Spinal Cord - Adverse Effects
Fluorinated and Fluoride Pesticides

A Superior Cervical Ganglion
B Coeliac Ganglion
C Superior Mesenteric Ganglion
D Inferior Mesenteric Ganglion
The coloured circles represent the paravertebral ganglionic chain.
Note the complex interactions of sympathetic nerves from various regions of the spinal cord.
Remember this diagram is highly simplified for clarity!!
Ref: http://greenfield.fortunecity.com/rattler/46/ans7.htm

The use of high doses increases the likelihood that potentially significant toxic effects will be identified. Findings of adverse effects in any one species do not necessarily indicate such effects might be generated in humans. From a conservative risk assessment perspective however, adverse findings in animal species are assumed to represent potential effects in humans, unless convincing evidence of species specificity is available.

-- Food and Agricultural Organization of the United Nations

Note: This is not an exhaustive list.
When time allows more information will be added.

Bromethalin - Rodenticide - CAS No. 63333-35-7

Abstract: Bromethalin is a new rodenticide for the control of commensal rodents. Doses in excess of the LD50 (2 mg/kg in rats) will cause death within 8-12 hr and it is preceded by one to three episodes of clonic convulsions with death usually due to respiratory arrest. Multiple low doses or sublethal intoxication yields hind leg weakness and loss of tactile sensation in rodents. Histopathology of the brain and spinal cord of these animals revealed a spongy degeneration of the white matter which was shown upon ultramicroscopic examination to be intramyelenic edema.
Ref: Fundam Appl Toxicol 1988 Nov;11(4):664-72 The toxicity and mechanism of action of bromethalin: a new single-feeding rodenticide. by van Lier RB and Cherry LD.


Chlorfenapyr - Acaricide, Insecticide - CAS No. 122453-73-0

-- MRID No. 42770219 (1993)-- 90-Day oral toxicity rats. NOAEL = 24.1 mg/kg/day. LOAEL = 48.4, based on spongiform myelopathy in the brain and spinal cord of male rats, decreased body weight gain and increased relative liver weight in males and females, increased absolute liver weight in females, and decreased hemoglobin in females.
Ref: Federal Register: September 26, 2003. Chlorfenapyr; Pesticide Tolerance. Final Rule.

ii. Subchronic Oral Toxicity in Mice... Spongiform encephalopathy was noted in the brain and myelin of the spinal cord of both males and females receiving the 320 ppm treatment level. The LEL is 14.8 mg/kg/day (80 ppm) for male mice and 40.0 mg/kg/day (160 ppm) for female mice, based on hepatic cell hypertrophy in  20% of the test animals at this treatment level. The NOEL is 7.1 mg/kg/day (40 ppm)... The RfD Committee also recommended that a special developmental neurotoxicity study be conducted based upon the effects of a spongyform myelopathy and/or vacuolation seen in the brain and spinal cord of treated rats and mice. They concluded that the registrant should also conduct a mechanistic study to determine the cause/relationship of CNS/myelinopathic alterations to neurotoxicity (including developmental)...
Chronic-Term (greater than several months) Occupational/Residential Dermal NOEL: 3 mg/kg/day (decreased body weight gains brain lesions (vacuolation) and/or scabbing of the skin in a 1 year neurotoxicity study in rats and a chronic/carcinogenicity study in mice) Acceptable MOE = 1000 (includes FQPA Factor)
Ref: US EPA, Feb 12, 1998: Chlorfenapyr - 129093: Health Effects Division Risk Characterization for Use of the Chemical Chlorfenapyr.


