Adverse Effects
Dichlofluanid
CAS No.1085-98-9
 
 

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Activity: Fungicide, Acaricide, Wood Preservative
Structure:

Adverse Effects:
Blood
Bone - Cranial osteosclerosis
Brain
Carginogenic
Endocrine: Ovary; Vitellogenesis

Endocrine: Pituitary
Endocrine: Suspected Disruptor
Endocrine: Testicular

Endocrine: Thyroid
Genotoxic - Potent Cytoxicant
Kidney

Liver
Contamination
Environmental

Dichlofluanid is widely used on food crops in Japan. Also widely used on food crops in the European Union up to July 25, 2003 - after which date it is not allowed to be used.


Dichlofluanide has been reported as a hormonally active substance in the environment in a review of the German Umweltbundesambt (Schramm et al., 1996). However, a concentration range for which this "hormonal activity" was found, was not reported (page 44).
[Schramm K.-w., thumm W. * Kettrup A. (1996). Hormonal active substances in the environment: exposition, impact and detection. Expert Round. Endocrinically active chemicals in the environment. UBA Texte 3/96. Umweltbundesamt, Germay.]

Ref: RIVM report 601506005. BIOCIDES (II). Refined aquatic environmental risk assessment of 28 priority biocides. B.J.W.G. Mensink. November 2000. RIVM = Rijksinstituut voor Volksgezondheid en Milieu. National Institute of Public Health and the Environment.
http://www.rivm.nl/bibliotheek/rapporten/601506005.pdf


Blood (click on for all fluorinated pesticides)

-- One-year Study. A repeat-exposure study using Beagles (4/dose/sex) is available; it was GLP and OECD Annex V compliant. Animals were administered either vehicle or 2.5, 12.5 or 37.5/62.5 mg kg -1 d -1 of dichlofluanid (90 % purity) in capsule form for one year. The top dose was reduced at week 15 to 37.5 mg kg -1 d -1 because of excessive toxicity. As a NOEL could not be established with the initial dosing regime, a subsequent study was carried out in which 0 or 1.25 mg kg -1 d -1 dichlofluanid was used. Interim blood samples were taken at 13, 26, 39 and 52 week (terminal bleed); in addition samples were taken from some animals in the top-dose group at 14, 15 and 19 weeks... The haematology findings in males receiving 37.5 mg kg -1 d -1 from 6 months onwards were decreased numbers of erythrocytes (4 %), haemoglobin concentration (7.5 %) and haematocrit (7.4 %). Mild to moderate hepatic haemosiderin deposition was reported and was particularly extensive in two animals. None of these effects achieved statistical significance. However, as they were outside the range of supplied historical control data they were considered to be treatment related. The following data, in animals at the top dose, outside the range of supplied historical control data (еееее2SD), except BUN, creatinine, and triglyceride levels in females. This clinical chemistry data refers to the first study and unless otherwise stated the data were collected at study termination. Increases in ALP (215 % and 18 % males and females respectively), AST (81 % males only*), ALT (595 % and 293 % males and females respectively) and gammaGT (360 % males only) levels were reported in animals 37.5 mg kg -1 d -1 . An increase in ALT levels (350 % males only) at 12.5 mg kg -1 d -1 was also reported. Serum concentrations of cholesterol were elevated in animals receiving 12.5 mg kg -1 d -1 (20 % and 23 % males and females respectively) and 37.5 mg kg -1 d -1 (132 %* and 89 % males and females respectively). The serum concentration of triglycerides were elevated in females only (63 % and 59 % at 12.5 mg kg -1 d -1 and 37.5 mg kg -1 d -1 respectively). Elevated BUN (males only 114 %) and creatanine levels were reported (77 %* and 22 %* males and females respectively) at 37.5 mg kg -1 d -1 . One male receiving 12.5 mg kg -1 d -1 was also reported to have elevated BUN and creatanine levels (*statistically significant)...
Ref:
January 2003 - Evaluation on: Booster biocides in antifouling products. Full review of Dichlofluanid. No. 206. Evaluation of Fully Approved or Provisionally Approved Products. Prepared by : The Health and Safety Executive Biocides & Pesticides Assessment Unit, Magdalen House, Stanley Precinct Bootle Merseyside L20 3QZ Available from: Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK.

Bone (click on for all fluorinated pesticides)

-- In the chronic studies, the most consistent findings were cranial osteosclerosis in the rat, and findings consistent with fluorosis in a 2-year mouse study. Clinical chemistry findings with supportive histopathology were observed in a 1-year study in the dog which were indicative of renal and liver damage. A detailed assessment of cranial osteosclerosis was performed in a 2-year study in the rat; a LOEL was established at 10-14 mg kg -1 d -1 . There was a clear increase in the incidence of cranial osteosclerosis in the low- and middle-dose groups, with almost all animals affected at the top dose. These findings are likely to be secondary to fluorosis in these animals. In terms of interspecies comparisons, in a mouse 2-year study, thickening of both the appositional bone of the cranial vault and nasal turbinates, and tooth alveolitis were observed at the top dose of 1,731-1,873 mg kg -1 d -1 . These findings are also considered to be a secondary consequence of fluorosis in these animals. No evidence of fluorosis was observed in the dog studies. . In this study a NOAEL of 2.5 mg kg -1 d -1 was established with nephropathy reported at 12.5 mg kg -1 d -1 .
-- It is considered that cranial osteosclerosis is likely to represent a fluoride mediated perturbation of bone metabolism but is not considered to be of concern for human health. It is also considered that the observed renal and liver damage is of concern to human health. For professional operators the ACP considered that the most appropriate NOAEL to use in risk assessments was the figure of 2.5 mg kg -1 d -1 taken from the one year dog study. Professional operators would not be expected to use products for prolonged periods, therefore a value from a one year study would be suitable. The other reported end points (thyroid tumours and osteosclerosis were associated with chronic exposure and much higher doses. Acceptable risk assessments would require a safety margin of about 100 over the NOAEL 2.5 mg kg -1 d -1 . Consequently these would also offer a high margin of safety against the longer term end points.

