Reaction products of sodium glucoheptonate with zinc sulfate and sodium hydroxide

Toxicity to reproduction: other studies

Administrative data

Endpoint:

toxicity to reproduction: other studies

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1985-1986

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Cross-reference

Reference

To address the endpoint toxicity to reproduction, read-across on gluconates and derivatives and zinc compounds was performed within the frame of a weight-of-evidence approach.The underlying hypothesis for the read-across is that glucoheptonates and gluconates, structurally similar sugar-like carbohydrate metal-complexes, share the same metabolism pathways in mammals (they are oxidized by pentose phosphate pathway) and that their possible toxicity is a function of the metal cation rather than of the gluconate or glucoheptonate anion.

Data on zinc salts

The influence of zinc feeding on conception of rats was studied using anhydrous ZnSO4 (Pal and Pal, 1987). Two tests were conducted involving the dosing of female, virgin rats with zinc either after coitus or 21 to 26 days prior to mating. The dosage was continued during the pregnancy until the female rats were sacrificed on day 18 of gestation. Weight of the placenta was not significantly different between the experimental group and their respective control group. Regarding the test without ZnSO4 gavage prior to mating, 12 out of 15 animals of the control group and the treated group were mated, of which 12 and 5 females, respectively, conceived during the study. In the test with ZnSO4 gavage prior to mating, 11 out of 18 animals of the control group and 15 out of 18 animals of the treated group were mated, of which 10 and 14 females, respectively, conceived during the study. When zinc was first added to the food after coitus, the "implanation sites per pregnant female was lower in the zinc treated group (5.0) than in the control rats (7.0) however the difference was not significant (t-test). Implantation sites per mated female were 7.0 in the control group and 2.1 in the zinc fed experimental group." When zinc treatment started 21 to 26 days prior to mating there was no significant difference in incidents of conception between the treated group and the control group. Also, there was no significant difference between the two groups regarding implantation sites expressed per mated or pregnant female. Also, the mean fetal and placental weights were similar. No stillbirth or malformation of the fetuses for either of the tests was detected. For the female parent, the dose of 4,000 ppm zinc showed either no effects (in case of dosage start prior to mating) or a slight effect on reproduction performance (in case of dosage started after coitus). For the F1 generation (examination of fetuses) no effect of the dosage of the female parent animal was observed. Converted to the target substance zinc glucoheptonate, this corresponds to a NOAEL of 25247.71 ppm or 1262.39 mg/kg bw/day.

The effect of zinc on reproduction toxicity was studied by Uriu-Hare et al. (1989). Starting on day 0 of gestation, rats were fed a low-Zn diet (4.5 mg/kg diet, 1.42 mg ZnGHA/kg bw/day), an adequate-Zn diet (24.5 mg/kg diet, 7.732 mg ZnGHA/kg bw/day), or a high-Zn diet (500 mg/kg diet, 157.8 mg ZnGHA/kg bw/day) throughout gestation. Fetuses were taken by cesarean section on gestation day 20. Among the control groups, dams fed the low-Zn diet had significantly less body weight gain on days 18-20 of pregnancy than controls fed the adequate- or high-Zn diets. There was no effect of dietary Zn on maternal weight gain in the diabetic groups. "Increasing dietary Zn tended to lower the resorption frequency. No diet-related differences in the concentrations of liver and kidney Mn, Cu, Zn, Ca, or Mg were found. Dietary Zn did not affect maternal kidney metallothionein concentrations. As dietary Zn increased, plasma Zn concentrations also increased. Placental concentrations of Cu, Zn, Fe, and Ca were similar among the groups.

