Carrageenan, a substance with hydrocolloid properties owing to the presence of sulfated polyglycans with average relative molecular masses well above 100 kDa, is derived from a number of seaweeds of the class Rhodophyceae. It has no nutritional value and is used in food preparation for its gelling, thickening, and emulsifying properties. Three main types of carrageenan are used commercially, which are known in the food industry as iota (iota), kappa (kappa), and lambda (lambda) carrageenans. These names do not reflect definitive chemical structures but only general differences in the composition and degree of sulfation at specific locations in the polymer. Processed Eucheuma seaweed is derived from either E. cottonii (kappa-carrageenan) or E. spinosum (lambda-carrageenan), also Rhodophyceae.

Carrageenan is obtained by extraction of the seaweed into water or aqueous dilute alkali and may be recovered by alcohol precipitation, by drum drying, or by precipitation in aqueous potassium chloride and subsequent freezing. In contrast, the preparation of processed Eucheuma seaweed consists of soaking the cleaned seaweed in alkali for a short time at elevated temperatures. The treated material is then thoroughly washed with water to remove residual salts and further washed with alcohol, dried and milled to a powder. For both carrageenan and processed Eucheuma seaweed, the alcohols that may be used during purification are restricted to methanol, ethanol and isopropanol. Articles of commerce may include sugars for standardization purposes, salts to obtain specific gelling or thickening characteristics, or emulsifiers carried over from drum drying processes.

Carrageenan was reviewed by the Committee at its thirteenth, seventeenth, twenty-eighth, and fifty-first meetings (Annex 1, references 19, 32, 66 and 137). At its twenty-eighth meeting, the Committee established an ADI ‘not specified’¹ on the basis of the results of a number of toxicological studies on carrageenans obtained from various seaweed sources.

Processed Eucheuma seaweed was considered by the Committee at its thirtieth, thirty-ninth, forty-first, forty-fourth, and fifty-first meetings (Annex 1, references 73, 101, 107, 116 and 137). At its forty-fourth meeting, the Committee concluded that, because of the chemical relationship between processed Eucheuma seaweed and traditionally refined carrageenan, the toxicological data on carrageenan were relevant to the safety assessment of the carrageenan polysaccharide constituents of processed Eucheuma seaweed, but could not replace adequate toxicological studies on processed Eucheuma seaweed itself. Following submission of the results of a 90-day study on toxicity with processed Eucheuma seaweed, the Committee concluded at its fifty-first meeting that the toxicities of this material and carrageenan were sufficiently similar for the previous ADI ‘not specified’¹ for carrageenan to be extended to a group ADI including processed Eucheuma seaweed. At its fifty-first meeting, the Committee also considered all studies on carrageenan that had been published since its twenty-eighth meeting and noted the identity of the seaweed source and type of carrageenan used in earlier studies. It expressed concern about the potential promotion of colon carcinogenesis by carrageenans and processed Eucheuma seaweed and therefore made the group ADI ‘not specified’¹ temporary; it also requested clarification of the significance of the promotion of colon cancer observed in studies in rats. At its present meeting, the Committee reviewed the available evidence for the promoting and related effects of these compounds in the rat colon.

Groups of 30 male and 30 female MRC rats and Syrian golden hamsters were fed diets containing 0.5, 2.5, or 5% carrageenan (Gelcarin HMR derived from Chondrus crispus, largely composed of kappa components) ad libitum from 7 weeks of age until they died or were killed when moribund. The average intake of carrageenan was 360, 2000, and 4000 mg/kg bw per day for the rats and 370, 2200, and 3700 mg/kg bw per day for the hamsters at the three concentrations, respectively. Animals occasionally had soft stools, particularly near the start of the experiment. There was no statistically significant increase in tumour incidence in either species. Histological examination of all sections of the gastrointestinal tract revealed a low incidence of lesions in the stomach and caecum in animals at all concentrations and in controls. These were considered to be consistent with the age, species, and strain of animals used and could not be attributed to the action of carrageenan (Rustia et al., 1980).

