc., for a period of 15 days. The fluid consumption was determined and the unused portions were discarded. The data in Table 12 indicate that intermittent administration of 0.025% and 0.04% sulfaquinoxaline solutions does not adversely affect the growth of young tur-
keys. These dosages of sulfaquinoxaline do not cause any toxic manifestations during or after administration. The feed consumption is not affected although the fluid intake is decreased during the administration of the medicated solutions. Continuous Feeding for 11 Weeks to Turkeys in Floor Pens. Sulfaquinoxaline was fed continuously at 0.005% to 0.02% in an open-formula turkey starting ration (C-4) to Bronze and White Holland turkey poults from 1 day t o l l weeks of age. Two experiments were conducted with 90 poults in each pen. The results in Table 13 show that turkeys tolerate these levels of sulfaquinoxaline in the feed without noticeable effect on body weight, feed efficiency or viabilityContinuous Administration to Ducks. The effect of feeding sulfaquinoxaline to White Pekin ducklings was determined. TABLE 13.—Effect of continuous administration of sulfaquinoxaline to turkey poults from 1 day to 11 weeks of age Percent in feed
No. poults
Mean body w „ _15n . Percent weight at fjff-"! ,!; mortality rlb 11 weeks, f e e gd „K ' (nonam in lbs. coccidial)
None 360 0.005 270 0.010 270 0.015 270 0.020 270 Least difference between) means for significance a t [ 0.05 probability J
5.86 5.92 5.85 5.88 5.79
2.60 2.64 2.61 2.64 2.62
2.8 3.0 3.7 4.4 1.5
0.26
0.05
3.1
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Schedule: 2—3—2—3—2--3 None 39 0.025 14 0.04 14 None 5 0.025 5 Schedule: 3—3—3—3—3 0.025 14 0.04 14
of intermittent administration 0} sulfaquinoxaline to young turkeys
875
SULFAQUINOXALINE TOLERANCE TABLE 14.—Effect of continuous administration of sulfaquinoxaline to 2-week-old Pekin ducks
TABLE 16.—Effect of continuous administration of sulfaquinoxaline for 3-13 weeks on plasma prothrombin times in chickens
Mean body weight in grams Percent in feed
15 ducks/group — Initial After 5 Weeks
None 0.0125 0.025 0.05 0.1
1,838 1,929 1,891 1,801 1,781
344 344 343 343 340
%
8 ducks/group After 5 weeks
After 9 weeks
1,853 1,913 1,866 1,792 1,762
2,495 2,460 2,548 2,507 2,390
TABLE 15.—Effect % sulfaquinoxaline
Ration
Plasma prothrombin times—Seconds time3—Seconds Mean
Range
None 0.1 0.2
5 5 10
5 5 5
14 17 18
13-15 15-22 14-24
None 0.1 0.4
10 10 10
5 5 5
11 12 23
9-12 10-15 14-31
None 0.1
10 10
9 9
11 15
9-12 12-19
None 0.4
10 10
10 10
15 17
13-18 14-22
10 20 16 18
15 15 14 14
16 13 15 21
14-18 10-17 10-28 15-28
None 0.1 0.2 0.4
13 12 12
verse effects on the growth of ducks. There was no mortality attributable to sulfaquinoxaline. The data suggest that
of sulfaquinoxaline medication: on whole blood cloth'ng times in chickens
Schedule
No. weeks adm.
No. chicks
Age in weeks
Clotting time—Minutes Mean
Range
None 0.025—water 0.04 —water 0.025—water
L L L L
Intermittent Intermittent Continuous
2 2 2 2
15 10 10 10
4 4 4 4
6.2* 5.7* 4 2* 7 >
3.33.12.02.5-
8.6 10.0 8.0 23.0
None 0.025—feed 0.2 —feed
L L L
Continuous Continuous
3 3 3
10 10 10
6 6 6
4.8 4.3 5.3
3.42.72.9-
6.4 6.8 7.9
None 0.025—feed 0.2 —feed
C-l C-l C-l
Continuous Continuous
3 3 3
10 10 10
6 6 6
4.9 4.1 6.0
2.72.24.0-
5.7 5.8 9.4
None—feed 0.025—feed 0.1 —feed 0.4 —feed
C-2 C-2 C-2 C-2
Continuous Continuous Continuous
3 3 3 3
20 10 10 10
6 6 6 6
4.7 4.4 3.9 >25.4
None—feed 0.1 —feed 0.04 —water
C-2 C-2 C-2
Continuous Continuous
2 2 2
10 10 10
8 8 8
3.6 3.9 4.0
1.92.02.5-
4.9 8.7 5.2
None 0.015—feed
C-2 C-2
Continuous
11 11
20 10
11 11
5.1 5.5
3.23.5-
8.5 8.5
2.38.8 2.85.6 1.95.2 4.3->30.0
* These clotting times were determined at room temperature (approx. 25°C.) instead of 40°C.