In the study by Lastra et al. (1997) mice received zinc acetate in drinking water at concentrations of 500 and 1000 mg/I during the periods of gestation, lactation and post-weaning. The sequence employed in this study was: (I) 0/0 (II) 500/500 (III) 1000/1000 (IV) 0/0/0 (V) 500/500/500 and (VI) 1000/1000/1000 with their respective controls. Each group consists of 30 animals. No changes were observed in the general appearance, growth curves, hematocrit or signs of achromotrichia between treated and control animals. Group II and III showed a significant increase in 3H-thymidine-determined splenic lymphoproliferation, while groups V and VI exhibited an important decrease. A significant increase in plaque - forming cell response (IgM) was observed after the period of lactation in groups II and III as well as in groups V and VI. Zinc concentrations determined by atomic absorption in liver and thymus were significantly higher in all treated mice 42 days after birth. The applied doses of 500 and 1000 mg Zn/L correspond to doses of 179.89 mg ZnGHA/kg bw/day and 359.78 mg ZnGHA/bw/day. Results suggest that for carefully monitored periods and doses, oral zinc supplements might have a beneficial effect over some immune responses in the perinatal stages.

Data on gluconates and derivatives (SIDS, 2004)

No reproduction toxicity study was available for any of the gluconates of the category. However, negative results in the histopathology of the reproductive organs in repeated-dose studies on sodium gluconate and negative data on the teratogenicity of glucono-delta-lactone support the lack of reproductive toxicity for all the gluconates of the category. On the basis of these data showing a lack of toxicity and considering that gluconates have been recognized direct food additives, no further tests are considered necessary.

 

The repeated-dose studies of sodium gluconate were in detail:

A 28-day study was conducted by feeding rats by gavage with sodium gluconate at doses of 0, 500, 1000, 2000 mg/kg bw/day in water at a volume of 1 mL/ 100g bw.

No deaths or clinical signs of abnormality were observed in any of the groups. Histopathological examination showed a thickening of the limiting ridge of the stomach in 5 out of 12 males at 2000 mg/kg bw/day dose. No toxic changes associated with the test article were detected. As the limiting ridge is a tissue specific to rodents, this lesion is not toxicologically relevant for humans. Other lesions occurred incidentally and were not treatment - related. The NOAEL was estimated to be 1000 mg/kg bw/day for males and 2000 mg/kg bw/day for female (Mochizuki, M, Bozo Research Center, 1995a).

 

A 28-day oral feeding study was conducted. Rats were fed with a diet containing 5 % sodium gluconate at doses of 0, 1000, 2000 and 4100 mg/kg bw/day (max. 4100 mg/kg bw/day for males and 4400 mg/kg bw/day for females). A control group received equivalent concentration of sodium in the form of NaCl in order to differentiate the potential effects of high doses of sodium intake.

No deaths occurred during the study period. No revisions in the general condition, body weight, or food and water intake were observed in the animals over the study period. No changes were observed in the investigated ophthamologic tests, urinalysis, hematology, and blood chemistry over the study period. In addition, histopathological examination indicated no adverse effects as a result of the treatment regime. Statistically significant differences in some urinary parameters reported in animals receiving 2.5 or 5 % sodium gluconate were comparable to those observed in the NaCl control group, and were interpreted as related to the high sodium concentration of the diet.

The authors concluded that the NOAEL was 5% (equal to 4100 mg/kg bw/day). However, the JECFA committee who evaluated this report has concluded that the study was not suitable for identifying a NOAEL because of the small group sizes and the positive findings in the qualitative analysis, even if they have acknowledged that the effects shown in the qualitative urine analyses were related to the high sodium intake (Mochizuki, M. Bozo Research Center, 1997). Nonetheless, this study demonstrates the lack of effects of the gluconate anion even in large doses as the urinary effects were attributed to the high sodium intake and was therefore considered as critical for this endpoint.

A 28-day oral feeding study in Beagle dogs were conducted with sodium gluconate administered orally for 4 weeks at 500, 1000, 2000 mg/kg bw/day doses. None of the animals died during the period of treatment in any dose group and no significantly toxicologically changes were detected in the body weight, food intake, water intake, urinalysis, haematological test, blood chemistry analysis, ophthalmologic test, electrocardiography, autopsy and organ weight or in histopathological examination. However, increased frequency of vomiting and loose or watery stools was observed in the 1000 and 2000 mg/kg bw/day dose groups, as compared to controls. On the basis of these results, the non-toxic dose was estimated to be 500 mg/kg bw/ day. However, the toxicological effects observed (vomiting, passage of loose or waters stools) were considered extremely slight since other tests did not show the same changes.

