### Appendix G: HED Toxicology Assessment Tables

Table G-1. Summary of Results from Ac ute Toxicity Assays of Endosulfan.

Guideline# Study Type MRID Results Toxicity Category

870.1100 Acute Oral (50% wettable powder) 41183502 LD 50 = 82 mg/kg in

_ LD 50 = 30 mg/kg in

_ I

870.1200 Acute Dermal (50% wettable powder) 41183503 LD 50 = 2000 mg/kg III

870.1300 Acute Inhalation 50% wettable powder) 41183504 LC 50 = 0.16-0.5 mg/L II

870.2400 Primary Eye Irritation 50% wettable powder) 41183505 Eye irritant (Residual opacity at day 13) I

870.2500 Primary Skin Irritation 50% wettable powder) 41183506 Non-irritant IV

870.2600 Dermal Sensitization 41183507 Not a dermal sensitizer NA



### Table G-2. Subchronic, Chronic, and Other Toxicity

Guideline #/Study Type MRID # /Year/Classification/Doses Results

870.3100

13-week subchronic feeding study in rats (97.2%) 00145668 (1985) Acceptable/Guideline 0,0.5, 1.5, 3.0, &18 mg/kg/d LOAEL=1.5 mg/kg/d based on kidney abnormalities & increased spleen weight in male rats. NOAEL=0.5 mg/kg/d

870.3100

13-week subchronic feeding study in mice (97.2%) 00147182 (1984) Acceptable/Guideline 0, 0.24, 0.74, 2.13, & 7.3 mg/kg/d for males. 0, 0.27, 0.80, 2.39, & 7.52 mg/kg/d for

females. LOAEL=7.3 mg/kg/d based on high incidences of mortality in both males & females. NOAEL=2.1 mg/kg/d in males.

870.3200 30-day subchronic dermal toxicity study in rats (49.5%) 41048506 (1987) Acceptable/Guideline 0, 160, & 640 mg/kg/d for males. 0, 80, & 160 mg/kg/d in females. Systemic LOAEL=640 mg/kg/d in males based on body weight. LOAEL=80 mg/kg/d in females based on mortality & decreased plasma ChE activity. NOAEL=160 & 40 mg/kg/d in males & females, respectively.

870.3200 21-day dermal toxicity study in rats (97.2%) 146841 (1985) & 147744 (1985). Acceptable/Guideline 0, 12, 48, 96, & 192 mg/kg/d for males. 0,3, 6, 12, & 48 mg/kg/d for females. 21 applications over 30 days. Systemic NOAEL=12 mg/kg/d for females & 96 mg/kg/d for males. LOAEL=48 mg/kg/d for females & 192 mg/kg/d for males based on increased mortality &

increased serum ChEI.

870.3200 21-day dermal toxicity study in 257684 & 257685 (1985) Acceptable/Guideline 0, 1, 3, 9, & 27 mg/kg/d for males & females, & 6 males only at 81 mg/kg/d, for 21 Systemic NOAEL=9 mg/kg/d for females & 27 mg/kg/d for males. LOAEL=27 mg/kg/d in females & 81 mg/kg/d in males based on increased mortality in both sexes.



### G-1rats (97.2% w/w) applications over 30 days.

870.3455 21-day inhalation study in rats (97.2%) 41667501 (1990) supplemental to 00147183 (1984) Acceptable/Guideline 0, 0.0005, 0.0010, & 0.0020 mg/L air (0.097, 0.194, 0.387 mg/kg/d) both sexes nose-only for 6 hrs/d for 21 exposures over 29 days. NOAEL=0.001 ai/L (0.194 mg/kg/d) & LOAEL= 0.002 ai/L (0.387 mg/kg/d) based on decreased body weight gain & decreased leukocyte counts in males & increased

creatinine values in females.

870.4100 1-year chronic toxicity feeding study in dogs (96.5%) 41099501 (1989) Acceptable/Guideline 0, 3, 10, 30, & 30/45/60 ppm (0, 0.65, 1.75, 0.65-1.30 mg/kg/d for males & 0, 0.57, 1.75, and 0.65-1.30 mg/kg/d for females). NOAEL= 10 ppm (0.65 and 0.57 mg/kg/d in males & females, respectively) & LOAEL= 30 ppm (1.75 mg/kg/d) based on decreased body weight gain in males & increased incidences of neurologic findings in males & females (loss or weakening of placing & righting reactions, tonic contractions of abdominal muscle & masticatory muscles a few hours after feeding).

870.4300

Chronic/Carcinogenic Feeding Study in Rats (97.1%) 41099502 (1989) Acceptable/Guideline 0, 3, 7.5, 15, and 75 ppm (0, 0.1, 0.3, 0.6, 2.9 mg/kg/d for males and 0, 0.1, 0.4, 0.7, and 3.8 mg/kg/d for females) for 104 weeks Systemic NOAEL= 15 ppm (0.6 & 0.7 mg/kg/d for males & females, respectively) & LOAEL= 75 ppm (2.9 & 3.8 mg/kg/d for males & females, respectively) based on decreased body weight gain in males & females, enlarged kidneys in females, & increased incidences of marked progressive glomerulonephrosis in males & females, & blood vessel aneurysms in males. Dosing was considered adequate.