ONCOGENICITY, MOUSE . 066; 147076; "A Chronic Dietary Toxicity and Oncogenicity Study with AC 303,630 in Mice" (L. Bernier, Bio-Research Lab., Ltd., Quebec, Canada, Project # 84580, 8/22/94). AC 303,630 (Batch AC-7504-59A, 94.5% purity) administered orally in the diet to 65 CD-1 mice/sex/dose for 80 weeks at 0, 20, 120, or 240 ppm (Males: 0, 2.8, 16.6, or 34.5 mg/kg/day; Females: 0, 3.7, 21.9, or 44.5 mg/kg/day). Reduced survival rate was noted in high dose females (60% vs. 80%, p < 0.05). However, overall survival rate of this group was more comparable to that of the historical controls. Treatment with AC 303,630 resulted in reduced mean body weight gain in high dose males and females and in mid dose females (Males: 70% of control, p < 0.01, Females: 86% of control, p < 0.05 for mid and high dose groups). Food consumption was also reduced in mid and high dose animals. Histopathology revealed vacuolation of the white matter of the brain in animals treated at mid and high dose levels. Also, vacuolation was detected in spinal cord sections as well as optic nerve tissues in mice at 240 ppm. There was no evidence of carcinogenicity. NOAEL (M/F) = 240 ppm [No adverse effect]. NOEL (M/F) = 20 ppm (2.8 and 3.7 mg/kg/day for males and females, respectively; based on histopathological changes in the brain, optic nerve and spinal cord). acceptable (Leung, 7/24/96)
-- NEUROTOXICITY ** 061; 147070; "A One-Year Dietary Neurotoxicity Study with AC 303,630 in Rats"; (J.A. Foss; Argus Research Laboratories, Inc., Horsham, PA; Study No. 101-019; 5/10/94); AC 303,630 technical (purity: 94.5%) was administered in the diet to 25 animals/sex/group at doses of 0, 60, 300, and 600 ppm for up to 52 weeks ((M)-0, 2.6, 13.6, 28.2 mg/kg/day, (F)-0, 3.4, 18.0, 37.4 mg/kg/day). Surviving animals were observed for an additional 16 weeks of a recovery phase. No treatment-related effects were noted in the functional observational battery or the motor activity evaluation. In the neurohistopathology, myelin sheath swelling of the spinal nerve roots was evident in the males of the 600 ppm treatment group after 13 and 52 weeks of treatment. Extensive vacuolar myelinopathy was noted in the brain and spinal cord of the 300 and 600 ppm males after 52 weeks of treatment. These effects were no longer present after the 16 week recovery period. No treatment-related lesions were noted in the females. No adverse effects were evident. NOEL: (M) 60 ppm (based upon the incidence of extensive vacuolar myelinopathy in the central nervous system); (F) 600 ppm; NOAEL: 600 ppm (based on recovery). Study acceptable. (Moore, 7/29/96)

-- SUBCHRONIC STUDIES ** 010, 031; 125163; "AC 303,630: A 13 Week Dietary Toxicity Study in the Albino Rat", J.E. Fischer; 821; Rat; American Cyanamid Co., Agricultural Research Division, Toxicology Department, Princeton, NJ; Study No. T-0316; 4/8/93; AC 303,630 Technical (purity: 93.6%); 20 animals/sex/group; Doses: 0, 150, 300, 600, 900, 1200 ppm (M: 0, 10.9, 22.0, 44.9, 69.5, 92.2 mg/kg/day, F: 0 11.7, 24.1, 48.4, 72.5, 97.5 mg/kg/day), in the diet, 13 weeks; No treatment-related mortality; Clinical Observations: red. body wgt. gain (M,F-900, 1200 ppm), red. food consumption (M-600 ppm and up); Ophthalmology, Urinalysis: no treatment-related effects; Hematology: red. hematocrit (M,F-1200, F-900 ppm), red. hemoglobin (M,F-1200, F-600, 900 ppm), red blood cells (M,F-1200, F-900 ppm), Clinical Chemistry: incr. BUN (M,F-1200 ppm, week 6, M-1200 ppm, week 13), incr. alk. phosphatase activity (M,F-900, 1200 ppm, week 13); Necropsy: incr. mean abs. liver wgt. (F-600 ppm and up), red. abs. kidney wgt (M,F-900, 1200 ppm), incr. abs. spleen wgt. (M,F-900, 1200 ppm), incr. rel. liver wgt. (M,F-600, 900, 1200, M-300 ppm), increased relative spleen weight (M,F-900, 1200 ppm); Histopathology: spongiform myelopathy in brain, spinal cord (M-(2/20), 1200, 900 ppm, (1/20), 600 ppm), lesion present in sciatic nerve (M-(1/20), 1200 ppm), lymphoid cell infiltrate in kidneys (M,F-900, 1200 ppm); Target organ: central nervous system; Adverse Effect: spongiform myelopathy in the nervous system; NOEL: (M) 300 ppm (occurance of spongiform myelopathy in the nervous system of the 600 ppm group) (F) 300 ppm (based on increased mean abs. liver wgt. in 600 ppm group); (Study previously unacceptable, possibly upgradeable with submission of GLP compliance and QA audit statements (Moore, 2/1/95)) requested information submitted; Study acceptable. (Moore, 8/9/95)
August 24, 2001 - Summary of Toxicological Data. California EPA. Department of Pesticide Regulation. Medical Toxicology Branch. Also available at: http://www.cdpr.ca.gov/docs/toxsums/pdfs/3938.pdf

