Appendix G: HED Toxicology Assessment Tables 

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

Guideline# Study Type MRID Results Toxicity 

Category

870.1100 Acute Oral 

(50% wettable powder) 

41183502 LD50 = 82 mg/kg in _

LD50 = 30 mg/kg in _

I 

870.1200 Acute Dermal 

(50% wettable powder) 

41183503 LD50 = 2000 mg/kg III 

870.1300 Acute Inhalation 

50% wettable powder) 

41183504 LC50 = 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-1
rats (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 % mortality, 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-2
generation. 

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 decreased 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 μg/ml w/o S9 

activation, seven doses from 6.25-100 μg/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 μg/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 αor 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, endosulfan (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 endosulfan 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 concentrations 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 28th 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-3
870.7600 

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/cm2

) 

% 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 nerve. 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