 

These results are also relevant for zinc glucoheptonate, as the glucoheptonate-residue is also a derivative of gluconic acid. Therefore, the fact that sodium gluconate is not toxic after repeated oral intake and the fact that it does not provoque any effects on the reproductive system ishows that no reproductive toxicity can be attributed to the glucoheptonate moiety of zinc glucoheptonate.

Conclusion

Based on the given information the NOAEL of 1262.39 mg/kg bw/day, which is derived from data on ZnSO4 (Pal and Pal, 1987) is regarded as suitable hazard value for the assessment of the reproductive toxicity of the registered substance.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 262.39 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The quality of the whole database is considered sufficient for estimation of reproductive toxicity potential, because of the multipicity of available data for the different read-across substances.

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

To address the endpoint developmental toxicity read-across on gluconates and derivatives and zinc compounds was performed within the frame of a weight-of-evidence approach.The underlying hypothesis for the read-across is that glucoheptonates and gluconates, structurally similar sugar-like carbohydrate metal-complexes, share the same metabolism pathways in mammals (they are oxidized by pentose phosphate pathway) and that their possible toxicity is a function of the metal cation rather than of the gluconate or glucoheptonate anion. Besides publications on zinc and gluconate, public reports were studied to assess the developmental toxicity of zinc.

Assessment of Zinc toxicity in public reports

The following summaries have been adopted from Risk Assessment Reports (RARs) on zinc oxide (2008a) and zinc sulphate (2004):

“Developmental toxicity studies, according to a study design similar to OECD 414, with mice, rats, hamsters and rabbits were described with unspecified zinc sulphate. These studies do not permit the derivation of a proper NOAEL because neither reproductive nor developmental or maternal effects were observed, not even at the highest dose tested" .

“With respect to effects on reproduction, zinc deficiency is known to result in impairment of fertility and of foetal development. In humans additional zinc up to 0.3 mg Zn2+/kg bw/day during pregnancy did not result in adverse effects. Available data in animals on zinc excess indicate that adverse effects on fertility and foetal development may occur at dose levels of 200 mg Zn²⁺/kg bw/day, in conjunction with other effects such as perturbation of parental and foetal copper homeostasis. In humans a small disturbance (if any) of normal physiology, presumably indicative for copper deficiency, has been demonstrated at zinc excess of 50 and 150 mg Zn²⁺/day (0.83 and 2.5 mg Zn²⁺/kg bw/day, respectively), while 150 mg Zn²⁺/day (2.5 mg Zn²⁺/kg bw/day) resulted in clinical signs. As the margin between the dose at which in humans clinical signs are manifested and the dose at which in animals reproductive effects have been reported is so high (i.e. 80), it is considered unlikely that in humans reproductive effects will occur at exposure levels at which clinical signs do not manifest. Therefore, neither fertility nor developmental toxicity is considered endpoints of concern for humans. Based on the available information there is no reason to classify either metallic zinc or any of the zinc compounds considered for reproductive toxicity”

These statements are in line with those presented by the US Agency for Toxic Substances and Disease Registry (ATSDR, 2005) and WHO (2001).

Conclusively, the NOAEL for teratogenic effects is regarded to be 0.3 mg Zn/mg bw day as a worst-case value. This corresponds to a concentration of 1.89 mg/kg bw/day of the registered substance, when converting the NOAEL of elemental zinc to the registered substance under consideration of the molecular weight and the purity.

