Testing Status of Agents at NTP
Executive Summary Chaconine and Solanine: Table 6
Table 6. Embryotoxicity and Teratogenicity of a-Chaconine and a-Solanine
| Species, Strain, Age | Number and Sex of Animals | Chemical Forma, Purity | Dose | Exposure/ Observation Period | Results/Comments | Reference |
|---|---|---|---|---|---|---|
| 9.2.1 Oral Administration | ||||||
| Rats (Wistar, mature) | 4 F | a-chaconine, purity n.p. | 1.5 mg/kg/day (0.002 mmol/kg/day) by gavage | exposed on days 6 to 15 of gestation; observed to day 22 of gestation | No teratogenic or embryolethal effects were observed. | Ruddick et al. (1974) |
| Rats (Wistar, mature) | F (number n.p.) | a-chaconine, purity n.p. | 50 mg/kg (0.06 mmol/kg) by gavage | single exposure on day 9 of gestation; observed to day 21 of gestation | No signs of maternal toxicity were observed. In the fetuses, no exencephaly, micrognatia, or skeletal abnormalities were observed. | Waalkens-Berendsen et al. (1992) |
| Hamsters (Syrian, mature) | F (number n.p.) | a-chaconine, purity n.p. | 200 mg/kg (0.23 mmol/kg) by gavage | single exposure on day 8 of gestation; observation period n.p. | 6 cases (percentage n.p.) of maternal toxicity and 12% embryotoxicity were observed. 7/8 live litters had at least one CNS-malformed embryo (exencephaly and cranial bleb). | Renwick (1982) |
| Hamsters (Syrian, mature) | F (number n.p.) | a-chaconine, purity n.p. | 150, 165 or 180 mg/kg (0.18, 0.19, or 0.21 mmol/kg) by gavage | single exposure on day 8 of gestation; 15 day observation | Number of hamster dam deaths was increased at the 165 and 180 mg/kg doses as compared to controls. Dam deaths at 150 mg/kg were n.p.
The number of malformed litters was dose-related. Percentage of malformed litters was negligible at the low dose, 63% at the middle dose, and 88% at the high dose. Teratogenic malformations were restricted to those of the neural tube, mostly cranial bleb and exenchephaly. | Renwick et al. (1984) |
| Hamsters (Syrian, mature) | F (number n.p.) | 22R, 25S-a-chaconine, pure | 160-200 mg/kg (0.19-0.23 mmol/kg) by gavage | single exposure on day 8 of gestation; observation period n.p. | The incidence of malformations (craniofacial defects) was 20%.
Based on teratogenicity data from administered doses of a-chaconine, a-solanine, and solanidine, the authors concluded that dam toxicity is not responsible for the teratogenicity of a-chaconine and a-solanine. | Gaffield et al. (1992) |
| Hamsters (Syrian, mature) | F (number n.p.) | a-chaconine, 'pure' | 0.21 or 0.29 mmol/kg by gavage | single exposure on day 8 of gestation; observed to day 15 of gestation | Fetal abnormalities observed at the 0.21 mmol/kg dose were not statistically significant, but the one litter from a dam dosed with 0.29 mmol/kg had a statistically significant number of abnormal fetuses. Abnormalities included exencephaly, encephalocele, and anophthalmia. | Gaffield and Keeler (1996) |
| Rats (Holzman, approx. 4-months-old) | F (number n.p.) | solanine, purity n.p. | 30 or 40 mg/kg/day (0.03 or 0.05 mmol/kg/day) in the basal diet | Exposed through gestation and weaning; observation period n.p. | An increased number of litters in which all pups died was observed with administration of both doses compared to controls: control, 1/ll; 30 mg/kg solanine, 6/10; 40 mg/kg solanine, 5/10.