870.4200

Chronic/Carcinogenic Feeding Study in Mice (97.9%) 40792401 (1988) Acceptable/Guideline for carcinogenicity but, not acceptable for a combined chronic/ carcinogenicity study in mice because some clinical chemistry parameters were not evaluated. 0, 2, 6 & 18 ppm (0, 0.3, 0.9 & 2.6 mg/kg/day) for 24 months. Systemic NOAEL= 6 ppm (0.9 mg/kg/day), & LOAEL = 18 ppm (2.65 mg/kg/day), based on increased incidences of mortality in females. At the doses tested, there was no

treatment related increase in tumor incidence when compared to controls. Dosing was considered adequate.

870.3700 Developmental Toxicity in Rats (97.3%) 43129101 (1993) Acceptable/Guideline 0 (sesame oil), 0.7, 2.0, & 6.0 mg/kg/d from days 7 through 16 of gestation by gavage. This study was a repeat study for an unacceptable developmental toxicity study (ACC# 243707). Maternal toxicity NOAEL= 2.0 mg/kg/d & LOAEL= 6.0 mg/kg/d based on 80 % morta lity, tonoclonic convulsions, increased salivation, & decreased body weight gains & food consumption. Developmental toxicity NOAEL= 2.0 mg/kg/d & LOAEL= 6.0 mg/kg/d based on a slight

increase in the incidence of fragmented thoracic vertebral centra & a slight increase in the occurrence of fetuses/litter weighing less than 3 grams.

870.3700 Developmental Toxicity in Rabbits (97.3%) 00094837 (1981) Acceptable/Guideline 0, 0.3, 0.7, & 1.8 mg/kg/d from days 6 through 28 of gestation by gavage Maternal NOAEL= 0.7 mg/kg/d & LOAEL= 1.8 mg/kg/d based on decreased body weight, as well as increased incidences of deaths, convulsions, rapid breathing, salivation & hyperactivity. Developmental NOAEL= 1.8 mg/kg/d, the highest dose tested

870.3800

2-Generation Reproductive Toxicity in Rats (97%) 00148264 (1984) Acceptable/Guideline 0, 3, 15, & 75 ppm (0, 0.2, 1.0, & 5.0 mg/kg/d in males & 0, 0.2, 1.2, & 6.2 mg/kg/d in females) in the diet for two generations Parental toxicity NOAEL= 15 ppm (1.2 mg/kg/d) & LOAEL= 75 ppm (6.2 mg/kg/d) based on decreased body weight. Reproductive NOAEL= 75 ppm (6.2 mg/kg/d), the highest dose tested. Developmental (offspring) toxicity NOAEL= 15 ppm (1.2 mg/kg/d) & LOAEL= 75 ppm (6.2 mg/kg/d), based on increased pituitary & uterine weights; decreased litter and pup weight observed during the lactation to weaning period in both matings in the Fo



### G-2generation.

870.6200

Acute Neurotoxicity

screen in rats (98.6%) 44403101 (1997) Acceptable/Guideline One control group was assigned to males, dosed by gavage at 25, 50 & 100 mg/kg & females dosed at 3, 6 & 12 mg/kg. The other control group was assigned to males dosed at 6.25 & 12.5 mg/kg & females at 0.75 & 1.5 mg/kg. NOAEL= 12.5 mg/kg for males, 1.5 mg/kg for females. LOAEL= 25 mg/kg for males based on increased incidences of stilted gait, squatting posture, & irregular respiration, as well as d ecreased spontaneous activity. LOAEL= 3 mg/kg for females based on an increased incidence of stilted gait, squatting posture, straddled hindlimbs, irregular respirations, panting & bristled coat & decreased spontaneous activity.

870.5300

Chromosome

Aberrations in mice (97.2%) 00148266 (1984) Acceptable Six doses ranging from 6.25- 50 μ g/ml w/o S9 activation, seven doses from 6.25-100 μ g/ml with S9 activation induced a significant increase in mutations at the thymidine kinase (TK) locus in L5178Y mouse lymphoma. Non-mutagenic in the mouse lymphoma forward mutation

assay.

870.5550

Unscheduled DNA Synthesis in rat (97.2%) 00148265 (1984) Acceptable Cytotoxicity & UDS assay were performed in parallel. Fifteen test concentrations ranging

from 1020- 0.102 μ g/ml. Inactive in primary rat hepatocyte unscheduled DNA synthesis (UDS) assay.

870.7485

Metabolism in

Rabbits 05003503 (1979) Intravenous 2 mg/kg The fraction of unchanged α endosulfan in 5 days urine was 37% of the dose while unchanged β -endosulfan amounted to only 11% of the doses. These fractions in feces were only 2.7% and 0.4%, respectively.

870.7485

Metabolism in Dogs 00073212 (1964) Gavage 0.35 and 1.75 mg/kg/day for 28 days Only small traces of α - and β -endosulfan and the sulfate metabolite were detected in blood, brain and kidney. No α or β -endosulfan was detected in muscles, liver, or fat.