Data on zinc

The effect of zinc on reproduction toxicity was studied by Uriu-Hare et al. (1989). Starting on day 0 of gestation, rats were fed a low-Zn diet (4.5 mg/kg diet,1.42 mg ZnGHA/kg bw/day), an adequate-Zn diet (24.5 mg/kg diet, 7.732 mg ZnGHA/kg bw/day), or a high-Zn diet (500 mg/kg diet,157.8 mg ZnGHA/kg bw/day) throughout gestation. Fetuses were taken by cesarean section on gestation day 20. Maternal dietary Zn had a minor effect on fetal malformation frequency. The adequate- and high-Zn diets improved fetal length and weight.

Fetuses from dams fed the low-Zn diet had low liver Zn levels compared with those fed the adequate- and high-Zn diets. Maternal dietary Zn had an affect on fetal outcome. Fetal length was shortest in the low-Zn group. With the adequate-Zn diet, linear growth was increased. However, there was no further improvement in length with the high-Zn diet. Fetuses receiving the adequate-Zn diet had 11% more calcified sternal sites than fetuses fed the low-Zn diet. No further improvement in calcification with the high-Zn diet was observed. Ossification of fetal vertebrae, metacarpals, and anterior phalanges was lowest in the low-Zn group and increased compared with fetuses from the adequate-Zn group. Ossification of these three sites did not improve in group fed the high-Zn diet. Dietary Zn had only a modest effect on fetal malformation frequency, there wasno further improvement in the frequency of fetal abnormalities when the high-Zn diet was fed.

Data on gluconates and derivatives (SIDS, 2004)

Glucono-delta-lactone was administered to Wistar rats for 10 days (from day 6 - 15 of gestation) at doses of 0, 5.94, 27.6, 128.0, 594.0 mg/kg bw/day. A NOAEL of > 594 mg/kg bw/day for maternal and developmental toxicity (teratogenicity) was determined.

Glucono-delta-lactone was administered to CD-1 mice for 10 days (from day 6 - 15 of gestation) at doses of 0, 6.95, 32.5, 150, 695 mg/kg bw/day. A NOAEL of > 695 mg/kg bw/day for maternal and developmental toxicity (teratogenicity) was determined.

Glucono-delta-lactone was administered to hamster for 5 days (from day 6 - 10 of gestation) at doses of 0, 5.60, 26.0, 121, 560 mg/kg bw/day. A NOAEL of > 560 mg/kg bw/day for maternal and developmental toxicity (teratogenicity) was determined.

Glucono-delta-lactone was administered to Dutch rabbits for 13 days (from day 6 - 18 of gestation) at doses of 0, 7.80, 36.2, 168.5, 780.0 mg/kg bw/day. A NOAEL of > 780 mg/kg bw/day for maternal and developmental toxicity (teratogenicity) was determined.

 

Moreover, further experiments with glucono-delta-lactone in rats and mice are available.

Glucono-delta-lactone was administered orally to female nulliparous rats or mice for 10 days and the fetuses were observed by laparotomy on pregnancy day 21 or 18, respectively. Several dams in each group were allowed to deliver spontaneously, and the offspring were observed until postnatal day 21. The report does not contain specific information on the method used. During pregnancy, no abnormalities were observed in the general condition, body weight change or food consumption in any of the dose groups, nor were any death. In observation of dams after laparotomy, no abnormalities were detected in the number of implantations, dead foetuses, live offspring or mean body weight of offspring, nor was there any influence of the drug on the external appearance, organs, or skeletons of the foetuses. Observation of the dams allowed to deliver spontaneously, protraction of the duration of pregnancy or abnormalities at birth were not observed, nor any influence of the drug detected in the mortality rate, body weight gain, behavior, external appearance or visceral abnormalities of the offspring during the period of nursing.

A NOAEL of > 4000 mg/kg bw/day was established for rats and mice.

 

Conclusion

In summary, these negative data on the teratogenicity of glucono-delta-lactone, together with the natural occurrence of gluconic acid in the human metabolism sufficiently support the lack of developmental toxicity for all the gluconates of the category.