Groups of 15 male and 15 female Sprague-Dawley rats were given diets containing extracts of three forms of undegraded carrageenan (kappa from C. crispus; lambda from Gigartina acicularis; and iota from Eucheuma spinosum) at a concentration of 1 or 5% for 40 weeks. ‘Alphacel’ (specification not given) was included at 5% in the diet of control rats. The body weights of treated and control rats were comparable. The incidence of occult faecal blood was lower in animals receiving carrageenan than in the controls. Soft and fluid stools were reported for a few animals receiving carrageenan but not for controls. Samples of gastrointestinal tract were taken for histological examination, but the results were not reported (Coulston et al., 1975).

Nineteen male and 21 female rhesus monkeys were given carrageenan (Gelcarin HMR from C. crispus) at a dose of 0, 50, 200, or 500 mg/kg bw per day by gavage on 6 days/week for 5 years, and the substance was then then incorporated into the diet for a further 2.5 years. Stool consistency was decreased and the incidence of faecal occult blood was increased in dose-related trends over the entire 7.5 years. At necropsy, one male at 50 mg/kg bw per day and one monkey of each sex at 500 mg/kg bw per day were reported to have multiple mucosal haemorrhages and reddening of the mucosa of the caecum, colon and ano-rectal junction. However, these areas appeared normal on microscopic observation, and no treatment-related changes were found (Abraham et al., 1983).

Processed kappa carrageenan from E. cottonii and iota carrageenan from E. spinosum were incorporated into the diet of groups of 20 male and 20 female Sprague-Dawley rats at a concentration of 0.5, 1.5, or 5% for at least 90 days. Control groups of 30 males and 30 females received the basal diet for the same period. The study was conducted to GLP and in accordance with OECD guideline No. 408. It was considered in detail by the Committee at its fifty-first meeting (Annex 1, reference 138). The weight of the full caecum was significantly increased in rats fed processed Eucheuma seaweed from either source. After a 28-day recovery period, the caecum weights were not significantly different from those of controls. Microscopic examination revealed no abnormal changes in the caecum or colon (Robbins, 1997).

Groups of 15–30 weanling female Fischer 344 rats were fed semi-purified diets containing 20% fat and 0 or 15% undegraded carrageenan (Viscarin 402, origin not stated). The control diet contained additional corn starch and dextrose in place of the carrageenan. At 7 weeks of age, all animals except for controls were given azoxymethane subcutaneously at a dose of 8 mg/kg bw once weekly for 10 weeks or N-methyl-N-nitrosourea (MNU) intrarectally at a dose of 2 mg per rat twice a week for 3 weeks. Animals given MNU were autopsied 30 weeks after the first injection, and those gtiven azoxymethane and controls were autopsied after 40 weeks. Animals receiving carrageenan gained less weight than controls, with a mean terminal body weight approximately 85% that of controls. Food consumption measured during the third week of the experiment was reported to be approximately equal: 8.6 and 9.9 g/rat per day on control and carrageenan diets, respectively. No tumours were induced in the colon or other organs of control rats, but one rat given carrageenan diet without carcinogen had a colon adenoma. Administration of azoxymethane or MNU to animals on the control diet resulted in incidences of colorectal tumours of 57 and 69%, respectively. In carcinogen-treated animals on the carrageenan-containing diet, the tumour incidence was increased to 100% and the multiplicity of tumours per animal was also increased. All untreated animals on the carrageenan diet showed chronic inflammatory changes in the large intestine, composed of oedematous thickening and aggregation of macrophages in the lamina propria and submucosa. The effects were considered not to be associated with the lower body-weight gain, as caloric restriction is usually associated with decreased tumour incidence. The authors noted that the experimental diets contained 0.3% supplemental methionine (Watanabe et al., 1978).