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The ducks were fed a commercial starting ration until 2 weeks of age, at which time groups of 15 ducklings were given the sulfaquinoxaline medicated feed or only the basal feed. At the end of the 5th week, the number of ducks in each group was reduced from 15 to 8 by retaining alternate band-numbered animals. The results given in Table 14 indicate that sulfaquinoxaline in concentrations of 0.0125% to 0.1% has no detectable ad-
sulfaNo. j ^ Age quinoxa- weeks •, • V in cmcKS line in adm. weeks feed (C-l)
876
A. C. CUCKLER AND W. H. OTT
TABLE 17.—Concentrations of sulfaquinoxaline in plasma of chickens after 3 to 13 weeks administration of medicated feed or water
%
uinoxaline
Schedule
No. weeks adm.
No. chicks
Age in weeks
Sulfaquinoxaline plasma concentration, mg. % Mean
Range
—'
Continuous Continuous Continuous
3 6 12
5 5 5
5 8 14
3.2 1.6 1.6
0.025 in feed 0.025 in feed 0.025 in feed
Continuous Contmuous Continuous
3 6 12
5 5 5
5 8 14
4.5 2.2 2.6
—1
0.05 0.05 0.05
in feed in feed in feed
Continuous Continuous Continuous
3 6 9
5 10 6
4 7 10
4.3 5.0 3.5
Ei
0.05 0.05 0.05
in feed in feed in feed
Intermittent Intermittent Intermittent
3 6 9
5 10 6
4 7 10
3.5 3.2 4.0
—'
0.05 0.05 0.05
in water in water in water
Continuous Continuous Continuous
3 6 12
5 5 5
5 8 14
14.2 8.4 12.3
0.1 0.1 0.1 0.1 0.1
in in in in in
Continuous Continuous Continuous Continuous Continuous
3 6 9 12 13
20 10 6 5 20
5 8 11 14 15
9.8 10.6 10.1 11.4 9.4
8.0-12.9
0.1 0.1 0.1
in feed in feed in feed
Intermittent Intermittent Intermittent
3 6 9
5 10 6
4 7 10
6.2 7.3 7.4
—1
0.2 0.2 0.2
in water in water in feed
Continuous Continuous Continuous
3 6 12
5 5 18
5 8 14
45.6 38.2 18.1
12.1-21.2
0.4 0.4 0.4
in feed in feed in feed
Continuous Continuous Continuous
3 8 12
10 9 18
5 10 14
18.9 22.6 21.0
15.2-23.1 19.0-26.5 13.4-24.5
feed feed feed feed feed
—>
6.5-13.6 2
1 2
Pooled sample. The values were 0.3-4.2 (1.3) and 0-1.8 (0.3) 48 and 72 hours, respectively, after withdrawal of medicated feed.
0.0125% to 0.1% sulfaquinoxaline-medicated feeds might be used safely for the control of diseases in ducks caused by sulfaquinoxaline-sensitive organisms. HEMATOLOGICAL EFFECTS
Effect on Blood Clotting. Studies were performed on the effect of various dosages of sulfaquinoxaline on the whole blood clotting times of chickens. The sulfaquinoxaline was administered in the feed
or water to groups of 10 to 20 White Leghorn or New Hampshire chickens for 2 to 11 weeks. The data summarized in Table 15 demonstrate that sulfaquinoxaline may be given continuously for 2 or 3 weeks in a cencentration of 0.2% without effect on whole blood clotting times. The recommended continuous use concentration of 0.015% may be given for 11 weeks without having effect on blood clotting time
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0.0125 in water 0.0125 in water 0.0125 in water
877
SULFAQTJINOXALINE TOLERANCE
TABLE 18—Concentrations of sulfaquinoxaline in plasma, of turkeys and ducks after 2 to 10 weeks administration of medicated feed or water
Animal
%
No. animals
Age in weeks
Sulfaquinoxaline plasma concentration, mg. %
sulfaquinoxaline
Schedule
No. weeks adm.
