Table 9.
Summary of the outcomes of the toxicological studies of HBCDDs in experimental animals on repeated dose
| Test compound | Species | Exposure | Outcome | NO(A)EL/LO(A)EL | Reference |
|---|---|---|---|---|---|
| HBCDDs Isomer mixture ‘neat’ (CAS 3194‐55‐6) (Promochem) Purity: 99.2% No information on stereoisomer composition | Mice (BALB/c) Juvenile (25 days old at start of the experiment) F | Dietary (fish based), 28 days 10 animals/group Feed ration: 15% (w/w)/kg bw per day 0, 49.5 μg/kg bw per day, 199 mg/kg bw per day Vehicle: DMSO, 0.4 mL/kg feed Control: diet based on casein | Liver: Increased relative liver weight (high dose). Increased vacuolation in hepatocytes (at both doses), increased pyknotic nuclei (at both doses), lymphocytic infiltration (at both doses) and hyperaemic vessels (at both doses). Uterus: Increase in incidence of reduction in endometrial glands density and irregular multistratification of the luminal epithelium (low dose). Thymus: Cortical invasivity (high dose) or signs of tissue stress (Hassal's bodies) (low dose). Thyroid: Increased ratio between follicle and colloid areas (at both doses), desquamation into follicular lumen and foaming colloid (low dose), increased ratio of follicular epithelium areas and number of nuclei (low dose). Spleen: Increase lymphocyte hyperplasia (high dose). Hormones: Lower serum concentration of 17β‐oestradiol (low dose); increased concentration of testosterone (high dose); and increase ratio testosterone to 17β‐oestradiol (at both doses). See further details in Appendix C . | LOEL = 49.5 μg/kg bw per day | Maranghi et al. (2013), Rasinger (2011), Rasinger et al. (2014, 2018). Data from the same animal trial published in three articles and PhD thesis. |
| HBCDDs Purity: not reported (Sigma‐Aldrich) No information on stereoisomer composition | Mice (C57BL/6J) M 5–6 animals/group | 0, 1.75, 35, 700 μg/kg bw, once per week by gavage Normal and high‐fat diet From 6 to 20 weeks | Metabolic effects: Body and liver weights increases at the two highest doses, along with paralleled increases in blood glucose and insulin levels and microvesicular steatosis and macrophage accumulation in adipose tissue in the high‐dose group. | Increased body and liver weight in combination with high‐fat diet: NOEL = 1.75 μg/kg bw/week (or 0.25 μg/kg bw per day) LOEL = 35 μg/kg bw/week (or 5 μg/kg bw per day) | Yanagisawa et al. (2014) |
| α‐HBCDD Produced from γ‐HBCDD by thermal rearrangement Purity: not reported | Mice (BALB/c) F 3 weeks of age 8 animals/group | Dietary, 28 days 46 ng/kg bw (control), 107 μg/kg bw per day, 116 mg/kg bw per day LC n‐3 PUFAs: 4.9 g/kg | Influence of LC n‐3 PUFAs on α‐HBCDD mediated effects: The highest dose of α‐HBCDD affected liver lipid composition and increased body and liver weight as aggravated by high PUFA intake. The highest dose also reduced thymus weight. The lowest dose slightly reduced body weight gain and liver somatic index. The lowest dose reduced serum cholesterol and the highest dose reduced triacylglycerol. Increased AST serum level was observed at the highest dose and an increase in catalase activity was noted at the low dose. Proteomics of the high‐dose group indicated effects on ß‐oxidation in liver. | Some effects at the lowest dose (107 μg/kg bw per day) but different directionality compared with the highest dose (116 mg/kg bw per day). LOAEL= 116 mg/kg bw per day | Bernhard et al. (2016) |
| HBCDDs Purity: 95% (Sigma Aldrich) 1% α‐, 1% β‐, 98% γ‐HBCDD | Rats (F344 M and F, Sprague‐Dawley F, Wistar F) 34–37 days old | Dietary, 28 days 0, 250, 1,250, 5,000 mg/kg diet (measured levels in the diet: 0, 221, 1,125, 3,549 mg/kg diet) Calculated daily consumption: F F344 rats: 0, 20, 102, 430 mg/kg bw per day M F334 rats: 0, 19, 94, 400 mg/kg bw per day F Sprague‐Dawley rats: 0, 21, 107, 412 mg/kg bw per day F Wistar rats: 0, 20, 112, 466 mg/kg bw per day 5 animals/group | Effects on liver, thyroid gland, immune system and endocrine system: Sex differences in metabolism (tissue concentration levels), immune response parameters and in number and severity of thyroid and liver lesions following exposure to T‐HBCDD, with greater responses in M. Wistar rats: thyroid (minimal to mild follicular hypertrophy). Sprague Dawley rats: liver (increase relative weight), thyroid (mild follicular hypertrophy). Decreased T‐cell and increased B‐cell population. F344 rats: liver (increase relative weight in F); thyroid (increase relative weight in