Groups of 15–20 male Fischer 344 rats, 7 weeks of age, were fed a semi-purified diet containing 6% fat and 0 or 6% undegraded carrageenan (CS-47, kappa type, species not specified) for 24 weeks. The control diet contained additional cornstarch in place of the carrageenan. Groups of animals on the control and carrageenan-containing diets also received weekly subcutaneous injections of dimethylhydrazine at a dose of 20 mg/kg bw for 16 weeks. Body-weight gain and food intake were comparable with and without carrageenan, but faecal weight was increased by treatment. No colon tumours were observed in the absence of dimethylhydrazine, but administration of this carcinogen to rats on control diet resulted in a 40% incidence of colon tumours, which was increased to 75% in rats on the carrageenan-containing diet. The multiplicity, size, and distribution of the tumours in the proximal as compared with the distal colon were also increased in the rats receiving carrageenan. There was no visible ulceration in tumour-free colonic mucosa of the carrageenan-fed rats. The authors reported that the lower faecal beta-glucuronidase activity in carrageenan-fed rats may have been due to alterations in the bacterial flora (Arakawa et al., 1986).

Groups of 18 male Fischer 344/DuCrj rats were injected subcutaneously with dimethylhydrazine at 20 mg/kg bw once a week for 4 weeks to initiate colorectal carcinogenesis. One week after the final injection, the animals were given diets containing lambda carrageenan at a concentration of 0, 1.2, 2.5, or 5.0% for 32 weeks. Concomitant control groups received carrageenan in the diet without dimethyl-hydrazine, and 0.2% dietary cholic acid was used as a positive control, with and without dimethylhydrazine treatment. There were no clinical signs of treatment. The body-weight gain was decreased in rats receiving 5% carrageenan without dimethylhydrazine but not in the group receiving combined treatment. Food consumption was similar in all treated groups, but carrageenan-treated animals tended to drink more water than controls. The spleen weight was decreased by 5–10% in both groups of rats receiving 5% carrageenan when compared with the control groups. Table 1 shows the incidences of nodules and tumours in the colons of dimethylhydrazine-treated rats, with no statistically significant differences between groups. The distribution of the nodules in rats treated with 5% carrageenan differed from that in other groups, more of the nodules occurring in regions close to the caecum. There were no statistically significant differences in the incidences of inflammatory lesions. A similar low incidence of aberrant crypt foci was found in the colons of rats that received basal diet or 5% carrageenan without dimethylhydrazine, and the number of aberrant crypts per focus was also similar in these groups. The authors concluded that carrageenan at a dietary concentration of 5% did not promote colorectal carcinogenesis in rats (Hagiwara et al., 2001).

Female Fischer 344 rats aged 35 weeks were injected intraperitoneally with azoxymethane at 20 mg/kg bw to initiate colon cancer. Seven days later, they received pure water (controls) or undegraded carrageenan (type I, mainly kappa) at either 0.25% (liquid) or 2.5% (solid gel) in place of drinking-water for 100 days. The dose of carrageenan was cited as 0, 0.2, or 4 g/kg bw per day. Rats receiving 2.5% carrageenan gained less weight, the terminal body weight being 93% of that of controls; food consumption was not reported. The number of animals with aberrant foci was not reported, but a statistically significant decrease in the number of aberrant crypt foci per colon was found in rats receiving carrageenan at either dose. At the higher dose, there was a significant increase in the number of crypts per aberrant crypt focus, indicating that the size of the foci was increased (Corpet et al., 1997).