Chlorodifluoromethane - Insecticide, Fungicide, Propellant, EPA List 2 Inert - CAS No. 75-45-6

mouse lowest published toxic concentration: 50 gm/m3/6 hour/43 week- intermittent Brain and Coverings: Other degenerative changes: Spinal Cord. Other degenerative changes. Behavioral: Alteration of classical conditioning. [Trudy Leningradskogo Sanitarno-Gigienicheskogo Meditsinskogo Instituta. (Leningrad, Russia) 75,231,1963]
Ref: NIOSH. Registry of Toxic Effects. July 2000.

Fluazinam - Fungicide - CAS No. 79622-59-6

Oral 1 year 95.3%, Beagles, 0, 1, 10, 50 mg/kg/d, 6/sex/dose NOAEL 1 mg/kg/d LOAEL 10 mg/kg/d 10 mg/kg/d 8 Nasal dryness &. 8 Incidence and severity of gastric lymphoid hyperplasia. 9 Myeloid to erythroid ratios in bone &. 50 mg/kg/d 8 Nasal dryness and salivation % and &. 9 bwg in both sexes, but only significant in &. 9 Myeloid to erythroid ratios in bone &. 9 Hematocrit, hemoglobin, RBC % and . 8 WBC mid and high doses % and &. 8 Alk phos, cholesterol % and &. 8 Abs and rel liver weight % and 8 Incidence and severity of white matter vacuolation in brain and spinal cord 8 Incidence and severity of gastric lymphoid hyperplasia.
Ref: Canada: Regulatory Note REG2003-12. Fluazinam. Pest Management Regulatory Agency. Health Canada. Ottawa. October 27, 2003.

Flufenacet - Herbicide - CAS No. 142459-58-3

Chronic toxicity. A 1-year dog chronic feeding study with a NOEL was 40 ppm [1.29 mg/kg/day in males and 1.14 mg/kg/day in females] and a LOEL of 800 ppm [27.75 mg/kg/day in males and 26.82 mg/kg/day in females] based on increased alkaline phosphatase, kidney, and liver weight in both sexes, increased cholesterol in males, decreased T2, T4 and ALT values in both sexes, and increased incidences of microscopic lesions in the brain, eye, kidney, spinal cord, sciatic nerve and liver. A rat chronic feeding/carcinogenicity study with a NOEL less than 25 ppm [1.2 mg/kg/day in males and 1.5 mg/kg/day in females] and a LOEL of 25 ppm [1.2 mg/kg/day in males and 1.5 mg/kg/day in females] based on methemoglobinemia and multi-organ effects in blood, kidney,
spleen, heart, and uterus. Under experimental conditions the treatment did not alter the spontaneous tumor profile. In a mouse carcinogenicity study the NOEL was less than 50 ppm [7.4 mg/kg/day] for males and the
NOEL was 50 ppm [9.4 mg/kg/day] for females and the LOEL was 50 ppm [7.4 mg/kg/day] for males and the LOEL was 200 ppm [38.4 mg/kg/day] for females based on cataract incidence and severity. There was no evidence of carcinogenicity for flufenacet in this study.
Ref: Federal Register. June 23, 1998. Pesticide Tolerance Petition.

In an acute rat neurotoxicity study the NOEL was less than 75 mg/kg and the LOEL was 75 mg/kg/day based on decreased motor activity in males. In a rat subchronic neurotoxicity study the NOEL was 7.3 mg/kg/day in males and 8.4 mg/kg/day in females and the LOEL was 38.1 mg/kg/day in males and 42.6 mg/kg/day in females based on microscopic lesions in the cerebellum/medulla and spinal cords.
Ref: Flufenacet. Pesticide Fact Sheet. US EPA, April 8, 1998.