M, mild follicular hypertrophy and colloid depletion); brain (decrease relative weight in F); kidney (mild chronic nephropathy and mild multifocal tubular mineralisation in all treated M); spleen (atrophy in two high‐dose M, decrease splenocytes proliferation in M and F); ovaries: (significant reduction in the number of growing follicles). Decrease in IgG serum immunoglobulin in F. Decreased T‐cell and increased B‐cell population, increase in NK‐cells in M. Changes in multiple haematological parameters in M and F at the two highest doses. Changes in clinical chemistry parameters (AST and creatine kinase) in all strains, more pronounced in F344 rats. Decrease serum T4 level at the three dose levels in M F344 rats. Increase cholesterol and triglycerides in the two high doses in F F344 rats. Wistar and Sprague Dawley rats: Concentration of γ‐isomer was more abundant than α‐isomer in serum, adipose tissues and also in the liver (lower concentration); the β‐isomer was not detected. F344 rats: higher α‐ and γ‐ isomers accumulation in F compared to M, except for the α‐isomer in serum. | LOAEL F344 rats = 19 mg/kg bw per day LOAEL F Wistar rats = 20 mg/kg bw per day LOAEL F Sprague‐Dawley rats = 21 mg/kg bw per day | Gannon et al. (2019a) |
| HBCDDs enriched with α‐HBCDD (A‐HBCDD) Purity: 95% (Technical HBCDD) (Sigma Aldrich) 81% α‐, 7% β‐, 12% γ‐HBCDD | Rats (F344) F, M 5 animals/group | Dietary, 28 days 0, 250, 1,250, 5,000 mg/kg diet (measured levels in the diet: 0, 200, 898, 3,938 mg/kg diet) Calculated daily consumption: M: 0, 19, 97, 395 mg/kg bw per day F: 0, 19, 99, 363 mg/kg bw per day | Effects on liver, thyroid gland, immune system and endocrine system: Increased relative liver weight at two high doses in M and F, and thyroid weight at high dose in M and F, decreased thymus and brain weight in two high‐dose F. Changes in haematological and clinical chemistry parameters in M and F. A‐HBCDD residue concentrations: α‐isomer was more abundant than the γ‐isomer in serum, adipose tissues and also in the liver (lower concentration). Significantly higher A‐HBCDD accumulation in F. Histopathological effects: liver (increased incidence and severity zone 3 hepatocellular hypertrophy), thyroid (dose‐related increase in incidence and severity of follicular hypertrophy and hyperplasia, colloid depletion), spleen (dose‐related increase in lesions: mild to marked PALS atrophy, mild follicular and MZ atrophy), ovaries (increase proportion of growing follicles) Decrease in splenocytes proliferation. Increase in serum immunoglobulin IgA at high dose. Changes in blood lymphocytes populations: decrease in TH cells and increase in Tc cells in high‐dose F, but no change in T‐cell/B‐cell ratio; changes in T‐cell and B‐cell populations at the highest dose in M, decrease in TH cells, TH/Tc ratio and increase in NK and B cells. Treatment‐related effect in thymus lymphocyte subpopulations in M. | NOAEL = 19 mg/kg bw per day | Gannon et al. (2019a) |
| HBCDDs Purity: not reported (Sigma‐Aldrich) No information on stereoisomer composition | Mice (C57BL/6) M 3–4 weeks of age 6 animals/group | 0, 50 μg/kg bw per week For 31 weeks from 3–4 weeks of age | Adipogenic effects. Increased epididymal white adipose tissue weight and hypertrophy. | Increased epididymal white adipose tissue weight and hypertrophy: LOEL = 50 μg/kg bw per week | Xie et al. (2019) |
| HBCDDs Purity: 96% (Gojira Fine Chemicals) No information on stereoisomer composition | Rat (Harlan Sprague Dawley) M 7‐week old 6 animals/group | 0, 0.1, 1, 10, 100, 1,000 μM/kg bw per day (corresponding to 0, 0.06, 0.641, 6.41, 64.1, 641 mg/kg bw per day, as reported by the authors) Gavage 5 days Vehicle: corn oil | Liver: increased weight (1.2 X) and incidence of centrilobular hepatocyte hypertrophy at HD and significant increase UDP GT1a1 enzyme at two highest doses. Thyroid: no histological changes. | NOAEL = 6.41 mg/kg bw per day | Shockley et al. (2020) |
AST: aspartate aminotransferase; BMDL: benchmark dose lowest confidence interval; DMSO: Dimethyl sulfoxide. F: female; HBCDDs: hexabromocyclododecanes; IgA: immunoglobulin A; IgG: Immunoglobulin G; M: male; LC n‐3 PUFAs: long‐chain omega‐3 polyunsaturated fatty acids; MZ atrophy: marginal zone atrophy; LOEL: lowest‐observed effect; LOAEL: lowest‐adverse‐effects level; NK‐cells: natural killer cells; NOEL: no‐observed‐effect level; PALS: periarteriolar lymphatic sheaths; Tc cells: cytotoxic T cells; TH cells: T helper cells; T4: thyroxine.