Percentage of pups weaned was decreased at both doses compared to controls: control, 82.6%; 30 mg/kg solanine, 31.0%; 40 mg/kg solanine, 31.1%. | Kline et al. (1961) |
| Rats (Wistar, mature) | 9 F per group | a-solanine, purity n.p. | 0.3, 1.0, or 3.0 mg/kg/day (0.0003, 0.001, or 0.003 mmol/kg/day) by gavage | exposed on days 6 to 15 of gestation; observed to day 22 of gestation | At the 0.3 mg/kg/day dose, one fetus had twisted pelvic limbs and an absent tail. At the 3 mg/kg/day dose, one fetus had craniorachischisis and exopthalmos. These effects did not appear to be treatment-related. | Ruddick et al. (1974) |
| - | - | - | 6 mg/kg/day (0.007 mmol/kg) by gavage | exposed on days 7 to 10 of gestation; observed to day 22 of gestation | No evidence of teratogenicity was observed. | - |
| - | 3-4 F per group | - | 2, 10, or 25 mg/kg/day (0.002, 0.01, or 0.03 mmol/kg/day) by gavage | exposed on days 8 to 11 of gestation; observed to day 22 of gestation | - | - |
| Rats (Wistar, mature) | F (number n.p.) | a-solanine, purity n.p. | 50 mg/kg (0.06 mmol/kg) by gavage | single exposure on day 9 of gestation; observed to day 21 of gestation | No signs of maternal toxicity were found. No exencephaly, micrognatia, or skeletal abnormalities were observed in the fetuses. | Waalkens- Berendsen et al. (1992) |
| Hamsters (Syrian, mature) | F, number n.p. | a-solanine, purity n.p. | 217 mg/kg (0.25 mmol/kg) by gavage | single exposure on day 8 of gestation; observation period n.p. | 3 cases (percent incidence n.p.) of maternal toxicity and 41% embryotoxicity were observed. 20/34 live litters had at least one CNS-malformed embryo (exencephaly, cranial bleb, and other unspecified abnormalities). | Renwick (1982) |
| Hamsters (Syrian, mature) | F (number n.p.) | a-solanine, purity n.p. | 200 mg/kg (0.23 mmol/kg) by gavage (other doses were administered, but n.p.) | single exposure on day 8 of gestation; 15 day observation | Number of hamster dam deaths was increased as compared to controls.
The number of malformed litters was dose-related. Teratogenic malformations were restricted to those of the neural tube, mostly cranial bleb and exenchephaly. a-Chaconine produced the same results at a 21% lower dose than a-solanine. | Renwick et al. (1984) |
| Hamsters (Syrian, mature) | F (number n.p.) | 22R, 25S-a- solanine, 'pure' | 200-288 mg/kg (0.23-0.33 mmol/kg/day) by gavage | single exposure on day 8 of gestation; observation period n.p. | The incidence of malformations (craniofacial defects) was 20%.
Based on teratogenicity data from administered doses of a-chaconine, a-solanine, and solanidine, the authors concluded that dam toxicity is not responsible for the teratogenicity of a-chaconine and a-solanine. | Gaffield et al. (1992) |
| Hamsters (Syrian, mature) | F (number n.p.) | 22R,25Sa- solanine, 'pure' | 0.28 mmol/kg by gavage | single exposure on day 8 of gestation; observed to day 15 of gestation | 21% (5/24) of the litters had fetuses with abnormalities, including exencephaly, encephalocele, and anophthalmia. | Gaffield and Keeler (1996) |
| Rats (Wistar, mature) | 14 F | cooked and freeze-dried visibly blighted tubers, as 73% of the diet | 19,700 mg/kg/day in the diet (mean consumption) | exposed on day 1 to 22 of gestation; no additional observation period | The content of the glycoalkaloids in the diet was not determined.
No evidence of maternal toxicity, fetal toxicity, or teratogenicity was observed. | Ruddick et al. (1974) |
| Hamsters (strain n.p., mature) | 12-15 F per group | freeze-dried potato concentrate | 50% freeze-dried, unblighted potato concentrate (diet 1), 50% Phytophthora infestans infected freeze-dried, blighted potato concentrate (diet 2), or 50% Alternaria solani infected freeze-dried, blighted potato concentrate (diet 3) | exposed on day 5 to 10 of gestation; observed to day 15 of gestation | The content of the glycoalkaloids in the diet was not determined.
Feed consumption, maternal body weight gain, litter size, number of resorptions, and fetal weight were not affected by any of the treatments. The most frequent gross anomaly (hemorrhagic necrosis of the central nervous system) was not treatment related: diet 1, 1/114; diet 2, 3/153; and diet 3, 0/135. | Sharma et al. (1978; cited by JECFA, 1993) |
| Hamsters (Simonsen, mature) | F (number n.p.) | potato sprout material | 2.7-6.3 g/kg (a glycoalkaloid dose of 94.5-346.5 mg/kg [0.11-0.40 mmol/kg]) in the diet | single exposure on day 7 or 8 of gestation; observed to day 15 of gestation | Sprout material was both teratogenic and embryolethal. The number of resorptions was dramatically increased when compared to the controls. Types of malformations included cranial bleb, exencephaly, microphthalmia, and spina bifida; incidence varied with different potato strains. | Keeler et al. (1978) |
| Hamsters (Simonsen, mature) | F (number n.p.) | potato peel or tuber material, sprouted or unsprouted | potato peel: 10-20 g/kg (a glycoalkaloid dose of 20-40 mg/kg [0.023-0.047 mmol/kg]) in the diet
potato tuber: 10-20 g/kg (a glycoalkaloid dose of 0.3-0.6 mg/kg [0.0003-0.0007 mmol/kg]) in the diet | single exposure on day 7 or 8 of gestation; observed to day 15 of gestation | No significant embryolethal or teratogenic effects were observed. | Keeler et al. (1978) |
| Rabbits (New Zealand, mature) | 2-6 F | freeze-dried potato concentrate | 50% freeze-dried, unblighted potato concentrate (diet 1), 50% Phytophthora infestans infected freeze-dried, blighted potato concentrate (diet 2), or 50% Alternaria solani infected freeze-dried, blighted potato concentrate (diet 3) | exposed through gestation; observation period n.p. | The content of the glycoalkaloids in the diet was not determined.