In a subsequent study from the same laboratory, the role of the intestinal microflora in promotion of aberrant crypt foci in the colon was studied in conventional and germ-free female Fischer344 rats. The germ-free rats were inoculated with faecal samples from three healthy children who had previously been given a carrageenan-containing dessert three times a week for 3 weeks to adapt their gut flora. Groups of 30 conventional or human flora-associated rats were injected intraperitoneally with azoxymethane at 20 mg/kg bw to initiate colon cancer and, after 7 days, were given undegraded carrageenan for 100 days, as described by Corpet et al. (1997). As the rats receiving 2.5% carrageenan tended to lose weight, they were given the liquid 0.25% carrageenan on 2 days/week. The intakes of carrageenan were reported to be 0, 0.22, and 2.8 g/kg bw per day for conventional rats and 0, 0.51, and 2.5 g/kg bw per day for human flora-associated rats. Both groups of rats receiving 2.5% carrageenan gained less weight, with terminal body weights approximately 93% those of controls. The data for the conventional rats were identical to those reported by Corpet et al. (1997). Administration of carrageenan to human flora-associated rats had no effect on the incidence or size of aberrant crypt foci. The authors suggested that the gut flora of rats, but not of humans, is associated with the enhancement of colon tumours by carrageenan (Taché et al., 2000).

Groups of six weanling male Sprague-Dawley rats were fed a diet containing 0 or 7.4% carrageenan (type and origin not specified) for 28 days. One hour before sacrifice they were injected intraperitoneally with [³H]thymidine. A 1-cm segment of colon was taken about 2 cm from the anus and processed for autoradiographic examination. For each rat, the number of cells and the number of labelled cells were determined in 25 crypts. In addition, the concentrations and amounts of bile acids were determined in faecal material collected on days 27 and 28. There were no significant differences in the number of cells per crypt or in the proportion of labelled cells. Subcutaneous administration of dimethylhydrazine dihydrochloride at 200 mg/kg bw 1 week before the start of dietary carrageenan also had no effect. The carrageenan diet resulted in a decreased concentration of faecal bile acids but not in the total bile acid secreted. The percentage of bile acids present as cholic acid was significantly decreased, indicating that bile acid degradation had been increased (Glauert & Bennink, 1983).

Groups of six male Fischer 344 rats, 7 weeks of age, were fed a semi-purified diet containing 6% fat and 0 or 6% undegraded carrageenan (CS-47, kappa type, species not specified) for 3 weeks. The control diet contained additional corn starch in place of the carrageenan. Groups of animals on control and carrageenan-containing diets also received weekly subcutaneous injections of dimethylhydrazine at a dose of 20 mg/kg bw for 3 weeks, but it is not clear whether this treatment was concurrent or consecutive. The distribution of the molecular mass of faecal carrageenan was similar to that in the diet, indicating that carrageenan was not broken down in the gut. The concentration and total amount of faecal lithocholic acid were increased in carrageenan-fed rats. The concentration of the total measured bile acids (cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid, and hyodeoxycholic acid-like substance) was decreased in the carrageenan-fed rats, whereas the amount of total bile acids was similar or slightly higher than in controls. The authors suggested that the promoting effect of carrageenan on colon tumorigenesis is mediated by increased excretion of lithocholic acid, which has been associated with tumour promotion and cell proliferation in the colon (Arakawa et al., 1988).

Groups of eight male Fischer 344 rats were fed diets containing various dietary fibres for 4 weeks and then the activity of thymidine kinase, expressed relative to protein content, was measured in homogenized mucosal scrapings from the distal 12 cm of the colon. The animals were fasted before autopsy, but no information was provided on the time at which the autopsies were performed. Undegraded carrageenan (mainly lambda-carrageenan from Gigartina species) at 5% in the diet resulted in a significant increase in thymidine kinase activity, whereas 5% guar gum or 10% wheat bran had no effect. Three of the carrageenan-treated animals had slight congestion and erythema of the distal 4–5 cm of the colon at autopsy, but the thymidine kinase activity of these animals did not differ from that of the other carrageenan-treated animals. The increase in thymidine kinase activity was considered to be indicative of a substantial increase in colonic mucosal cell proliferation (Calvert & Reicks, 1988).