-- One-year Study. A repeat-exposure study using Beagles (4/dose/sex) is available; it was GLP and OECD Annex V compliant. Animals were administered either vehicle or 2.5, 12.5 or 37.5/62.5 mg kg -1 d -1 of dichlofluanid (90 % purity) in capsule form for one year. The top dose was reduced at week 15 to 37.5 mg kg -1 d -1 because of excessive toxicity. As a NOEL could not be established with the initial dosing regime, a subsequent study was carried out in which 0 or 1.25 mg kg -1 d -1 dichlofluanid was used... The pathology report on the interim kills revealed "a whitish hardening" of the cranium (still present at study termination). At the interim kill, the absolute heart weight was significantly decreased in both sexes at the top dose only (18 % and 14 % males and females respectively). The increases in relative liver weight in both sexes, and relative kidney and brain weight in females, reported at 4500 ppm reflected the previously noted decreases in body weight. In males at study termination the absolute organ weights of the kidney (5 %) and testes (5.6 %) were significantly increased at the top dose. At study termination the relative testes weight was increased in the top-dose group (18 %). The reported increases in relative organ weights reflected the decreases in body weights noted earlier. Histopathology of the satellite groups revealed a dose-dependent increase in cranial osteosclerosis in females, achieving statistical significance in the middle (8/10) and top-dose groups (9/10) when compared to control animals (1/10). In males however a significant increase in cranial osteosclerosis was only found in the low- (7/10) and top-dose groups (9/10); control (1/10). An increase in cranial lamellar growth patterns was also reported in males at the top dose (7/10, and controls 0/10). The forestomachs of males from the top-dose group were found to have a higher incidence of hyperkeratosis and acanthosis (0/10 and 5/10 controls and 4500 ppm respectively). The thyroids of males exhibited follicular cell hypertrophy; 0/50 (control), 2/10 (180 ppm), 1/10 (900 ppm) and 3/10 (4500 ppm). Histopathology of the main groups (24 months) revealed a significant increase in hyperkeratosis and acanthosis of the forestomach in males (2/49 and 21/49 controls and 4500 ppm respectively) and females (0/49 and 12/49 controls and 4500 ppm respectively). A significant increase in the incidence of cranial osteosclerosis was apparent in males of all treatment groups and in females at the top dose. These data also suggest an increase in severity with increasing dose. See Table 3.10. A significant decrease in sternal chondrodystrophy reported in females of the top-dose group. A significant increase in cranial lamellar growth patterns was reported in both sexes at the top dose (45/49 and 37/50 males and females respectively) compared to the controls (1/49 and 0/50 males and females respectively)... [Unpublished, 1993(b)]

Dichlofluanid: Table 3.9 : Fluoride Content Of Bones And Teeth At Study Termination
males
site 0 ppm 180 ppm 900 ppm 4500 ppm
teeth* 0.12 0.27 1.17 3.92
bones* 0.43 0.97 2.91 13
females
site 0 ppm 180 ppm 900 ppm 4500 ppm
teeth* 0.11 0.32 1.12 5.36
bones* 0.66 1.44 3.53 11.46
* mg fluoride/g ash

Dichlofluanid: Table 3.10 : Incidence And Severity Of Cranial Osteosclerosis
  males (dose ppm) females (dose ppm)
grade 0 180 900 4500 0 180 900 4500
minimal 0 6 4 0 12 1 1 1
slight 11 14 24 4 0 7 13 8
moderate 0 11 6 18 0 10 2 22
marked 0 3 0 26 0 2 0 9
severe 0 0 0 1 0 0 0 6
total 11 34* 34* 49* 12 20 16 46*
* statistically significant

Dichlofluanid: Table 3.12 : Incidence Of Skull And Nasal Turbinate Thickness And Tooth Alveolitis Reported On Necropsy
 
numbers
 
controls
5000 ppm
pathology males females males females
skull thickness 0/45 0/46 39/42 40/40
turbinate thickness 0/45 0/46 23/42 35/40
tooth alveolitis 0/45 1/46 17/42 19/40

The fluoride content of teeth and bone was found to be significantly increased at all doses and time points for both sexes. See Table 3.13.

Dichlofluanid: Table 3.13 : Fluoride Content of Bones and Teeth (mg g -1 ash)
 
teeth
bone
 
week 53
week 104
week 53
week 104
dose male female male female male female male female
0 0.4 0.4 0.2 0.3 1.1 0.9 1.1 1.2
200 0.7 0.6 0.7 0.8 2.4 1.5 3.6 2.9
1000 2.2 2.1 2.4 2.2 6 4.3 8.3 7.3
5000 10.9 9.9 15.7 13.8 17.4 14.5 18.7 17.5

Ref: January 2003 - Evaluation on: Booster biocides in antifouling products. Full review of Dichlofluanid. No. 206. Evaluation of Fully Approved or Provisionally Approved Products. Prepared by : The Health and Safety Executive Biocides & Pesticides Assessment Unit, Magdalen House, Stanley Precinct Bootle Merseyside L20 3QZ Available from: Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK.