No effects were observed from treatment with diet 1 (0/9 abnormal fetuses). 3/21 fetuses from mothers fed diet 2 had incomplete closure of the caudal vertebral column. 2/21 were very small and had shortened appendages. 2/28 of the fetuses from mothers fed diet 3 had incomplete closure of the caudal vertebral column, 1/28 had a very small brain and the cranial cavity was filled with fluid, and 2/28 were abnormally small. The authors noted that feeding blighted potatoes to pregnant rabbits produces a low incidence of the caudal vertebral column malformation. However, the conclusion should be taken with caution due to a small size of the control group which does not allow for the determination of spontaneous rates of this malformation. | Sharma et al. (1978; cited by JECFA, 1993) |
| Swine (Miniature, mature) | 2 F per group | freeze-dried potato concentrate | 50% freeze-dried, unblighted potato concentrate (diet 1), 50% Phytophthora infestans infected freeze-dried, blighted potato concentrate (diet 2), or 50% Alternaria solani infected freeze-dried, blighted potato concentrate (diet 3) | exposed through the 1st half of gestation (about 57 days); observed to the end of gestation (day n.p.) | The content of the glycoalkaloids in the diet was not determined.
Diet 3 depressed weight gain in the maternal swine. 1 fetus out of 15 from the swine fed diet 2 had anencephaly with extensive internal hydrocephaly. No other fetuses were affected. The authors concluded that feeding potatoes blighted with P. infestans may cause anencephaly in miniature swine, but that definitive conclusions cannot be drawn due to the small sample size. | Sharma et al. (1978; cited by JECFA, 1993) |
| Marmosets (Callithrix jacchus, 5-yrs-old) | 6 F | freeze-dried potato concentrate, blighted | 4.7 g/kg/day in the diet (a glycoalkaloid dose of 0.9 mg/kg/day [0.001 mmol/kg/day]) | 50 day exposure, on either days 0-50 or 20-70 of gestation; observed to day 80-120 of gestation | 4/11 fetuses had cranial osseous defects. There was a replacement of bone by a collagenous membrane in the occipital area. The lateral ventricle of the brain was enlarged.
The authors concluded that the results are suggestive of the teratogenicity of blighted potatoes. | Poswillo et al. (1972; 1973; cited by JECFA, 1993) |
| - | 7 F | freeze-dried potato concentrate, blemished | 4.7 g/kg/day in the diet (a glycoalkaloid dose of 0.78 mg/kg/day [0.0009 mmol/kg/day]) | exposed through gestation (length n.p.); newborns were observed at regular intervals up to 6 months. | Behavior anomalies of 3 sets of twins included continuous clinging to parents or siblings and prolonged weaning time. The significance of these behavior responses was not determined.
No anatomical abnormalities were observed. | Poswillo et al. (1973; cited by JECFA, 1993) |
| - | 6 F | freeze-dried potato concentrate of unblemished potatoes | 4.7 g/kg/day in the diet (a glycoalkaloid dose of 0.56 mg/kg/day [0.0007 mmol/kg/day]) | - | No anatomical or behavioral abnormalities were observed. | - |
| - | 5 F | freeze-dried potato concentrate of potatoes infected with Erwinia carotovera | 4.7 g/kg/day in the diet (a glycoalkaloid dose of 0.07 mg/kg/day [0.00008 mmol/kg/day]) | exposed for 90 to 110 days; no additional observation period | All marmosets had previously produced normal offspring, and dosing began 10 days postpartum of the previous litter. Females were sacrificed between days 90 and 110 of gestation. Fetuses were examined grossly and radiographically for abnormalities.