These results are also relevant for zinc glucoheptonate, as the glucoheptonate-residue is also a derivative of gluconic acid. Therefore, no teratogenicity can be attributed to the glucoheptonate moiety of zinc glucoheptonate.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1.89 mg/kg bw/day

Species:

other: human

Quality of whole database:

The quality of the whole database is considered sufficient for estimation ofthe developmental toxicity potential, because of the multipicity of available data for the different read-across substances.

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

The following human data regarding the effects of zinc supplementation during pregnancy provide further evidence that zinc compounds are not teratogenic.

human data

Data on zinc sulphate (Mahmoud et al, 1989)

The objective of this study was to see whether zinc supplementation during pregnancy improves maternal and fetal outcome. The prospective study started at booking and continued till discharge of mother and baby from the maternity hospital. Mothers were randomly assigned to receive zinc supplementation or placebo in a double blind trial. Women booking before 20 weeks of gestation who agreed to take part in the study were the test subjects. A total of 494 mothers were followed up till the end of pregnancy. There was no difference between the groups given zinc and placebo in their social or medical backgrounds.

Mothers in the active treatment group received one capsule of 20 mg elemental zinc daily and those in the placebo treated group a capsule identical in appearance and taste with the active capsule but which contained inert substances. Various adverse outcomes were tested, including maternal bleeding, hypertension, complications of labour and delivery, gestational age, Apgar scores, and neonatal abnormalities. The main outcome measure was birth weight.

There were no differences whatsoever between mothers given a zinc supplement and those given a placebo. Zinc supplementation in pregnancy in the United Kingdom does not seem to offer any benefits to the mother or her fetus.

The tested concentration of 20 mg elemental zinc per day did not show adverse effects, either. Therefore, a concentration of 20 mg/d can be regarded as NOEL, which corresponds to a NOEL of 126.26 mg/d and 2.1 mg/kg bw/day (person of 60 kg) for zinc glucoheptonate.

Data on Zinc aspartate (Kynast and Saling, 1986) and zinc citrate (Simmer et al. 1991) (please refer to 'Exposure related observations in human')

The beneficial effects of the oral application of zinc aspartate in pregnancy is investigated in a randomly selected study group of 179 patients and a control group of 345 patients (Kynast and Saling, 1986). This study confirms the prophylactic effectiveness of zinc replacement in reducing the overall complication rate for both mother and fetus and in particular for large-for-date and small-for-date infants. The therapy is well tolerated and accepted by the patients and causes no side effects. The results are in line with those of other working groups reporting on zinc as an important element with protective effects on fetal growth and development in pregnancy.The results of this study can be summarized as follows: (1) Maternal and fetal complications occur less often in both pregnancy and labor in patients who received zinc therapy; (2) the incidence of both large-for-date (LFD) and small for date (SFD) infants is reduced with zinc therapy; (3) oral zinc therapy is well tolerated and accepted by the patients and caused no deleterious side effects. The applied dose of 20 mg zinc aspartate/day corresponds to a concentration of 25.2 ZnGHA/day.

A double-blind randomised trial of oral zinc supplementation was carried out during the last two trimesters of pregnancy (Simmer et al. 1991). Fifty-six women at risk of delivering a small-for-gestational-age baby received either zinc citrate (22.5 mg daily) or placebo. Twenty-nine of the women were compliant. Zinc significantly reduced the incidence of intrauterine growth retardation, and most measured indices of labour and fetal health were better in the supplemented group. Side-effects were generally no more frequent in the supplemented group than in the placebo group, but the three patients with vomiting were taking Zn. No adverse effects of Zn therapy were found.

The analysis of existing metabolism data of gluconate and glucoheptonate moieties allow to conclude that toxicity effects of the target substance glucoheptonate-Zn complex can be predicted by using the toxicological data of structurally related gluconate complexes with the same metals.Therefore, these results are also relevant for zinc glucoheptonate. The applied dose of 22.5 mg zinc citrate/day corresponds to a concentration of 15.62 ZnGHA/day.