870.7485

Metabolism in

Mice & Rats 05007464 (1968) Gavage,intraperitoneally and duodenally adm. For both mice and rats, endo sulfan (parent) and its

metabolites were excreted in both the urine and feces, the latter being the predominant route of excretion.

870.7485

Metabolism in

Rats 050037030 (1978) Gavage and Dietary Metabolites accumulated in tissues, especially in the kidney

& liver. Metabolites include endo sulfan sulfate, endosulfan diol, endosulfan ether, endosulfan alpha-hydroxy ether, &

endosulfan lactone.

870.7485

Metabolism in

Mice 00004257 (1966) Gavage and Dietary Large amount of endosulfan sulfate was recovered in the liver, small intestine & visceral fat with a trace of this

metabolite in the muscle.

870.7485 Special

Metabolism in Rat 45546201 (1998) Toxicokinetic study-gavage

4 Wistar rats/sex/dose 1 mg/kg/day for 28 days. Treatment-free period for 5 days Labeled tissue residue concentrations increased, reaching maximum concentrations by day 23 and plateauing thereafter. Highest concentrati ons of labeled residues were found in kidney, which peaked at 43 mg/kg in males and 32 mg/kg in females. The major metabolite of the kidney was endosulfan sulfate. 90% of the radioactivity was eliminated prior to the 28 th dose. These data indicate that

endosulfan does not bioaccumulate in the rats. Approximately 60-63% labeled endosulfan was eliminated via the feces, while urinary elimination accounted for approximately 12-14%.



### G-3870.7600

Dermal

Penetration in Rats (94.6%) 40223601 (1986) Acceptable Males treated topically with radiolabeled suspension at nominal doses of 0.1, 1.0, & 10 mg/kg & exposed for 0.5, 1, 2, 4, 10 & 24 hrs. % doses absorbed over 24-hour period were 2.2-21.6, 0.32-21.52, & 0.08-8.38 for the 0.1, 1.0, & 10 mg/kg dose groups, respectively. % doses remaining in/on the skin after soap & water washes over a 24-hour period were 62.1-56.5, 78.1-57.7, & 80.2-66.7 for the 0.1, 1, & 10 mg/kg dose groups, respectively. Significant portions of the dose

remained on the skin.

870.7600 Dermal Absorption in Rats (94.6%) 41048504 (1988) Acceptable Females treated topically with radiolabel at nominal doses of 0.1, 1, & 10 mg/kg (1.9, 21.9, & 231.4 mg/cm 2 ) % doses absorbed at 24 hours were 22.1, 16.1 & 3.8% & at 168 hours were 44.8, 46.4 & 20.3% for the 0.1, 1, & 10 mg/kg dose groups, respectively. % doses remaining on/in skin at 168 hours were 41.4, 56.2 & 72.8% for the 0.1, 1, & 10 mg/kg dose groups, respectively. Dermal absorption factor of 45 % at 168 hours post-exposure.

870.6100 Delayed Neurotoxicity-Hen (97.2%) 00147181 Unacceptable/Guideline White leghorn hens gavaged with 96 mg/kg,

corn oil vehicle Neurotoixicty study inconvlusive. In the 9/40 hens examined at 42 days after initial challenge (day 21), there was no evidence of progressive nerve damage in the brain, spinal cord, or peripheral nerv e. Numerous deficiencies contributed to the unacceptance of the study (TXR0050722)

870.6200

Subchronic Neurotoxicity (96.5- 98.1%) 46444401 (2004) Acceptable 0, 40, 225 or 600 ppm Males: 0,2.11,13,7,37.2 mg a.i./kg/day; Females: 0,2.88,16.6,45.5 mg a.i../kg/day) for

13 wks Based on the effects seen in this study, the LOAEL was 13.7 mg/kg/day based on absolute and relative kidney weight increase in males and females. Absolute and relative liver weight increase occurred in males and females and plasma cholinesterase inhibition in females, and possible increases in locomotor activity only at wk 8 and the first interval at 225 and 600 ppm. The NOAEL of 2.88 mg/kg. With the exception of the kidney weight increase at 225 ppm and 600 ppm, the convulsions and death at 600 ppm and possible neurotoxic digestion chambers at 600 ppm in 3 males and 3 females, the remaining effects have not been shown to be adverse in this study.

870.6300 Developmental Neurotoxicity Study- rat (99.1%) 46968301 (2006) Acceptable

Females was administered nominal doses of 0,50,150, or 400 ppm or 0.3.74,10.8 or 29.8 mg/kg bw/day from gestation day 6 through postnatal day 21 There was no NOAEL for pups. The LOAEL was the LDT at 3.74 mg/kg/day based on decreased pup weight at PND 22 and decreased weight gain at PND 4-11. At the MDT, possible delayed preputial separation in males occurred. The NOAEL for dams is 3.7 mg/kg/day. The LOAEL is 10.8 mg/kg/day based on decrease body weight, food consumption and food efficiency.



### G-4