Fluoroacetic Acid - Rodenticide - CAS No. 144-49-0

Abstract: Fluoroacetic and fluorocitric acid toxicity is often characterized by seizures, however the mechanism of this activity is unknown. Intrathecal (i.t.) injection of fluorocitrate in mice resulted in seizures after an average latency of 15 s, while intracerebroventricular (i.c.v.) injection produced seizures after 36.5 min, and required higher doses to achieve this effect. This indicates the probable site of fluoroacetate and fluorocitrate neurotoxicity is the spinal cord. To mimic citrate accumulation, characteristic of fluoroacetate and fluorocitrate poisoning, citric acid was injected i.t. and also found to produce seizures. The structurally unrelated compounds EDTA, EGTA, glutamic acid and lactic acid also produced seizures identical to fluorocitrate. The ability of these compounds to chelate Ca2+ correlates well with their ability to cause seizures when administered i.t. and coadministration of calcium greatly attenuated the neurotoxicity of these compounds as well as fluoroacetate and fluorocitrate. In contrast, Ca2+ was unable to inhibit seizures elicited by strychnine, suggesting calcium's ability to inhibit chelators of divalent cations is not due to a general anticonvulsant effect. These results suggest that changes in Ca2+ concentration in the spinal cord may be responsible for some forms of seizure activity.
Ref: Hornfeldt CS, Larson AA (1990). Seizures induced by fluoroacetic acid and fluorocitric acid may involve chelation of divalent cations in the spinal cord. Eur J Pharmacol. 1990 Apr 25;179(3):307-13.

Mipafox - Acaricide, Insecticide - CAS No. 371-86-8

Ref: TOXNET profile for Mipafox from Hazardous Substances Data Base.

Short term clinical and neuropathological effects induced by tri-ortho-tolyl-phosphate (78308) (TOTP), diisopropyl-fluorophosphate (55914) (DFP), phenyl-saligenin-phosphate (4081236) (PSP), mipafox (371868), malathion (121755), dichlorvos (62737), and carbaryl (63252) were studied in rats. Male Long-Evans-rats were administered 300 to 1000mg/kg TOTP or 300 to 2000mg/kg malathion orally, injected intramuscularly with 5 to 24mg/kg PSP, injected subcutaneously with 1 to 3mg/kg DFP, or injected intraperitoneally with 3 to 30mg/kg mipafox or dichlorvos or 30 to 160mg/kg carbaryl. The rats were also treated with atropine-sulfate to protect against cholinergic symptoms. Selected rats were killed 4 hours after DFP, PSP, mipafox, dichlorvos, and carbaryl or 48 hours after TOTP and malathion and the brains and spinal cords were removed and assayed for acetylcholinesterase (AChE) and neurotoxic-esterase (NTE) activity. The remaining rats were weighed and evaluated on a functional observational battery (FOB) that measured motor activity and responses to being handled or approached 1, 7, 14, and 21 days after dosing. The rats were then killed and the brains, spinal cords, and tibial nerve branches leading to the gastrocnemius muscle were examined for histopathological changes. The highest doses of all compounds except PSP induced transient cholinergic symptoms and caused 8.3 to 61% mortality within 48 hours. The highest doses of TOTP, DFP, and malathion significantly decreased body weight after 14 days. All compounds caused dose related inhibitions of brain and spinal cord AChE and NTE activity. DFP was the most potent and PSP the least potent. All compounds induced significant changes in FOB parameters related to behavioral and central nervous system excitability 21 days after dosing. Mipafox, PSP, dichlorvos, and carbaryl induced these changes 1 day after dosing. TOTP, DFP, PSP, and mipafox caused mild to moderate myelinated fiber degeneration in the rostral fasciculus gracilis 21 days after dosing. Mipafox was the most potent. DFP also induced Wallerian like degeneration in the tibial nerve branches. Dichlorvos, malathion, and carbaryl did not cause any neurological changes. The authors conclude that some cholinesterase inhibitors cause behavioral changes even after cholinergic signs are no longer evident.
Ref: Ehrich M et al. (1993). Short-Term Clinical and Neuropathologic Effects of Cholinesterase Inhibitors in Rats. Journal of the American College of Toxicology, Vol. 12, No. 1, pages 55-68. As cited at Toxnet.

Definition: Fasciculus gracilis.
White matter in the dorsal, medial area of the spinal cord. It forms the entire dorsal column in the lumbar and sacral levels and the medial division of the dorsal column in the thoracic and cervical regions. It carries sensory information from the lower extremities. In the thoracic and cervical regions it is located between the fasciculus cuneatus and the dorsal median fissure. In the lumbar and sacral regions it is found between the dorsal horn and the dorsal median fissure.

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