Effects on reproductive performance/fertility and developmental toxicity were assessed by means of a read-across approach. The read-across substances zinc sulfate, zinc acetate, elemental Zinc and gluconates and derivatives caused no reproductive toxicity and no teratogenicity in the rats and dogs in the available toxicity studies. The NOAEL of zinc glucoheptonate after oral application was calculated from the source substance zinc sulfate. The NOAEL for reproductive toxicity was 1262.39 mg/kg bw/day. The NOAEL for developmental toxicity was regarded to be 1.89 mg/kg bw/day as a worst-case value derived with data on human exposure.

Accordingly, zinc glucoheptonate is not subject to classification for toxicity to reproduction and developmental effects according to the Regulation (EC) No 1272/2008.

Data source

Reference

Reference Type:

publication

Title:

Zinc supplementation during pregnancy: a double blind randomised controlled trial

Author:

Mahomed, K., James, D.K., Golding, J., McCabe, R.

Year:

1989

Bibliographic source:

Br Med J 1989;299:826-30

Materials and methods

Principles of method if other than guideline:

One capsule containing either 20 mg elemental zinc or a placebo capsule containing inert substances was taken daily for breakfast. 246 women received the zinc supplementation, 248 were given the placebo. The women were less than 20 weeks pregnant at the beginning of the study. They took one capsule (either zinc supplement or a placebo) daily, until they delivered.

GLP compliance:

no

Type of method:

in vivo

Test material

Test material information

Constituent 1

Reference substance name:

Zinc sulphate

EC Number:

231-793-3

EC Name:

Zinc sulphate

Cas Number:

7733-02-0

Molecular formula:

H2O4S.Zn

IUPAC Name:

zinc sulfate

Specific details on test material used for the study:

capsules containing 66 mg zinc sulphate (corresponding to 20 mg elemental zinc) were prepared by Smith Kline and French Ltd.

Test animals

Species:

other: human

Sex:

female

Details on test animals or test system and environmental conditions:

Women who were less than 20 weeks pregnant were allowed to participate in the study. "There were no differences in their social and biological backgrounds. They were of similar age and had similar obstetric histories. No differences in maternal weight, blood pressure measurements, or haemoglobin, ferritin, or leucocyte zinc concentrations were present at the time of enrollment. The proportion of smokers within both groups was similar as was the prevalence of a history of nausea or vomiting and of urinary infections."

Administration / exposure

Route of administration:

oral: capsule

Details on exposure:

One capsule containing either 20 mg elemental zinc or a placebo capsule containing inert substances was taken daily for breakfast.
If supplements were prescribed, patients were advised to take the iron and folate tablet in the evening and to avoid taking the iron und study capsule together.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

The women were less than 20 weeks pregnant at the beginning of the study. They took one capsule (either zinc supplement or a placebo) daily, untill they delivered.

Frequency of treatment:

daily one capsule for breakfast

Doses / concentrations

Dose / conc.:

20 other: mg/d

Remarks:

elemental zinc

No. of animals per sex per dose:

246 women received the zinc supplementation, 248 were given the placebo.

Control animals:

yes, concurrent vehicle

Details on study design:

"Enough capsules were provided to last till the next hospital visit. The mothers were seen by the research midwife at the 28-32 week visit and again on the day after delivery. At each visit information was obtained about the use of any other drugs or iron or vitamin supplementation. Compliance was assessed by the regularity with which the study capsules were taken. Those who took the supplement daily or on most days were grouped as compliers, and the rest were regarded as non-compliers. At the 28-32 week visit the mothers were asked to complete a seven day dietary diary."

Statistics:

"Information on outcome was coded by a person who did not participate in the clinical care of the woman, and the data were analysed with the statistical package for the social sciences (SPSS-X) and the biomedical programs data package. Comparison of frequencies was by the chi² test with Yates's correction where appropriate. When numbers were very small Fisher's exact test was employed. t Tests were used to compare means and the Mann-Whitney U test to compare median values. Statistical significance was taken at the 5% level. Though the study was designed to look at beneficial effects, we were also keen to examine adverse outcomes, so two tailed tests were used."