Brain (click on for all fluorinated pesticides)

-- Mouse Carcinogenicity Study A 2-year OECD-compliant carcinogenicity study carried out to GLP is available. Animals (SPF mice B63CF1 60 sex/group) received dietary administration of either 0, 200, 1000 or 5000 ppm dichlofluanid (89-93 % purity); equivalent to 50.1, 273.9 or 1731.3 and 63.7, 337 or 1872.7 mg kg -1 d -1 in females and males respectively. The scheduled study termination was after 104 weeks, with an interim kill at 52 weeks; all animals were necropsied plus any dying or sacrificed intercurrently... There were effects on both the relative and absolute organ weights. The following absolute organ weights were reduced : brain (5 % males and 6 % females), spleen (14 % females), and kidney (18 % females) at the top dose.
-- There were effects on both the relative and absolute organ weights. In males, at the top dose, there were significant decreases in the absolute organ weights of the lung (20 %), brain (8 %) and testes (6 %). In females at the top dose there were significant decreases in the absolute organ weights of the brain (8 %), spleen (42 %) and kidney (18 %). The relative organ weights of the brain (13 %), liver (44 %), spleen (36 %) and testes (5 %) were increased in males at the top dose. In females the relative brain (7 %) and liver (47 %) weights were increased and the kidney (6 %) and ovary weights (28 %) were decreased. No incidences of toxicologically significant histopathology (liver included) were reported.
Ref: January 2003 - Evaluation on: Booster biocides in antifouling products. Full review of Dichlofluanid. No. 206. Evaluation of Fully Approved or Provisionally Approved Products. Prepared by : The Health and Safety Executive Biocides & Pesticides Assessment Unit, Magdalen House, Stanley Precinct Bootle Merseyside L20 3QZ Available from: Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK.

Carginogenic (click on for all fluorinated pesticides)

PubMed abstract: Seven different endpoints for detection of genotoxicity have been used to demonstrate the DNA-altering properties of Dichlofluanid, a fungicide commonly used in viticulture pest control. Each endpoint (DNA synthesis inhibition test, alkaline viscosimetry, umu-test, alkaline filter elution, FADU-test, 32P-postlabeling, and electron microscopy) shows clear evidence of genotoxicity. These data indicate that application of the fungicide dichlofluanid may be mutagenic and/or carcinogenic for exposed humans.
Ref: Environ Mol Mutagen 1991;17(1):20-6. Genotoxicity of the fungicide dichlofluanid in seven assays; by Heil J, Reifferscheid G, Hellmich D, Hergenroder M, Zahn RK.

Endocrine: Ovary (click on for all fluorinated pesticides)

-- Two-year Study. The following study is considered to be flawed due to the lack of histopathological evaluation and it was not GLP compliant. Beagles (4/sex/group) received dietary administration of either 0, 100, 300, 1000 or 3000 ppm dichlofluanid (90 % purity); equivalent to 3.6, 10.5, 34 and 107 mg kg -1 d -1 (males) and 3.4, 11, 34 and 101.4 mg kg -1 d -1 (females) respectively, for a two year study period... Absolute organ weights in males of the liver, lung, spleen, kidneys, adrenals, pancreas and heart were all decreased at 3000 ppm; the greatest being a 35 % decrease in testes weight. Decreases in relative organ weights were reported in males in the thyroid, heart, spleen and testes (20 % at 3000 ppm) at the top dose. The relative kidney and liver weights were elevated at both 1000 (21 and 3.4 %) and 3000 ppm (18 and 10 %). In females absolute organ weights were reduced : the thyroid in all treatment groups, by 32-36 %; ovaries 31-55 % from 100 ppm; and heart by 14-27 % at 1000 and 3000 ppm. The absolute spleen weights were raised in females at 1000 ppm and above by 18-20 %. In females there was a slight increase in the relative organ weights of the pancreas above 1000 ppm and spleen weight was elevated by 25 and 60 % at 1000 and 3000 ppm. A decrease in ovary weight was reported at all doses (55 % at 3000 ppm). The changes in organ weight in females preclude the setting of a NOEL. [Unpublished, 1969]
Ref: January 2003 - Evaluation on: Booster biocides in antifouling products. Full review of Dichlofluanid. No. 206. Evaluation of Fully Approved or Provisionally Approved Products. Prepared by : The Health and Safety Executive Biocides & Pesticides Assessment Unit, Magdalen House, Stanley Precinct Bootle Merseyside L20 3QZ Available from: Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK.

PubMed Abstract: Two types of reactions were observed on the alteration of Drosophila vitellogenesis [established biomarker for estrogen action] by the four fungicides used in this study. Dithane M45 resulted in stimulation associated with egg retention. However, the other three fungicides (Benlate, Bouillie bordelaise and Euparene) resulted in inhibition to a varying degree. Although the inhibition was comparatively limited due to Benlate it induced an egg retention. The inhibition was very high due to Bouillie bordelaise and Euparene [dichlofluanid]. With Bouillie bordelaise an egg retention occured together with the reduction of vitellogenesis and caused an increase in the rate of the follicle resorption. The latter depended on the duration of treatment. With Euparene [dichlofluanid], no egg retention was observed and the toxicity was only noticed on vitellogenesis.
Ref: J Environ Sci Health B 1997 May;32(3):411-28. [Ovarian activity of Drosophila melanogaster Meigen (Diptera), during a chronic intoxication with four fungicides: anatomical and cytological study] [Article in French] by Marchal-Segault D, Lauge G.

Dichlofluanide has been reported as a hormonal active substance in the environment in a review of the German Umweltbundesambt (Schramm et al., 1996). However, a concentration range for which this "hormonal activity" was found, was not reported (page 44). [Schramm K.-w., thumm W. * Kettrup A. (1996). Hormonal active substances in the environment: exposition, impact and detection. Expert Round. Endocrinically active chemicals in the environment. UBA Texte 3/96. Umweltbundesamt, Germay.]
Ref: RIVM report 601506005. BIOCIDES (II). Refined aquatic environmental risk assessment of 28 priority biocides. B.J.W.G. Mensink. November 2000. RIVM = Rijksinstituut voor Volksgezondheid en Milieu. National Institute of Public Health and the Environment.

http://www.rivm.nl/bibliotheek/rapporten/601506005.pdf

Endocrine- Pituitary (click on for all fluorinated pesticides)

