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49140301.der.pdf
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49140301
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Ethylenethiourea
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96-45-7
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600016
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Marty, M.; Zablotny, C.; Andrus, A.; et al. (2013) Ethylenethiourea (ETU): An F1 Extended One Generation Reproductive Toxicity Study in Crl:CD(SD) Rats. Project Number: 101119. Unpublished study prepared by The Dow Chemical Company. 2575p.
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2013.0
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Ethylenethiourea (ETU): In an extended one-generation reproductive toxicity study (MRID 49140301), ETU (100% a.i.; Lot no. BCBC9199V) was administered to 27 Crl: CD (SD) rats/sex/dose in the diet at dose levels of 0, 2.8, 28, or 140 ppm (0, 0.2, 2.0, and 10 mg ETU/kg/day, respectively) for at least 4 weeks prior to mating and during the 14-day mating period, throughout gestation, and through lactation until weaning. Parental males received the test diet for a total of 11 weeks. Parental females received the test diet through gestation and lactation days (LD) 0-22 after which they were sacrificed. On postnatal (PND) 4, litters were culled to 5 pups/sex/litter, when possible, by random selection excluding preferential culling of runts. Selected F1 offspring were weaned on PND 21 and received the test diet until PND 22 (Cohort 2B developmental neuropathology), PND 78 (Cohort 2A developmental neurotoxicity), PND 90 (Cohort 1A reproductive toxicity), or PND 120 (Cohort 1B reproductive/endocrine toxicity). Offspring not selected for one of the cohorts were sacrificed on PND 22 and evaluated for systemic toxicity. Evaluated parameters for the various cohorts included body weight, feed consumption, hematology, clinical chemistry, thyroid hormone analysis (parental, culled PND 4, PND 22, and PND 90), organ weights, estrous cycle, sperm count, motility, and morphology, ovarian follicle evaluation, puberty onset, anogenital distance (AGD), and histopathology, developmental neurotoxicity and pathology, and functional observation battery.
Parental mortality, clinical signs, body weight, body weight gain, feed consumption, clinical pathology, and macroscopic findings were similar among the groups. Thymus weights were significantly decreased in males and females of the mid- and high-dose groups (dose-related), although there were no accompanying histopathological lesions. There was a dose-related increase in the incidence of hypertrophy of individual cells in the pars distalis of the pituitary gland in both sexes of the parental animals. Thyroxin levels were decreased in the mid- (23%-36%) and high-dose (67%-75%) groups in both sexes, and TSH was increased in both sexes at the mid- (32%) and high-dose (322%-326%) levels, although statistical significance was not attained at the mid dose (TSH). Absolute and relative thyroid weights were significantly increased in males and females in the high-dose group. Diffuse follicular cell hyperplasia of the thyroid increased in incidence and severity in treated males and females in the mid- and high-dose groups. The incidence and severity of thyroid follicular cell hypertrophy was increased at all dose levels in males and at the mid- and high-dose levels in females. The decrease in TSH (19%) in males at the low dose level is inconsistent with the follicular cell hypertrophy that was observed in the majority of the low-dose males. In contrast, at other time points and lifestages, increased incidences of follicular cell hypertrophy are related to increases in TSH. The male rat appears to be more sensitive than the female rat, which is based on the greater body weight deficit in males than females and thyroid effects. It is concluded that, based on the fact that ETU is a known thyroid toxicant, the findings in the thyroid at the low dose in males provide the first indications that the hypothalamic-pituitary-thyroid (HPT) axis is being adversely impacted by ETU, which is supported by the findings in the PND 90 male rat.
Therefore, under the conditions of this study, the parental systemic LOAEL for ETU is 2.8 ppm (0.2 mg/kg/day), based on an increased incidence of diffuse follicular cell hypertrophy of the thyroid and hypertrophy of the pars distalis of the pituitary in males. The parental systemic NOAEL was not demonstrated.
There were no treatment-related effects on reproductive indices, precoital intervals, gestation length, gonadal function, estrous cycle, sperm maturation, parturition, lactation, or tissues and organs of the reproduction system in the parental and PND 90 animals. Therefore, under the conditions of this study, the reproductive LOAEL for ETU in rats is not established. The reproductive NOAEL is 140 ppm (10 mg/kg/day), the highest dose tested.
There were no treatment-related effects on live litter size, anogenital distance, pup sex ratio, pup survival, nipple/areolae retention, organ weights excluding the thyroid, or macroscopic findings. Body weights of males and females in the high-dose group were significantly decreased on PNDs 14 (11% and 12%) and on PND 21 (males ¿8%; females ¿ 9%), although statistical significance was not attained in females. Thyroid hormones (¿T4 and ¿TSH) were significantly altered on PND 22 in males (¿53% and ¿182%) and females (¿50% and ¿176%) of the high-dose group and in females (¿24% and ¿52%) of the mid-dose group; thyroid hormones in the mid-dose males (T4 ¿14% and TSH ¿20%) did not attain statistical significance. The magnitude of the increase in TSH in females at the low dose (18%) is approaching biological significance. Relative thyroid weights were significantly increased in PND 22 males of the high-dose group (25%), and absolute thyroid weights were increased also (18%), although statistical significance was not attained. Diffuse follicular cell hyperplasia of the thyroid was observed in males and females at the high dose, and diffuse follicular cell hypertrophy of the thyroid was observed in both sexes at the mid- and high-dose levels.