Results and discussion

Effect levels

1

Dose descriptor:

NOEC

Effect level:

20 other: mg/d

Based on:

element

Sex:

female

Basis for effect level:

other: fetus and neonatas properties, e.g. birth weight, mean head circumference, ...

2

Dose descriptor:

NOEC

Effect level:

0.3 mg/kg bw/day

Based on:

element

Sex:

female

Basis for effect level:

other: fetus and neonatas properties, e.g. birth weight, mean head circumference, ...

Remarks on result:

other: converted to mg/kg bw/day for a person of 60 kg

Any other information on results incl. tables

"There were no differences in outcome between the groups (table 1). In particular there was no evidence of a lower incidence of growth retardation or neonatal abnormalities in the zinc treated group. The condition of the infant at birth was identical in the two groups. There were three perinatal deaths in each group. In all, however, six pregnancies had either been terminated or ended in spontaneous abortion during the study, but the difference in distribution between the groups (one case in the zinc treated group, five cases in the control group) did not approach significance."

Table 1: Details of fetuses and neonates in the two groups. Except where stated otherwise figures are numbers (percentages) of fetuses/neonates.

		Zinc supplementation group	Placebo supplementation group
		(n = 248*)	(n = 249*)
Sex:	Male	118/247 (48)	116/245 (47)
	Female	129/247 (52)	129/245 (53)
Birth weight (g):	Median	3390 (n=247)	3370 (n = 244)
	Mean (SD)	3291 (581)	3319 (531)
	< 2500	15/247 (6)	13/244 (5)
	2500 - 3499	140/247 (57)	135/244 (55)
	≥ 3500	92/247 (37)	96/244 ( 39)
Congenital defects		5/248 (2)	8/249 (3)
Other abnormalities		34/248 (14)	47/249 (19)
Apgar scores:	1 minute < 6	16/244 (7)	22/243 (9)
	1 minute ≥ 6	228/244 (93)	221/243 (91)
	5 minutes < 8	7/243 (3)	8/243 (3)
	5 minutes ≥ 8	236/243 (97)	235/243 (97)
Outcome:	Stillbirth/died	3/248 (1)	3/249 (1)
	Alive	244/248 (98)	241/249 (97)
	Terminated/miscarried	1/248 (0)	5/249 (2)
	Median zinc concentrations in cord blood (µmol/10^10cells)	l-36(n = 131)	1-38 (n = 116)

* Two twin pregnancies occured in the zinc supplementation group and one in the controls.

Applicant's summary and conclusion

Executive summary:

The objective of this study was to see whether zinc supplementation during pregnancy improves maternal and fetal outcome. The prospective study started at booking and continued till discharge of mother and baby from the maternity hospital. Mothers were randomly assigned to receive zinc supplementation or placebo in a double blind trial. Women booking before 20 weeks of gestation who agreed to take part in the study were the test subjects. A total of 494 mothers were followed up till the end of pregnancy. There was no difference between the groups given zinc and placebo in their social or medical backgrounds.

Mothers in the active treatment group received one capsule of 20 mg elemental zinc daily and those in the placebo treated group a capsule identical in appearance and taste with the active capsule but which contained inert substances. Various adverse outcomes were tested, including maternal bleeding, hypertension, complications of labour and delivery, gestational age, Apgar scores, and neonatal abnormalities. The main outcome measure was birth weight.

There were no differences whatsoever between mothers given a zinc supplement and those given a placebo. Zinc supplementation in pregnancy in the United Kingdom does not seem to offer any benefits to the mother or her fetus.

The tested concentration of 20 mg elemental zinc per day (=0.3 mg/kg bw/day for a person of 60 kg) did not show adverse effects, either. Therefore, a concentration of 20 mg/day (=0.3 mg/kg bw/day for a person of 60 kg) can be regarded as NOEL.