-- One-year Study A repeat-exposure study using Beagles (4/dose/sex) is available; it was GLP and OECD Annex V compliant. Animals were administered either vehicle or 2.5, 12.5 or 37.5/62.5 mg kg -1 d -1 of dichlofluanid (90 % purity) in capsule form for one year. The top dose was reduced at week 15 to 37.5 mg kg -1 d -1 because of excessive toxicity... The pituitary glands of several animals from the top-dose group were found to have mild to severe hyperplasia (2 males and 2 females) of large pale staining cells (basophils) in the pars distailis, among pituitary basophils are the thyrotrophs. Testicular degeneration was noted in 2 animals receiving 37.5 mg kg -1 d -1 , the lesion was widespread and of moderate/severe grade. Thymic atrophy was also reported in males receiving 37.5 mg kg -1 d -1 (3/4 animals).
-- Rat Two-Year Combined Chronic Toxicity And Carcinogenicity Study A 2-year combined chronic toxicity and carcinogenicity study is available. This study was carried out to EPA guidelines and was both GLP and Annex V compliant. Wistar rats (BOR:WISW strain, 50 group/sex, plus 10/sex group interim kill) received dietary administration of either 0, 180, 900 or 4500 ppm dichlofluanid (89-93 % purity). This was equivalent to 9.4, 54.4 or 301.3 mg kg -1 d -1 and 13.5, 73.1 or 420.7 mg kg -1 d -1 for males and females respectively. Those animals scheduled as interim kills were sacrificed after 53 weeks and study termination was scheduled for 106 weeks. Interim blood samples were taken at weeks 26, 53 and 79 for clinical chemistry and haematology. Urinalysis was also carried out at these time points. Deaths were reported in both the satellite and main groups. In the main study the terminal mortalities were 12 %, 18 %, 30 % and 16 % at 0, 180, 900 and 4500 ppm in males and 26 %, 26 %, 22 % and 20 % at 0, 180, 900 and 4500 ppm in females.... No treatment-related neoplastic alterations were reported in the satellite group. Tumours found were a malignant lymphoma (male 4500 ppm), a malignant fibrosarcoma of the skin (male 4500 ppm) and a benign pituitary adenoma (female 180 ppm). In the main group, treatment-related tumours of the thyroid were noted.

Ref: January 2003 -
Evaluation on: Booster biocides in antifouling products. Full review of Dichlofluanid. No. 206. Evaluation of Fully Approved or Provisionally Approved Products. Prepared by : The Health and Safety Executive Biocides & Pesticides Assessment Unit, Magdalen House, Stanley Precinct Bootle Merseyside L20 3QZ Available from: Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK.

Endocrine: Suspected Disruptor (click on for all fluorinated pesticides)

Dichlofluanide has been reported as a hormonal active substance in the environment in a review of the German Umweltbundesambt (Schramm et al., 1996). However, a concentration range for which this "hormonal activity" was found, was not reported (page 44).
[Schramm K.-w., thumm W. * Kettrup A. (1996). Hormonal active substances in the environment: exposition, impact and detection. Expert Round. Endocrinically active chemicals in the environment. UBA Texte 3/96. Umweltbundesamt, Germay.]

Ref: RIVM report 601506005. BIOCIDES (II). Refined aquatic environmental risk assessment of 28 priority biocides. B.J.W.G. Mensink. November 2000. RIVM = Rijksinstituut voor Volksgezondheid en Milieu. National Institute of Public Health and the Environment.

http://www.rivm.nl/bibliotheek/rapporten/601506005.pdf

Endocrine: Testicular (click on for all fluorinated pesticides)