in in in in in
Continuous Continuous Continuous Intermittent Intermittent
10 10 10 2 2
10 10 10 7 7
10 10 10 8 8
1.2 2.7 6.4 4.6* 3.7
water water water water water
0.006 0.012 0.02S 0.025 0.04
Duck Duck Duck
0.0125> in feed 0.0125 in feed 0.0125> in feed
Continuous Continuous Continuous
3 7 9
15 8 8
5 9 11
0.6 0.3 0.4
Duck Duck Duck
0.025 in feed 0.025 in feed 0.025 in feed
Continuous Continuous Continuous
3 7 9
15 8 8
5 9 11
2.0 1.0 0.9
Duck Duck Duck
0.05 0.05 0.05
in feed in feed in feed
Continuous Continuous Continuous
3 7 9
15 8 8
5 9 11
4.0 "^ 2.7 3.3
Duck Duck Duck
0.1 0.1 0.1
in feed in feed in feed
Continuous Continuous Continuous
3 7 9
15 8 8
5 9 11
7.4 5.3 4.8
* The values were 3.1, 2.6 and 0.4 mg. % 24, 48 and 72 hours, respectively, after withdrawal of medicated water.
while administration of 0.4% sulfaquinoxaline for 3 weeks will produce prolonged clotting times. Effect on Plasma Prothrombin Time. Similar studies have been conducted on the effect of sulfaquinoxaline on the plasma prothrombin times in White Leghorn chickens. The results summarized in Table 16 indicate that sulfaquinoxaline may be fed continuously for 3 to 13 weeks in a concentration of 0.2% without having detectable effect on plasma prothrombin times. However, a concentration of 0.4% sulfaquinoxaline in the feed will produce a slight prolongation of prothrombin clotting times when fed for 3 to 12 weeks. Sulfaquinoxaline Concentrations in Plasma. The results obtained from the analysis of the plasma of chickens, turkeys and ducks for sulfaquinoxaline at various intervals and dosages have been summarized in Tables 17 to 18.
The data indicate that about twice as much sulfaquinoxaline is required in the feed as in the water to obtain a comparable plasma concentration. There is no indication that sulfaquinoxaline accumulates in the blood with continued longterm administration. Furthermore, the plasma concentrations are of similar order of magnitude for the same dosages administered continuously or intermittently. Although turkeys seem to absorb sulfaquinoxaline equally as well as chickens and have similar concentrations in plasma, ducks given the same dosages in the feed do not have plasma concentrations as high as chickens. DISCUSSION Extensive data have been presented on the effect of sulfaquinoxaline on normal poultry. The results have demonstrated that single oral doses of 4 gm./kg. are well-
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Turkey Turkey Turkey Turkey Turkey
878
<
A. C. CUCKLER AND W. H. OXT
0.025% sulfaquinoxaline solution to turkeys retards the growth slightly, but there is no mortality or other adverse effects. Sulfaquinoxaline medicated solutions are less palatable than water and this may be the cause of growth retardation. However, the intermittent administration of 0.04% sulfaquinoxaline in the water has no effect on growth of young turkeys. Likewise, the continuous use of 0.005% to 0.02% sulfaquinoxaline in the feed has been well-tolerated and there are no adverse effects on growth, feed conversion or viability. Ducks tolerate up to 0.1% sulfaquinoxaline in the feed for 9 weeks without growth retardation or mortality. Since sulfonamides and other anticoccidial agents have been considered as possible factors in hemorrhagic conditions in chickens, studies were conducted to determine the effect of sulfaquinoxaline medication on the whole blood clotting and prothrombin times. The intermittent or continuous administration of 0.025% and 0.04% sulfaquinoxaline solutions for 2 to 3 weeks does not alter the clotting times of chicken blood. The feeding of 0.1% and 0.2% sulfaquinoxaline in the ration for 2 to 3 weeks or 0.015% for 11 weeks also has no detectable effect on blood clotting. However, the administration of 0.4% sulfaquinoxaline continuously for 3 weeks greatly increased the clotting time. Studies on the prothrombin times of chicken blood have indicated that 0.1% and 0.2% sulfaquinoxaline-medicated feeds have not affected this component of the blood clotting system of chickens. The determinations on blood from chickens fed 0.4% sulfaquinoxaline for 3 to 12 weeks indicated a slight prolongation of prothrombin times. These observations, therefore, tend to confirm the effect noted on whole blood clotting by 0.4% sulfaquinoxaline, a concentration greatly in ex-