In a subsequent study from the same laboratory, groups of seven male Fischer 344 rats were fed a semi-purified diet containing carrageenan (mainly lambda-carrageenan from Gigartina species) at 0, 0.65, 1.3, or 2.6% for 4 weeks. After an overnight fast, the animals were autopsied and the activity of thymidine kinase, expressed relative to protein content, was measured in homogenized mucosal scrapings from the distal 12 cm of the colon. There were no statistically significant differences in body weight or energy intake. Faecal weight was increased with carrageenan intake and was significantly different from that of controls at all concentrations. The total protein content and thymidine kinase activity of the mucosal homogenates showed a dose-related increase, but the thymidine kinase activity was significantly different from that of controls only at the highest concentration of carrageenan. Histological examination revealed no evidence of infiltration by inflammatory cells in any treated group. The results were considered to indicate that carrageenan at 0.65% in the diet, representing approximately 25 times the maximal human intake, had no biologically significant effect (Calvert & Satchithanandam, 1992).

Groups of four male Fischer 344 rats were fed a diet containing 0 or 5% iota-carrageenan for up to 91 days. A 3-cm segment of distal colon was processed for staining for proliferating cell nuclear antigen (PCNA). Thymidine kinase activity, expressed relative to protein content, was measured in homogenized mucosal scrapings from the distal colon. The carrageenan diet resulted in increased thymidine kinase activity within 9 days, which reached a plateau at four- to fivefold that in rats on the basal diet after 14 days. In groups of animals returned to basal diet for 28 days, the thymidine kinase activity returned to the basal level. No increase in thymidine kinase activity was seen in animals receiving diets containing 0.2 or 1.5% carrageenan for 28 days. Staining for PCNA revealed a significant increase in positive cells in the upper third of the crypts of rats receiving 5% carrageenan for 91 days, but not for 28 days, or for 64 days followed by a 28-day recovery period on basal diet. No PCNA-positive cells were observed at the luminal surface. The authors contrasted the results with those obtained with polygeenan, which resulted in PCNA-positive cells at the luminal surface throughout the mucosa and failure to return to the normal distribution of staining after the 28-day recovery period. They considered that the pattern of PCNA staining seen with carrageenan was indicative of an adaptive response and would not contribute to an increased risk for colonic neoplasia (Wilcox et al., 1992).

Administration of iota-carrageenan (source not specified) to groups of six to eight male Sprague-Dawley rats, MF1 mice, or DSN hamsters at 5% in the diet for 30 days was associated with a two- to threefold enlargement of the caecum in all three species. The concentration of bacteria in the caecal contents was decreased in rats, mice, and hamsters, and the total number of bacteria per caecum was decreased in rats and mice but not in hamsters. The activities of microbial biotransformation enzymes were subject to marked changes, which were species-dependent. The total caecal activities of azoreductase and nitroreductase were inhibited to a greater extent in rats than in mice or hamsters. In rats, significant caecal enlargement and decreased bacterial content occurred after administration of carrageenan at 0.5 and 2% in the diet, but there was no clear dose–response relationship. Immunological analysis of bile samples indicated that, while the total immunoglobulin A concentration was unaffected, the concentration of antibody with binding specificity for caecal bacteria was significantly enhanced in the carrageenan-exposed rats (Mallett et al., 1984, 1985).

The ability of carrageenan (type and source not described) to inhibit gap-junctional intercellular communication was studied in a rat liver epithelial cell line (WB-F344). Concentration-related inhibition of intercellular communication was seen over the range of 0.000001–0.01% in the culture medium. Inhibition was maximal within 15 min and was restored almost to the control level after 1 h. There was no concurrent positive control, but the authors stated that this pattern of response was similar to that seen with phorbol ester. However, unlike phorbol ester, carrageenan did not induce hyperphosphorylation of connexin protein Cx43, suggesting that the mechanism of inhibition of intercellular communication was different (Suzuki et al., 2000).