-- One-year Study. A repeat-exposure study using Beagles (4/dose/sex) is available; it was GLP and OECD Annex V compliant. Animals were administered either vehicle or 2.5, 12.5 or 37.5/62.5 mg kg -1 d -1 of dichlofluanid (90 % purity) in capsule form for one year. The top dose was reduced at week 15 to 37.5 mg kg -1 d -1 because of excessive toxicity. As a NOEL could not be established with the initial dosing regime, a subsequent study was carried out in which 0 or 1.25 mg kg -1 d -1 dichlofluanid was used... There were also non-significant decreases in both absolute and relative thyroid weights (39 % and 33 % respectively) and testes weights (25 % and 15 % respectively). Two animals were found to have bilateral testicular degeneration; no control animals were reported with bilateral testicular degeneration. In females absolute (15-60 %) and relative (25-150 %) ovary weights were increased in all treatment groups. These increases were not dose related or statistically significant... Minimal to severe thyroid follicular cell degeneration was reported in all animals from the top-dose group and one male from the middle-dose group. The pituitary glands of several animals from the top-dose group were found to have mild to severe hyperplasia (2 males and 2 females) of large pale staining cells (basophils) in the pars distailis, among pituitary basophils are the thyrotrophs. Testicular degeneration was noted in 2 animals receiving 37.5 mg kg -1 d -1 , the lesion was widespread and of moderate/severe grade. Thymic atrophy was also reported in males receiving 37.5 mg kg -1 d -1 (3/4 animals). In the second study (0 or 1.25 mg kg -1 d -1 ), no obvious treatment-related effects were reported in the clinical chemistry, haematology or urinalysis parameters measured. At necropsy the following findings were reported. Both absolute and relative testes weights were decreased (29 % and 25 % respectively). However in the absence of a dose response (when compared to the higher doses used in the first study), and as the weights were within the range of historical control values, this observation was not thought to be of toxicological significance. No statistically significant treatment-related organ weight changes were reported in females. Inspection of the data revealed absolute and relative ovary weight increases (60 % and 175 % respectively). The large SD values and small numbers make it difficult to assess the significance of these data. One incidence of testicular degeneration was reported at necropsy in both control and treated animals. Overall the ACP concluded that the ovarian weight increases were not relevant and that a NOAEL of 2.5 mg kg -1 d -1 could be determined from these studies. [Unpublished, 1992] ... In males at study termination the absolute organ weights of the kidney (5 %) and testes (5.6 %) were significantly increased at the top dose. At study termination the relative testes weight was increased in the top-dose group (18 %)...
-- Two-year Study. The following study is considered to be flawed due to the lack of histopathological evaluation and it was not GLP compliant. Beagles (4/sex/group) received dietary administration of either 0, 100, 300, 1000 or 3000 ppm dichlofluanid (90 % purity); equivalent to 3.6, 10.5, 34 and 107 mg kg -1 d -1 (males) and 3.4, 11, 34 and 101.4 mg kg -1 d -1 (females) respectively, for a two year study period... Absolute organ weights in males of the liver, lung, spleen, kidneys, adrenals, pancreas and heart were all decreased at 3000 ppm; the greatest being a 35 % decrease in testes weight. Decreases in relative organ weights were reported in males in the thyroid, heart, spleen and testes (20 % at 3000 ppm) at the top dose. The relative kidney and liver weights were elevated at both 1000 (21 and 3.4 %) and 3000 ppm (18 and 10 %). In females absolute organ weights were reduced : the thyroid in all treatment groups, by 32-36 %; ovaries 31-55 % from 100 ppm; and heart by 14-27 % at 1000 and 3000 ppm. The absolute spleen weights were raised in females at 1000 ppm and above by 18-20 %. In females there was a slight increase in the relative organ weights of the pancreas above 1000 ppm and spleen weight was elevated by 25 and 60 % at 1000 and 3000 ppm. A decrease in ovary weight was reported at all doses (55 % at 3000 ppm). The changes in organ weight in females preclude the setting of a NOEL. [Unpublished, 1969]
--
-- Dichlofluanid (unspecified purity) was given by gavage at 200 mg kg -1 in DMSO (4 or 5 animals). Autoradiography of 3 H-thymidine labeled samples was used to measure testicular DNA synthesis. Dichlofluanid was reported to cause a statistically significant decrease in the incorporation of 3 H-thymidine into DNA and was therefore positive. [Unpublished, 1977]
Ref: January 2003 - Evaluation on: Booster biocides in antifouling products. Full review of Dichlofluanid. No. 206. Evaluation of Fully Approved or Provisionally Approved Products. Prepared by : The Health and Safety Executive Biocides & Pesticides Assessment Unit, Magdalen House, Stanley Precinct Bootle Merseyside L20 3QZ Available from: Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK.

Endocrine: Thyroid (click on for all fluorinated pesticides)

-- Professional operators would not be expected to use products for prolonged periods, therefore a value from a one year study would be suitable. The other reported end points (thyroid tumours and osteosclerosis) were associated with chronic exposure and much higher doses. Acceptable risk assessments would require a safety margin of about 100 over the NOAEL 2.5 mg kg -1 d -1 . Consequently these would also offer a high margin of safety against the longer term end points.
-- Carcinogenicity - The only carcinogenicity data relate to the oral route of exposure, with studies performed in the rat and mouse. No evidence of carcinogenic potential was observed in the mouse. However, in the rat dichlofluanid was found to cause an increase in the incidence of thyroid follicular cell tumours at the highest dose level of 300-420 mg kg -1 d -1 . These tumours occurred at a single site, were of late onset and generally benign pathology. Dichlofluanid has been thoroughly examined for genotoxic potential and the available data indicate that dichlofluanid was not an in vivo somatic cell or germ cell mutagen. The results of the histopathological examination of the thyroid follicular cell tumours are consistent with a non-genotoxic aetiology. Overall, it can be concluded that dichlofluanid is a non-genotoxic rat thyroid follicular cell carcinogen.
-- Dichlofluanid was found to cause an increase in the incidence of thyroid tumours at highest dose level of 300-420 mg kg -1 d -1 . These tumours occurred at a single site, were of late onset and generally benign pathology. These pathology findings are indicative of a non-genotoxic aetiology, consistent with the overall conclusions from the genotoxicity studies. Rat thyroid tumours arise as a secondary consequence of perturbations in thyroid hormone homeostasis, leading to prolonged stimulation of the thyroid gland via a positive feedback mechanism. Interspecies comparisons of the relative sensitivities of thyroid hormone homeostasis to disturbance by xenobiotics have shown that humans are markedly less sensitive than rats. Overall, the ACP considered that the rat thyroid follicular tumours would not be relevant to human health if they were due to treatment-related hormone imbalance. However it concluded that the in vitro studies did not convincingly demonstrate inhibition of thyroid peroxidase. Whilst it seemed probable that the mechanism was non-genotoxic, a more convincing explanation of the mechanism was required.
-- One-year Study. A repeat-exposure study using Beagles (4/dose/sex) is available; it was GLP and OECD Annex V compliant. Animals were administered either vehicle or 2.5, 12.5 or 37.5/62.5 mg kg -1 d -1 of dichlofluanid (90 % purity) in capsule form for one year. The top dose was reduced at week 15 to 37.5 mg kg -1 d -1 because of excessive toxicity. As a NOEL could not be established with the initial dosing regime, a subsequent study was carried out in which 0 or 1.25 mg kg -1 d -1 dichlofluanid was used... Levels of the thyroid hormones T3 (28 %) and T4 (37 %) were elevated at study termination in animals receiving 37.5 mg kg -1 d -1 . At necropsy, treatment-related pathology findings were reported in males receiving 37.5 mg kg -1 d -1 . Externally one animal was pale with discoloration of the kidney, liver and thyroid which was also reduced in size. There were also non-significant decreases in both absolute and relative thyroid weights (39 % and 33 % respectively) and testes weights (25 % and 15 % respectively). Two animals were found to have bilateral testicular degeneration; no control animals were reported with bilateral testicular degeneration. In females absolute (15-60 %) and relative (25-150 %) ovary weights were increased in all treatment groups. These increases were not dose related or statistically significant... Minimal to severe thyroid follicular cell degeneration was reported in all animals from the top-dose group and one male from the middle-dose group. The pituitary glands of several animals from the top-dose group were found to have mild to severe hyperplasia (2 males and 2 females) of large pale staining cells (basophils) in the pars distailis, among pituitary basophils are the thyrotrophs... The thyroids of males exhibited follicular cell hypertrophy; 0/50 (control), 2/10 (180 ppm), 1/10 (900 ppm) and 3/10 (4500 ppm)... In the thyroid gland a statistically significant increase in the lesion described as a focal follicular growth anomaly was established in both sexes at the top dose. In males the following data were presented : 1/50 (controls); 1/50 (180 ppm); 2/50 (900 ppm); and 3/49 (4500 ppm) and in females the data were : 0/50 (controls); 0/50 (180 ppm); 2/50 (900 ppm); and 4/49 (4500 ppm)... Two females sacrificed in extremis were found to have thyroid follicular cell carcinoma; one animal from each of the middle- and top-dose groups. No statistically significant neoplastic events were reported. However, a significant trend in the distribution of thyroid adenomas was found in both sexes. A NOEL could not be set due to the effects of excess fluoride and cranial osteosclerosis at the lowest dose. The NOEL for neoplasms could be set at 900 ppm (equivalent to 54.4 and 73.1 mg kg -1 d -1 for males and females respectively) due to the increase in thyroid tumours seen at the top dose. [Unpublished, 1993(b)]