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tolerated by chickens. Even an extremely large and almost practically impossible dose of 10.5 gm./kg. has only slight growth-retarding effect. Furthermore, the data indicate that chickens satisfactorily tolerate repeated daily administration of sulfaquinoxaline in a total dosage of 4 to 16 gm./kg. during a period of 2 weeks. Under these conditions of administration, there are no significant differences in the response of young chicks and mature hens to sulfaquinoxaline. When sulfaquinoxaline is fed to chickens for relatively short periods in dosages which are as high as 64 times the recommended concentration for use under severe conditions, the only significant effect observed is the retardation of growth. There is no evidence that variations in feeds have an effect since the chickens responded similarly when fed 4 different rations. The chickens were observed for indications of so-called "sulfonamide poisoning," i.e., hemorrhages beneath the skin, in the muscles, fluid in the peritoneal cavity, etc., but none were found. However, small agonal hemorrhages were seen in the birds at autopsy, and these occurred as frequently and as abundantly in the nonmedicated controls as in the sulfaquinoxaline-treated chickens. The continuous administration of 0.05% sulfaquinoxaline in the feed or of 0.025% in water for as long as 12 weeks had no adverse effects on chickens. Similarly, there was no evidence that the intermittent administration of sulfaquinoxaline at 0.05% in the feed or at 0.025% in the water for 2 to 5 weeks has any deleterious effects. The recommended intermittent administration of 0.04% sulfaquinoxaline in the water is tolerated satisfactorily, but the continuous administration of this dosage has a growth retarding effect. The continuous administration of
879
NEWS AND NOTES
cess of that commercially recommended. Analyses of the blood of chickens, turkeys and ducks given sulfaquinoxaline have indicated that chickens and turkeys have comparable plasma concentrations, while ducks maintain lower blood concentrations after receiving similar dosages. There is no suggestion that the drug accumulates in the blood after long-term administration.
The results have been presented of extensive studies on the effect of sulfaquinoxaline medication on normal chickens, turkeys and ducks. The data demonstrate that under both battery- and penrearing conditions sulfaquinoxaline is extremely well-tolerated by poultry. When up to 64 times the recommended use concentration of sulfaquinoxaline is fed to young chickens, the only significant effect is retardation of growth. Comparative studies with 4 different poultry rations have indicated that these sulfaquinoxaline medicated feeds are equally well-tolerated by chickens. There was no evidence of
REFERENCES Bratton, A. C , and E. K. Marshall, Jr., 1939. A new coupling component for sulfanilamide determination. J. Biol. Chem. 128: 537-550. Davies, S. F. M., and S. B. Kendall, 1953. Toxicity of sulphaquinoxaline (2-sulphanilamidoquinoxaline) for chickens. Vet. Rec. 65: 85-88. Delaplane, J. P., and J. H. Milliff, 1948. The grossand micropathology of sulfaquinoxaline poisoning in chickens. Am. J. Vet. Res. 9:92-96. Mushett, C. W., 1954. Personal communication. Quick, A. J., 1938. The nature of the bleeding in jaundice. J. Am. Med. Assoc. 110: 1658-1662.
NEWS AND NOTES {Continued from page 850) husbandry, genetics, nutrition, pathology and physiology. He explored and developed the multiple testing procedure for controlling pullorum disease. He helped to organize the North Carolina Hatchery Association and the North Carolina Poultry Council. Recognizing his services to them, the Hatchery Association presented a portrait of him to the College. It hangs in Scott Hall. He has served on the Southern States Cooperative College Feed Conference Board, and as a representative to the American Feed Manufacturers Association. He is a member of the Poultry Science Association, having been an Associate Editor of Poultry Science from 1933 to 1936, the American Association for the Advancement of Science, Sigma Xi, Phi Kappa Phi, and an Associate member of Alpha Zeta.
Dr. Edward W. Glazener succeeds Professor Dearstyne as Head of the Department. He was born in Raleigh in 1922 and graduated from Brevard Junior College in 1941. In 1943 he obtained a B.S. degree at North Carolina State College, a M.S. degree, specializing in genetics and physiology, in 1945 at the University of Maryland, and a Ph.D. degree at that University in 1949, specializing in genetics. He was Assistant County Agent in Chatham County in 1944, Assistant Professor of Genetics in the Poultry Department of the University of Maryland in 1945, and was appointed Associate Professor of Poultry Genetics at North Carolina State College in 1946, becoming Professor in 1949. Dr. Glazener was the research leader in develop-
{Continued on page 890)
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SUMMARY
"sulfonamide poisoning," but agonal hemorrhages were found as frequently in control as in sulfaquinoxaline-medicated chickens. Excessive dosage (0.4%) of sulfaquinoxaline was required to produce a prolongation in blood clotting time, but this dosage produced only a slight increase in prothrombin time. Under the conditions of our studies, gross pathological effects were not found. Turkeys and ducks appear to tolerate sulfaquinoxaline equally as well as chickens. Studies on plasma concentrations indicate that sulfaquinoxaline does not accumulate in the blood after long-continued administration.