No anatomical abnormalities were observed. | - |
| 9.2.2 Intraperitoneal Injection | ||||||
| Rats (Wistar, 9-wk-old) | 4-7 F per group | a-chaconine, purity n.p. | 2.5, 5, 10, or 20 mg/kg/day (0.003, 0.006, 0.01, or 0.02 mmol/kg/day) on days 5-12 of gestation, or 40 mg/kg/day (0.05 mmol/kg/day) on days 5-6 of gestation | see dose for exposure period; observed to day 21 of gestation | 10, 20, and 40 mg/kg/day were lethal to maternal rats. Additionally, intense endometrial inflammatory reactions were encountered in the uterus at the sites of fetal resorption.
Significant fetal growth retardation and embryolethality were observed at 5 mg/kg/day and higher. One incidence of irregular or fused ribs in a fetus was observed at 5 mg/kg. | Chaube and Swinyard (1976) |
| Mice (strain n.p., mature) | F (number n.p.) | a-solanine, purity n.p. | n.p. | single exposure on day 8, 9, or later in gestational period; observation period n.p. | a-Solanine markedly increased embryonic mortality following treatment on day 8 or 9 of gestation, but not later in gestation. Decidual swellings that were collected following dosing showed signs of destruction of mesenchymal cells, which interferes with allantois outgrowth and precedes embryo resorption. | Pierro et al. (1976) |
| Mice (ASH/CS1, adult) | 16 or 20 F per group | solanine, commercially extracted | 20 mg/kg/day (0.02 mmol/kg/day) on day 7, on days 7-10, or on days 7-11 of gestation | see dose for exposure period; observed to day 17 of gestation | The greatest embryotoxicity (defined as induced abortions) occurred in the group receiving treatment for 5 days. Treatment did not significantly increase the number of resorptions and no malformations were observed among the viable fetuses. | Bell et al. (1976) |
| Rats (Wistar, mature) | F (number n.p.) | solanine, purity n.p. | 5 or 10 mg/kg/day (0.006 or 0.01 mmol/kg/day) | exposed on days 7-17 of gestation; observed to day 21 of gestation | No maternal toxicity was observed. There was no fetal mortality at the low dose and 7% fetal mortality at the high dose. No neural tube defects were observed, but a high incidence of minor abnormalities (mild hydronephrosis, hydroureter, and ribs showing knobby protuberances on the posterior third of their length) was induced. | Swinyard and Chaube (1973) |
| - | - | - | - | exposed on days 5-12 of gestation; observed to day 21 of gestation | Findings matched those for administration on days 7-17 of gestation (above) except that there was 14% fetal mortality at the high dose. | - |
| Rats (Wistar, 9-wks-old) | 6-8 F per group | a-solanine, purity n.p. | 5, 10, or 20 mg/kg/day (0.006, 0.01, or 0.02 mmol/kg/day) on days 5-12 of gestation, or 40 mg/kg/day (0.05 mmol/kg/day) on days 5-6 of gestation | see dose for exposure period; observed to day 21 of gestation | No maternal deaths were induced, but intense endometrial inflammatory reactions were encountered in the uterus at the sites of fetal resorption.
Significant embryolethality was observed at 5 mg/kg/day and higher. Fetal growth retardation was observed at 20 and 40 mg/kg. Irregular or fused ribs were induced in fetuses at all doses. | Chaube and Swinyard (1976) |
| Rabbits (New Zealand White, mature) | 3 F | solanine, reference standard | 5 mg/kg (0.006 mmol/kg/day) | single exposure on day 0-8 of gestation; observed to day 22 of gestation | 1 rabbit that delivered prematurely had 2 normal, living fetuses, 2 dead fetuses with retarded growth, 2 extensively resorbed fetuses, and 4 totally resorbed fetuses. The 2 rabbits carrying pregnancy to the time of necropsy had a total of 13 normal, living fetuses; the rate of resorption was 18%. | Swinyard and Chaube (1973) |
| Rats (Wistar, mature) | F (number n.p.) | glycoalkaloids, purity n.p. | 10 or 20 mg/kg/day (0.01 or 0.02 mmol/kg/day) | exposed on days 5-12 of gestation; observed to day 21 of gestation | No maternal lethality was observed at either dose.