Table 3.19 : Thyroid Hormone Levels During The Study
 
T3 (ng 100 ml -1 )
T4 (mg 100 ml -1 )
day 0 4500 ppm % 0 4500 ppm %
7 55.2 45.7 -17.3 3.9 2.6 -32
21 52.9 45.3 14.5 4.2 3.5 -16
63 67.6 61.8 -8.7 5.7 5.1 -11.5

Table 3.20 : Thyroid Weights At Day 7
dose ppm control 150 500 1500 4500
weight mg 10 14 13 15 16
% increase - 40 30 50 60

Ref: January 2003 - Evaluation on: Booster biocides in antifouling products. Full review of Dichlofluanid. No. 206. Evaluation of Fully Approved or Provisionally Approved Products. Prepared by : The Health and Safety Executive Biocides & Pesticides Assessment Unit, Magdalen House, Stanley Precinct Bootle Merseyside L20 3QZ Available from: Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK.

In July 1998, discussing this pesticide because it was an Accession Treaty priority for A, the CMR Group agreed to classify it with Xn; R20 : Xi; R36 : R43 : N; R50-53. Symbols Xn and N. R-phrases 20-36-43-50/53. S-phrases (2-)24-37-60-61. The proposal was sent to DG XI and included in the 25th ATP. Regarding carcinogenicity, S argued that the evidence was too weak for classification; tumour findings were limited to high dose groups. B expressed doubts about the aetiology of the rat thyroid tumours and, in relation to this, UK noted that dichlofluanid was an inhibitor of thyroid peroxidase. As the carcinogenicity issue was not problematic under the Accession Treaty, the Group agreed to conclude the present discussion with no classification for carcinogenicity. However, dichlofluanid would be referred back to the Pesticides Group for further consideration of carcinogenicity classification. A explained that the thyroid tumours seen in rats were limited to high dose groups and suggested classification with Carc Cat 3; R40. A also noted cranial effects in rodents that justify R48/22. B, with support from IRL, P and E, considered the mechanism of tumour induction to involve liver enzyme induction which did not justify classification for carcino-genicity because it was not-relevant to humans. UK noted, however, data suggesting inhibition of thyroid peroxidase which would justify classification. The Group agreed that more information was required from Industry on these issues. A and UK offered to send their interpretation of the data made available by Ind.
Ref: EUROPEAN COMMISSION DIRECTORATE GENERAL JRC JOINT RESEARCH CENTRE Institute for Health and Consumer Protection Unit: Toxicology and Chemical Substances European Chemicals Bureau ECBI/12/99 Rev. 1 31.03.1999 SUMMARY RECORD Meeting of the Commission Working Group on the Classification and Labelling of Dangerous Substances Pesticides ECB Ispra, 18-20 November 1998

Genotoxic / Potent Cytoxicant (click on for all fluorinated pesticides)

Abstract: The cytotoxicity and lipid peroxidation of pesticides containing a halogen group were examined in isolated rat hepatocytes. We examined 9 pesticides of 3 different representative chemical families... The contents of the hydroperoxides in phospholipid, phosphatidylcholine hydroperoxide (PCOOH) and phosphatidylethanolamine hydroperoxide (PEOOH) were determined by the HPLC-chemiluminescence (CL-HPLC) method, which is sensitive and specific for lipid hydroperoxide. Chlorothalonil, dichlofluanid and captan were the most potent cytotoxicants evaluated by lactate dehydrogenase (LDH) leakage. PCP, NIP and CNP exhibited intermediate cytotoxicity. PCNB, fthalide and chlomethoxynil showed low cytotoxicity. The cellular phospholipid hydroperoxide (PCOOH and PEOOH) levels were remarkably increased by chlorothalonil (PCOOH, 23 times and PEOOH, 7 times), dichlofluanid (PCOOH, 523 times and PEOOH, 22 times) and captan (PCOOH, 518 times and PEOOH, 16 times) as compared with the control group. The PCOOH content was slightly increased by PCP (4.8 times) and NIP (6.3 times), whereas the other 4 pesticides did not change the phospholipid hydroperoxide level. Severe cytotoxicity was observed with a remarkable increase of phospholipid hydroperoxide by chlorothalonil, dichlofluanid and captan.
Ref: Biol Pharm Bull 1997 Mar;20(3):271-4. Cytotoxicity of organochlorine pesticides and lipid peroxidation in isolated rat hepatocytes; by Suzuki T, Komatsu M, Isono H.

