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Key value for chemical safety assessment

Toxicity to reproduction: other studies

Description of key information

A reproductive/developmental screening study was conducted on MTDID 665 according to OECD 421:

The result of the study was: NOAEC = 281.17 mg/L

The objective of this study was to provide data on the potential effects of MTDID 665 on reproductive performance, pup development, and general toxicity of rats by inhalation exposure. The study was conducted according to OECD 421 in compliance with OECD GLP. MTDID 665 was administered daily to rats (N= 10/sex/exposure concentration) by inhalation whole body exposure (6 hours/day) at target concentrations of 0 (control), 5000, 10000, and 20,000 ppm. Actual exposure concentrations were 0 (control), 72.25, 143.22, and 281.17 mg/L (5046, 10003, and 19637 ppm), respectively. Males were exposed for 14 days prior to mating and continuing through mating for a minimum of 28 days. Females were exposed for 14 days prior to mating and continuing through Gestation day 20; exposure resumed on Lactation day 5 and continued through Lactation day 12. The following parameters and endpoints were evaluated in this study: clinical signs, body weight gains, food consumption, estrous cycles, reproductive performance, parturition, litter viability and survival, anogenital distance, areolae/nipple anlagen, thyroid hormones, gross necropsy findings, organ weights, and histopathological examinations. Male rats were sacrificed after 28 days of treatment on study day 28/29 and female rats were sacrificed on day 13 of lactation. At necropsy, the adrenal glands, brain, epididymides, heart, kidneys, liver, ovaries with oviducts, pituitary gland, prostate gland, seminal vesicle (with coagulating gland and fluid), spleen, testes, thymus gland, and thyroids with parathyroids were collected and organ weights were obtained. Other tissues collected at necropsy and preserved include the brain, coagulating glands, kidneys, liver, mammary glands, ovaries and oviducts, pituitary gland, prostate gland, seminal vesicle, testes with epididymides and vas deferens, uterus with cervix and vagina, and all gross lesions. The previously identified tissues of all animals in the control and high-exposure groups underwent histopathological examination. Other tissues that were examined include the liver and kidney of male’s rats and gross lesions. All F0 animals survived to the scheduled necropsy. No substance-related clinical observations were noted at any exposure level. No test substance-related effects were noted on F0 body weight gains, food consumption, estrous cyclicity, reproductive performance (mating, fertility, copulation, and conception), gestation length, or parturition. Test substance-related higher liver weights were identified in the 5046, 10003, and 19637 ppm group males, which correlated with hepatocellular hypertrophy observed in histopathological evaluation of the liver. Higher thyroid/parathyroid weights were identified in the 5046 and 10003 ppm group males, and 19637 ppm group males and females. Lower mean T4 values were noted in F0 males at 5046, 10003, and 19637 ppm. Higher thyroid/parathyroid weight (secondary to thyroid follicular hypertrophy) has been reported in associated with hepatocellular hypertrophy and lower total T4 concentrations and may represent an adaptive change secondary to treatment-induced hepatocellular enzyme induction with secondary thyroxine metabolism. The thyroid/parathyroid glands were not evaluated histologically in the current study; however, the decreased serum T4 in conjunction with the increased liver weights, hepatocellular hypertrophy, and increased thyroid/parathyroid weight demonstrate that this effect is a non-adverse adaptive finding. No test substance-related effects were noted on F1 postnatal survival, growth, clinical condition, anogenital distance, areolae/nipple anlagen, thyroid hormone levels, or gross necropsy. Under the conditions of this study, there were no effects on F0 reproduction at any exposure concentration, and therefore an exposure level of 19637 ppm was the no-observed-adverse-effect concentration (NOAEC) for F0 reproductive toxicity of MTDID 665 when rats were exposed via whole body inhalation. A no-observed-effect-concentration (NOEC) for F0 male systemic toxicity could not be determined, and the NOEC for F0 female systemic toxicity was 281.17 mg/L (19637 ppm); the NOAEC for F0 male and female rats was considered to be 281.17 mg/L (19637 ppm). The NOAEC for F1 neonatal toxicity was 281.17 mg/L (19637 ppm) based on the absence of any adverse effects on postnatal development at any exposure level.

Justification for classification or non-classification

Based on the results of the study, MTDID 665 is not classified for reproductive or developmental toxicity (NOAEC = 281.17 mg/L)

Additional information