Fetal mortality was 50 and 100% at 10 and 20 mg/kg, respectively. No neural tube defects were observed, but a high incidence of minor abnormalities (mild hydronephrosis, hydroureter, and ribs showing knobby protuberances on the posterior third of their length) was induced. At 10 mg/kg, the total glycoalkaloid dose was 7 times more toxic than the same dose of solanine. | - |
| Rats (Wistar, 9-wks-old) | 6F per group | a-chaconine and a-solanine, purity n.p. | 10 mg/kg/day (0.01 mmol/kg/day) a-chaconine and 5 mg/kg/ day (0.006 mmol/kg/ day) a-solanine on days 5-12 of gestation | see dose for exposure period; observed to day 21 of gestation | The combined dose was not lethal to maternal or fetal rats. 6.7% of the fetal rats had irregular or fused ribs. | Chaube and Swinyard (1976) |
| 9.2.3 Intravenous Injection | ||||||
| Rats (Sprague-Dawley, mature) | 13 F | a-chaconine, purity n.p. | 1.7 mg/kg/day (0.002 mmol/kg/day) | exposed on days 6-13 of gestation; observed to day 19 of gestation | The average maternal blood serum concentration of a-chaconine was 340 ng/mL, which is more than 20 times greater than the average peak serum level reported for human volunteers after ingesting potatoes with a total glycoalkaloid content at the upper safe limit.
No signs of maternal toxicity were observed. Of the 143 fetuses in the treatment group, none had external malformations (soft tissue anomalies were not investigated). When treatment and control groups were compared, no statistical differences in number of resorptions or dead fetuses were observed, nor were there significant differences in fetal body weight per litter. | Hellens et al. (1992a) |
| 9.2.4 Injection into the Yolk Sac | ||||||
| Chicken eggs, (strain n.p., fertile) | n.p. | a-chaconine, purity n.p. | 0.5-1.5 mg/kg (0.00059-0.0018 mmol/ kg) before incubation or 12, 20, or 30 mg/kg (0.014, 0.023, or 0.035 mmol/kg) after 96 hours of incubation | single exposure; observation period n.p. | All doses except 0.5 mg/kg caused a reduction in hatchability. The mean body weights of hatched chicks were not significantly different from the controls at any dose. The incidence of congenital malformations (phocomelia, one-leggedness, absence of claws, and microcephaly) was not statistically significant. | Nishie et al. (1975) |
| Chicken eggs (Foghorn, fertile) | 41-88 per group | solanine, purity n.p. | 10, 19, or 25 mg/kg (0.01, 0.02, or 0.03 mmol/kg) on day 4 of incubation | single exposure; observed for 22 days | No statistically significant increase in abnormal chicks was observed. 25 mg/kg reduced hatchability by 29%. | Nishie et al. (1971) |
| Chicken eggs (strain n.p., fertile) | n.p. | a-solanine, purity n.p. | 0.5-1.5 mg/kg (0.00058-0.0017 mmol/ kg) before incubation or 19 mg/kg (0.022 mmol/ kg) after 96 hours of incubation | single exposure; observation period n.p. | The low doses (0.5-1.5 mg/kg) had no effect on hatchability, but 19 mg/kg reduced hatchability. The mean body weights of hatched chicks were not significantly different from the controls at any dose. The incidence of congenital malformations (unfeathered skin in the retroinguinal area, unilateral anophthalmia) was not statistically significant. | Nishie et al., 1975) |
| Chicken eggs (white Leghorn, fertile) | 18-179 per group | solanine or mixed glycoalkaloids from potatoes infected with P. infestans | 0.015, 0.13, 0.17, 0.26, or 1.5 mg/egg (0.00002, 0.00015, 0.0002, 0.0003, or 0.0017 mmol/egg) solanine or 0.26 mg/egg (0.0003 mmol/egg) glycoalkaloids from blighted potatoes, injected between 0 and 26 hours of incubation | single exposure; observed for 72 hours of incubation | With the 1.5 mg/egg solanine treatment, most embryos died at the early stages of development.
In the other dose groups (including the glycoalkaloid dose from blighted potatoes), the percent of dead embryos was decreased, but the incidence (15-29%) of abnormalities was increased. Abnormalities included rumplessness (absence of the tail below the wing bud) and trunklessness (absence of a trunk below the wing bud). Fluid- or blood-filled vesicles in the lower trunk or tail region was also observed. | Mun et al. (1975) |
| Chicken eggs (white Leghorn, 2-4 days old) | 6 per group | ethanol extract from potatoes infected with P. infestans, extract from healthy potatoes, or solanine, 'pure' | 0.3 mg/egg (0.0003 mmol/egg) | subgerminal injections on day 2 of incubation; intraamniotic injection on days 3 and 4 of incubation | Equivalent doses of three treatments had the same effects. The dose interfered with the caudal morphogenetic system at the somite stages. Injections on the 3rd and 4th days led to malformations including cranioschisis, celosoma, and cardiac septal defects. | Jelínek et al. (1976) |
aThe chemical form is given as the original author(s) presented it.
Abbreviations: CNS = central nervous systems; F = Female; M = Male; n.p. = not provided
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