Abstract: Seven different endpoints for detection of genotoxicity have been used to demonstrate the DNA-altering properties of Dichlofluanid, a fungicide commonly used in viticulture pest control. Each endpoint (DNA synthesis inhibition test, alkaline viscosimetry, umu-test, alkaline filter elution, FADU-test, 32P-postlabeling, and electron microscopy) shows clear evidence of genotoxicity. These data indicate that application of the fungicide dichlofluanid may be mutagenic and/or carcinogenic for exposed humans.
Ref: Environ Mol Mutagen 1991;17(1):20-6. Genotoxicity of the fungicide dichlofluanid in seven assays; by Heil J, Reifferscheid G, Hellmich D, Hergenroder M, Zahn RK.

Kidney (click on for all fluorinated pesticides)

-- In the chronic studies, the most consistent findings were cranial osteosclerosis in the rat, and findings consistent with fluorosis in a 2-year mouse study. Clinical chemistry findings with supportive histopathology were observed in a 1-year study in the dog which were indicative of renal and liver damage. A detailed assessment of cranial osteosclerosis was performed in a 2-year study in the rat; a LOEL was established at 10-14 mg kg -1 d -1..
-- A detailed assessment of cranial osteosclerosis was performed in a rat 2-year study (summarised in section 3.3.5.1) in which a LOEL was established at 10-14 mg kg -1 d -1 . A clear increase in the incidence of cranial osteosclerosis was observed in the low- and middle-dose groups, with almost all animals affected at the top dose. These findings are likely to be secondary to fluorosis in these animals. In terms of interspecies comparisons, in a mouse 2- year study, thickening of both the appositional bone of the cranial vault and nasal turbinates, and tooth alveolitis were observed at the top dose of 1,731-1,873 mg kg -1 d -1 . These findings are also considered to be a secondary consequence of fluorosis in these animals. No evidence of fluorosis was observed in the dog studies. It is considered that these findings are likely to represent a fluoride mediated perturbation of bone metabolism but are not considered to be of concern for human health. It is considered that the observed liver and renal damage is of concern to human health.
-- In a 1-year dog study clinical chemistry findings with supportive histopathology, indicative of nephrotoxicity and liver damage, were observed. In this study a NOAEL of 2.5 mg kg -1 d -1 was established.
-- Two-year Study The following study is considered to be flawed due to the lack of histopathological evaluation and it was not GLP compliant. Beagles (4/sex/group) received dietary administration of either 0, 100, 300, 1000 or 3000 ppm dichlofluanid (90 % purity); equivalent to 3.6, 10.5, 34 and 107 mg kg -1 d -1 (males) and 3.4, 11, 34 and 101.4 mg kg -1 d -1 (females) respectively, for a two year study period. Interim blood sampling was carried out at 6 weeks, 6 months and 12 months for haematology, with interim clinical chemistry analysis being performed at 12 months... Changes reported in clinical chemistry parameters at 3000 ppm including increased ALP, ALT, bilirubin, cholesterol levels and BSP retention time, indicative of impaired hepatic function... Against a background of variable data, increases in serum creatinine (27 % males and 33 % females, at 3000 ppm) and urea levels (34 % males and 50 % females, at 3000 ppm) were reported, this being suggestive of impaired renal function. Direct measurements of kidney function at study termination revealed a decrease in both p-aminohippuric acid (PAH) and inulin clearance; (5 and 17 %) in males and (19 and 32 %) females at 24 months at 3000 ppm. These data provide further evidence for impaired renal function... The relative kidney and liver weights were elevated at both 1000 (21 and 3.4 %) and 3000 ppm (18 and 10 %).
Ref: January 2003 - Evaluation on: Booster biocides in antifouling products. Full review of Dichlofluanid. No. 206. Evaluation of Fully Approved or Provisionally Approved Products. Prepared by : The Health and Safety Executive Biocides & Pesticides Assessment Unit, Magdalen House, Stanley Precinct Bootle Merseyside L20 3QZ Available from: Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK.

Liver (click on for all fluorinated pesticides)

-- In the chronic studies, the most consistent findings were cranial osteosclerosis in the rat, and findings consistent with fluorosis in a 2-year mouse study. Clinical chemistry findings with supportive histopathology were observed in a 1-year study in the dog which were indicative of renal and liver damage. A detailed assessment of cranial osteosclerosis was performed in a 2-year study in the rat; a LOEL was established at 10-14 mg kg -1 d -1..
-- A detailed assessment of cranial osteosclerosis was performed in a rat 2-year study (summarised in section 3.3.5.1) in which a LOEL was established at 10-14 mg kg -1 d -1 . A clear increase in the incidence of cranial osteosclerosis was observed in the low- and middle-dose groups, with almost all animals affected at the top dose. These findings are likely to be secondary to fluorosis in these animals. In terms of interspecies comparisons, in a mouse 2- year study, thickening of both the appositional bone of the cranial vault and nasal turbinates, and tooth alveolitis were observed at the top dose of 1,731-1,873 mg kg -1 d -1 . These findings are also considered to be a secondary consequence of fluorosis in these animals. No evidence of fluorosis was observed in the dog studies. It is considered that these findings are likely to represent a fluoride mediated perturbation of bone metabolism but are not considered to be of concern for human health. It is considered that the observed liver and renal damage is of concern to human health.
-- In a 1-year dog study clinical chemistry findings with supportive histopathology, indicative of nephrotoxicity and liver damage, were observed. In this study a NOAEL of 2.5 mg kg -1 d -1 was established.
Ref: January 2003 - Evaluation on: Booster biocides in antifouling products. Full review of Dichlofluanid. No. 206. Evaluation of Fully Approved or Provisionally Approved Products. Prepared by : The Health and Safety Executive Biocides & Pesticides Assessment Unit, Magdalen House, Stanley Precinct Bootle Merseyside L20 3QZ Available from: Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK.