Two studies showed that carrageenan administered before, during, and after administration of known carcinogens (dimethylhydrazine, azoxymethane, N-methyl-N-nitrosourea) enhanced the tumorigenicity of these carcinogens. One of the studies involved administration of carrageenan at 15% in the diet, resulting in decreased body-weight gain. In the second study, involving administration of carrageenan at 6% in the diet, the body-weight gain was comparable to that of control animals. Enhanced carcinogenicity under these circumstances may result from promotion but may also result from altered toxicokinetics or biotransformation of the carcinogen. In addition, there were indications that the bacterial flora were altered as a result of the administration of carrageenan. In a study conducted to a classical initiation-promotion protocol, in which rats were initiated by treatment with dimethylhydrazine and promoted by administration of carrageenan at dietary concentrations up to 5%, the carrageenan treatment did not result in a statistically significant increase in the incidence of colon tumours in the rats that had been initiated.

Two further studies involved use of a conventional initiation–promotion protocol, but with formation of aberrant crypt foci as the end-point instead of tumour formation. These studies involved initiation by azoxymethane followed by administration of carrageenan in the drinking-water. The higher dose of 2.5% carrageenan was a solid gel, which may have altered the food and water consumption patterns of the animals. The first study demonstrated that dietary administration of carrageenan subsequent to the carcinogen resulted in a decreased number of aberrant crypt foci, with a significant increase in their size. A subsequent study in rats with human microflora demonstrated no effect of carrageenan on either the number or size of aberrant crypt foci. As the relationship between aberrant crypt foci and tumorigenesis is still unclear, it is difficult to interpret the biological significance of these results.

Increased cell proliferation has frequently been postulated as a mechanism of non-genotoxic carcinogenicity or promotion. The preferred methods of assessing cell proliferation are based on histological techniques, which allow identification of the nature and location of proliferating cells. There is no consistent pattern of colon damage in rats treated with carrageenan for prolonged periods. Some studies have shown caecal enlargement, but most have not shown histological damage. In one study in which rats underwent autoradiographic examination, no significant differences in the number of cells per crypt or in the proportion of labelled cells were seen in rats fed a diet containing 7.4% carrageenan for 28 days and compared with controls.

Methods for measuring cell proliferation that are based on measurement of cell cycle-dependent enzyme activities, such as thymidine kinase activity, are cruder methods for measuring overall cell proliferation in an entire tissue specimen. A significant increase in thymidine kinase activity, expressed relative to protein content, was found in homogenized mucosal scrapings from the colon of rats fed diets containing carrageenan at 2.6 or 5% for 4 weeks; no significant effects were observed with 0, 0.65, or 1.3% carrageenan in the diet for 4 weeks. Histological examination revealed no evidence of infiltration by inflammatory cells in any of the treated groups. In another study, the increased thymidine kinase activity observed in rats fed 5% carrageenan in the diet returned to the basal level within 28 days when the animals were returned to control diet. No increase in thymidine kinase activity was seen in animals receiving diets containing 0.2 or 1.5% carrageenan for 28 days. Staining for PCNA revealed a significant increase in PCNA-positive cells in the upper third of the crypts of rats receiving 5% carrageenan for 91 days, but not after 28 or 64 days, followed by a 28-day recovery period on basal diet. No PCNA-positive cells were observed at the luminal surface. The pattern of PCNA-staining seen with carrageenan was considered indicative of an adaptive response that would not contribute to an increased risk for colonic neoplasia.

In one study, carrageenan inhibited gap-junctional intercellular communication in vitro. However, the mechanism of action was different from that of a known promoter, phorbol ester, and the relevance of this observation is uncertain for a substance that is not absorbed in vivo.

Carrageenan and processed Eucheuma seaweed are used as thickeners, gelling agents, stabilizers, or emulsifiers in a wide range of foods at concentrations up to 1500 mg/kg. Data on intake available at the fifty-first meeting showed that the per-capita intakes in 1995 derived from poundage data for Europe and the USA ranged from 28 to 51 mg/day. These estimates corresponded well to those reported for 1993 by the Seaweed Industry Association of the Phillipines on the basis of sales of 44 mg/person per day for the populations of Canada and the USA and 33 mg/person per day for European populations.