There was a dose-related increase in TSH in the PND 4 pups (pooled sexes), which was significantly increased at the high dose. Additionally, T4 was significantly decreased at the low dose, and the possibility of a non-monotonic dose-response, based on statistical analyses, cannot be discounted. Further support for this is provided by the mode of action data for ETU. ETU inhibits thyroid peroxidase, the enzyme that catalyzes the synthesis of thyroid hormones, as well as the detoxification of ETU. Studies show that as the ETU concentration increases so does the lag phase in the inhibition of TPO-catalyzed iodide ion oxidation ¿ a critical step in thyroid hormone synthesis. The findings in the PND 4 pups, based on thyroid hormone disruption, are consistent with the findings at other life stages where hormone measures and thyroid pathology were evaluated.
There were no treatment-related effects on sexual development. Body weights (males 11%/ females 8%) of Cohort 1A (PND 90) males in the high-dose group were significantly decreased throughout the study, with the magnitude of the deficit increasing with time. Females of the same group showed a body weight deficit (8%) during the early post-weaning period. There was a dose-related, statistically significant decrease in T4 in both sexes at the mid- (males ¿14%; females ¿32%), and high-dose (males ¿62%; females¿78%) levels, although the magnitude of the effect in males at the mid-dose was less than 20%. Additionally, there was a dose-related increase in TSH, which was statistically significant only at the high dose in both sexes (males ¿500%; females ¿239%); however, the magnitude of the increase at all dose levels in males exceeded 30%. Absolute and relative thyroid weights were significantly increased (males 40%/ 55%; females 32%/38%) in animals of the high-dose group, and absolute (males 23%-31%; females 17%-31%) and relative (males 20%-23%; females 15%-28%) thymus weights were significantly decreased in animals of the mid- and high-dose groups. Thymic lymphoid atrophy was increased in incidence in males of the high-dose group. Diffuse follicular cell hyperplasia of the thyroid was increased in incidence and severity at the mid- and high-doses in males and at the high-dose in females. There was an increased incidence of thyroid follicular cell hypertrophy at all dose levels in males and in females at the mid and high dose levels. There was a dose-related increase in the incidence and/or severity of hypertrophy of individual cells in the pars distalis of the pituitary gland of males at all dose levels, which is consistent with the findings in the PND 78 males.
Body weights of Cohort 1B (PND 120) males in the high-dose group were significantly decreased throughout the study (7%-11%), and body weights were decreased during the early post-weaning period in females of the same group (8%), which is similar to the findings in Cohort 1A (PND 90). No effects were observed on puberty onset or AGD in either sex. Absolute and relative thymus weights were significantly decreased in animals of the mid- (20%-25%) and high-dose (23%-38%) groups. Absolute (37%-49%) and relative (38%-60%) thyroid weights were significantly increased in animals of the high-dose group, which is consistent with the findings in the PND 90 rats. The Agency notes that at lower dose levels resulting in altered thyroid hormone levels and histopathology of the thyroid, which are considered to be more sensitive measures of thyroid function than thyroid weight, no increase in thyroid weight was reported. These more sensitive measures are considered sufficiently robust to establish a LOAEL. Although thyroid hormones were not assessed in the PND 120 rats and histopathology examination of the thyroid was not performed, the LOAEL in the PND 120 rats is considered to be the same as that of the PND 90 rats.
Therefore, under the conditions of this study, the offspring LOAEL for ETU in rats is 2.8 ppm (0.2 mg/kg/day), based on an increase in the incidence and severity of hypertrophy of individual cells of the pars distalis of the pituitary in males, increased TSH in both sexes and decreases in T4 on PND4 pups, and diffuse follicular cell hypertrophy of the thyroid in males. The offspring systemic NOAEL was not attained.
There were no treatment-related effects on the functional observation battery, motor activity, and acoustic startle response or peripheral nerve neuropathology and brain morphometry of Cohort 2A (PND 78) or brain weight and neuropathological observations of Cohort 2B (PND 22) animals. There was a dose-related increase in the incidence and severity of hypertrophy of individual cells in the pars distalis of the pituitary gland of PND 78 males, which is similar to the findings in the PND 90 males. There was a decrease in brain size (brain weight and macroscopic brain measurements) of animals in the high-dose Cohort 2A group. Therefore, under the conditions of this study, the offspring developmental neurotoxicity LOAEL for ETU in rats is 140 ppm (10 mg/kg/day), based on decreased brain size (both sexes). The offspring developmental neurotoxicity NOAEL is 28 ppm (2 mg/kg/day).
This study is classified as Acceptable/Guideline and satisfies the OECD 443 guideline requirement for an extended one-generation reproductive toxicity study (OECD 443) in the rat as well as the guideline requirements for a 2-generation reproduction study (870.3800), a developmental neurotoxicity study (870.6300), and the data requirement for a thyroid function study for ETU.
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Reproduction
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NA [870.3800, Reproduction and fertility effects|870.6300, Developmental neurotoxicity study]
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Oral
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Treatment Duration: 1 Generation; Extended One-Generation Reproductive Toxicity Study
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56983.0
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2017-10-31
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2018-04-26
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Added by
Madison Feshuk
on Apr 25, 2022
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