Contamination (click on for all fluorinated pesticides)

Wood preservative ruined 200 homes
By: Christian Ege Jørgensen, The Danish Ecological Council.
A wood preservative with the active ingredient dichlofluanid (a sulfamide fungicide) has created a disaster in Denmark. It was marketed in Denmark under the retail product name "Rentolin", and without a warning against indoor uses. (In other EU countries the product name may be different. We know that some wood preservatives containing dichlofluanid are marketed as e.g. "Preventol" and "Flourofolpet").
--
Around 200 people used Rentolin indoors and suffered serious injury. Many houses are now uninhabitable, and several people suffer from chronic diseases. Some have the diagnosis of MCS [Multiple Chemical Sensibility], meaning that they have violent reaction to all kinds of volatile chemical substances, natural and manmade as well. The sufferers have now formed a union of "Rentolin-injured" people, and have sued the importer. However he escaped to the United States. Experts are not unanimous that the said injuries were caused by dichlofluanid, but to us it appears to be the most likely explanation. Danish EPA finds it more probable that the organic solvent (a kind of white spirit) in Rentolin caused the disorders. But if so, we find it hard to understand why similar disorders have not been seen with indoor use of other products containing organic solvents, such as floor varnishes. The Rentolin case is probably the worst chemical disaster Denmark has seen for decades. We have urged the Danish EPA to make a thorough investigation of the causes, but still this has not been done. Now the same demand has been raised in the Danish parliament.
According to the EU, dichlofluanid is being used in Ireland, UK, Luxembourg, Germany, Austria, France, Spain, Portugal, Italy, and Greece. It is not included in any of the lists for European re-assessment of active ingredients under 91/414, though. As for Sweden we know that Rentolin was always marketed with the label "Only for outdoor use", but we do not know about other countries. Dichlofluanid is on the EU list of hazardous substances, classified as an allergen and hazardous to the environment.
We have already informed NGOs in other countries via the EEB chemicals group and the PAN-Europe (Pesticide Action Network). We recommend that NGOs investigate whether similar injuries have been found in other countries. If investigations show that dichlofluanid caused such disorders a joint call for a ban on the production and use of dichlofluanid in Europe must be considered.
Ref: Issue 17, Chemical Awareness (2001)
http://www.chemical-awareness.com/news.php?nid=18&aid=433
Chemical Awareness is financially supported by the Danish Environmental Protection Agency, the Swedish National Chemicals Inspectorate and the Swedish Society for Nature Conservation.
http://www.fluorideaction.org/pesticides/dichlofluanid.denmark.poiso.htm

Environmental (click on for all fluorinated pesticides)

Very high toxicity to aquatic organisms.
Ref: Examples of substances requiring particular attention. Swedish National Chemicals Inspectorate in collaboration with the Swedish Environmental Protection Agency and the Swedish National Board of Occupational Safety and Health. NATIONAL CHEMICALS INSPECTORATE. Order No 510 622. Second, revised edition, 1998.

Dichlofluanid is toxic to the freshwater algae Scenedesmus subspicatus which had 96 h EbC50 and ErC50 values of > 1 mg l -1 ; this was the highest concentration tested. Dichlofluanid is toxic to Daphnia magna, with an acute study resulting in a 48 h EC50 value of 0.42 mg ai l -1 and a NOEC of 0.07 mg l -1 . In a chronic study, Daphnia reproduction was inhibited by 51.7 % at 0.2 mg ai l -1 . Acute toxicity studies on the rainbow trout and blue gill sunfish resulted in 96 h LC50 values of 0.010 and 0.030 mg ai l -1 respectively, with NOECs of < 0.024 and < 0.0026 mg l -1 for bluegill sunfish and rainbow trout respectively. A study investigating the effects of dichlofluanid on carp resulted in a NOEC of 0.05 mg l -1 ... Although no marine data were submitted, dichlofluanid was shown to be highly toxic to aquatic organisms. The species most sensitive to chronic effects was Daphnia magna, with a 24 - d NOEC (reduced reproduction) of 40 µg ai l -1 .
anuary 2003 - Evaluation on: Booster biocides in antifouling products. Full review of Dichlofluanid. No. 206. Evaluation of Fully Approved or Provisionally Approved Products. Prepared by : The Health and Safety Executive Biocides & Pesticides Assessment Unit, Magdalen House, Stanley Precinct Bootle Merseyside L20 3QZ Available from: Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK.

Organic booster biocides were recently introduced as alternatives to organotin compounds in antifouling products, after restrictions imposed on the use of tributyltin (TBT) in 1987. Replacement products are generally based on copper metal oxides and organic biocides. This ban has led to an increase in alternative coating products containing the above biocides. The most commonly used biocides in antifouling paints are: Irgarol 1051, diuron, Sea-nine 211, dichlofluanid, chlorothalonil, zinc pyrithione, TCMS (2,3,3,6-tetrachloro-4-methylsulfonyl) pyridine, TCMTB [2-(thiocyanomethylthio) benzothiazole], and zineb. Since 1993, several studies have demonstrated the presence of these biocides in European coastal environment as a result of their increased use. More recently, the presence of these biocides was also revealed in waters from Japan, United States, Singapore, Australia and Bermuda. This paper reviews the currently available data on the occurrence of these biocides in the aquatic environment. Some data dealing with the environmental fate, partitioning, behaviour and risk assessment of antifouling paint booster biocides are also reported in order to discuss the detected levels of contamination.
Ref: Worldwide occurrence and effects of antifouling paint booster biocides in the aquatic environment: a review.
I. K. Konstantinou, and T. A. Albanis. Environment International; Volume 30, Issue 2 , April 2004, Pages 235-248.

 
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