The estimates derived from poundage data were also consistent with those derived for the population of the USA in model diets, with reported mean intakes of carrageenan of 20 mg/day for consumers and 40 mg/day for consumers at the 90th percentile (derived by multiplying the mean by a factor of 2). The intakes were derived from data on the food consumption of individuals aged 2 years and over available in 1976 from nutrition surveys in the USA combined with the results of a 2-week study by the Marketing Research Corporation of America on the frequency of food consumption.

In the recent study with a classical initiation–promotion protocol, carrageenan at up to 5% in the diet did not promote colon carcinogenesis in rats initiated by dimethylhydrazine. The Committee noted, however, that the dietary concentrations of carrageenan used in the two studies that showed that carrageenan enhanced colon carcinogenesis in rats were higher and that carrageenan was administered before, during, and after the carcinogens. Enhanced carcinogenicity under these circumstances may result from promotion but may also result from altered toxicokinetics or biotransformation of the carcinogen. Therefore, the mechanism of the enhancement of colon carcinogenesis in these studies remained unresolved. Continuous feeding of high doses of carrageenan produced a generalized proliferative response, measured as increased thymidine kinase activity, in the mucosal tissue of the colon of male rats. This effect might play a role in the observed enhancement of the tumorigenicity of known colon carcinogens by high dietary concentrations of carrageenan. However, a proliferative effect of carrageenan on the mucosa of the colon was seen only with a dietary concentration of carrageenan at 2.6% or higher. Thus, no effect was seen with 1.5% carrageenan in the diet, corresponding to 750 mg/kg of body weight per day. This level greatly exceeded the estimated human intake of carrageenan or processed Eucheuma seaweed of 30–50 mg/person per day from their use as food additives. Bearing in mind that the enhancement of colon carcinogenesis in rats was seen at much higher doses and that 5% carrageenan in the diet did not act as a tumour promotor in rat colon in a classical initiation–promotion study, the Committee considered that the intakes of carrageenan and processed Eucheuma seaweed from their use as food additives were of no concern. It therefore allocated a group ADI ‘not specified’¹  to the sum of carrageenan and processed Eucheuma seaweed.

Abraham, R., Benitz, K.-F., Mankes, R.F., Rosenblum, I. & Ringwood, N. (1983) Studies on rhesus monkeys (Macaca mulatta) receiving native carrageenan (Chondrus crispus) orally for 7.5 years. Book 1. Unpublished summary of final report from Institute of Experimental Pathology and Toxicology, Albany Medical College, Albany, New York, USA. Submitted to WHO by R.J.H. Gray, Hercules Inc., Wilmington, Delaware, USA.

Arakawa, S., Okumura, M., Yamada, S., Ito, M. & Tejima, S. (1986) Enhancing effect of carrageenan on the induction of rat colonic tumors by 1,2,-dimethylhydrazine and its relation to beta-glucuronidase activities in feces and other tissues. J. Nutr. Sci. Vitaminol., 32, 481–485.

Arakawa, S., Ito, M. & Tejima, S. (1988) Promoter function of carrageenan on development of colonic tumors induced by 1,2,-dimethylhydrazine in rats. J. Nutr. Sci. Vitaminol., 34, 577–585.

Calvert, R.J. & Reicks, M. (1988) Alterations in colonic thymidine kinase enzyme activity induced by consumption of various dietary fibers. Proc. Soc. Exp. Biol. Med., 189, 45–51.

Calvert, R.J. & Satchithanandam, S. (1992) Effects of graded levels of high-molecular-weight carrageenan on colonic mucosal thymidine kinase activity. Nutrition, 8, 252–257.

Corpet, D.E., Taché, S. & Préclaire, M. (1997) Carrageenan given as a jelly, does not initiate, but promotes the growth of aberrant crypt foci in the rat colon. Cancer Lett., 114, 53–55.

Coulston, F., Golberg, L., Abraham, R., Benitz, K.-F. & Ford, W. (1975) Carrageenans (Hercules Incorporated). Safety evaluation, nine month study. Unpublished interim progress report (March 1975) from Institute of Comparative and Human Toxicology, Center of Experimental Pathology and Toxicology, Albany Medical College, Albany, New York, USA. Submitted to WHO by Marinalg International, Paris, France.

Glauert, H.P. & Bennink, M.R. (1983) Influence of diet or intrarectal bile acid injections on colon epithelial cell proliferation in rats previously injected with 1,2-dimethylhydrazine. J. Nutr., 113, 475–482.

Hagiwara, A., Miyashita, K., Nakanishi, T., Sano, M., Tamano, S., Asai, I., Nakamura, M., Imaida, K., Ito, N. & Shirai, T. (2001) Lack of tumor promoting effects of carrageenan on 1,2-dimethylhydrazine-induced colorectal carcinogenesis in male F344 rats. J. Toxicol. Pathol., 14, 37–43.

Mallett, A.K., Wise, A. & Rowland, I.R. (1984) Hydrocolloid food additives and rat caecal microbial enzyme activities. Food Chem. Toxicol., 22, 415–418.

Mallett, A.K., Rowland, I.R., Bearne, C.A. & Nicklin, S. (1985) Influence of dietary carrageenans on microbial biotransformation activities in the caecum of rodents and on gastrointestinal immune status in the rat. Toxicol. Appl. Pharmacol., 78, 377–385.

Robbins, M.C. (1997) A 90-day feeding study in the rat with semi-refined carrageenan from two sources, including a recovery phase. Unpublished report of project no. 3160/1/2/97 from BIBRA International, Carshalton, Surrey, United Kingdom. Submitted to WHO by Seaweed Industry Association of the Philippines, Searsport, Maine, USA.

Rustia, M., Shubik, P. & Patil, K. (1980) Lifespan carcinogenicity tests with native carrageenan in rats and hamsters. Cancer Lett., 11, 1–10.

Suzuki, J., Na, H.-K., Upham, B.L., Chang, C.-C. & Trosko, J.E. (2000) lambda-Carrageenan-induced inhibition of gap-junctional intercellular communication in rat liver epithelial cells. Nutr. Cancer, 36, 122–128.

Taché, S., Peiffer, G., Millet, A.-S. & Corpet, D.E. (2000) Carrageenan gel and aberrant crypt foci in the colon of conventional and human flora-associated rats. Nutr. Cancer, 37, 75–80.

Watanabe, K., Reddy, B.S., Wong, C.C. & Weisburger, J.H. (1978) Effect of dietary undegraded carrageenan on colon carcinogenesis in F344 rats treated with azoxymethane or methylnitrosourea. Cancer Res., 38, 4427–4430.

Wilcox, D.K., Higgins, J. & Bertram, T.A. (1992) Colonic epithelial cell proliferation in a rat model of nongenotoxin-induced colonic neoplasia. Lab. Invest., 67, 405–411.

¹ ADI ‘not specified’ is used to refer to a food substance of very low toxicity, which, on the basis of the available data (chemical, biochemical, toxicological, and other) and the total dietary intake of the substance arising from its use at the levels necessary to achieve the desired effect and from its acceptable background levels in food, does not, in the opinion of the Committee, represent a hazard to health. For that reason, and for reasons stated in individual evaluations, the establishment of an ADI expressed in numerical form is not deemed necessary. An additive meeting this criterion must be used within the bounds of good manufacturing practice, i.e., it should be technologically efficacious and should be used at the lowest level necessary to achieve this effect, it should not conceal food of inferior quality or adulterated food, and it should not create a nutritional imbalance.

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       Toxicological Abbreviations