2,4-diethyl-9H-thioxanthen-9-one

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

- Evidence from a reproduction / developmental toxicity screening test (OECD 421) conducted with the closely related substance 2-Isopropylthioxanthone ("ITX", CAS 5495-84-1, EC 226-827-9) indicates that the registration substance 2,4-diethyl-9H-thioxanthen-9-one ("DETX", CAS 82799-44-8, EC 280-041-0) is not a reproductive toxin.

- Under the conditions of this study, based on the adverse findings noted, the no observed adverse effect level (NOAEL) for all systemic, and the reproductive and developmental toxicity is 62.5 mg/kg/day.

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

62.5 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The study was performed to guidelines under GLP conditions and therefore the quality of the database is considered to be high.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

No studies for reproductive toxicity are available for the registration substance 2,4-diethyl-9H-thioxanthen-9-one ("DETX", CAS 82799-44-8, EC 280-041-0) itself.

However, reliable data of the closely related substance 2-Isopropylthioxanthone ("ITX", CAS 5495-84-1, EC 226-827-9) can be used to address the endpoint, which is entirely appropriate to draw conclusions on the reproductive toxicity potential of DETX.

The only difference between the source substance ITX and the target substance DETX can be reduced to slightly differing substituents: ITX possesses one isopropyl group, whereas DETX two ethyl groups.

The reproductive toxicity of the test material ITX was investigated in a Reproduction/Development Toxicity Screening study in rats, conducted in accordance with the standardised guideline OECD 421, under GLP conditions. The study was awarded a reliability score of 1 in accordance with the criteria set forth by Klimisch et al. (1997).

The objective of the study was to screen for effects of the test material on male and female reproductive performance (i.e. gonadal function, mating behaviour, conception, development of the conceptus and parturition) and offspring growth until Lactation Day (LD) 13.

Four groups of 10 animals/sex/group were administered 0 (control material [vehicle]), 62.5, 250, or 1000 mg/kg/day test material orally by gavage at a volume of 8 mL/kg. The control material (vehicle) was PEG 400. The test material was administered to males for 42 days (pre-pairing, pairing, and post-pairing) or to females for up to 56 days (pre-pairing, pairing, gestation, and up to LD 13).

Assessment of toxicity in adults was based on clinical observations, body weights, food consumption, oestrous cycles, mating, fertility and pregnancy indices, and offspring parameters. Pup clinical observations, litter size, sex, and body weights were recorded. Ano-genital distance was recorded on Postnatal Day (PND) 4, and nipple retention was recorded for male pups on PND 13. One pup/sex/litter/dose group was selected; these pups had their thyroid preserved.

Complete necropsies were performed on all animals, and any macroscopic abnormalities were noted. Blood samples for thyroid hormone assessment were collected at necropsy from all adult animals and selected pups on PND 4 and 13. Organ weights and microscopic examinations were conducted as indicated.

Daily oral (gavage) administration of 250 or 1000 mg/kg/day test material was not well tolerated by adult animals; this had a subsequent effect on pregnancy and lactation.

Seven test material-related decedents were noted; five animals administered 1000 mg/kg/day and two animals administered 250 mg/kg/day. These animals were observed to have a reduction in food consumption, weight loss, and adverse clinical observations. Additionally, two additional females administered 1000 mg/kg/day and one female administered 250 mg/kg/day were sacrificed after they lost their litters, between Lactation Day (LD) 1 and 2. Due to the number of decedents on study the five remaining females administered 1000 mg/kg/day were sacrificed early, just before or shortly after parturition, due to the severity of the clinical observations.

Staining of fur in animals administered 250 or 1000 mg/kg/day associated with weight loss and food consumption decreases, indicate general lack of grooming and suggest these to be indirectly related to test material administration.

An initial reduction in body weight gain was noted in males administered 250 mg/kg/day, males administered 1000 mg/kg/day show reduced body weight gain throughout the entire study duration. In males administered 1000 mg/kg/day, reduction in thyroxine (T4) values were also observed. These effects were attributed to the test material.

A reduction in mean food consumption was noted during the first week of dosing for females administered 250 or 1000 mg/kg/day and from GD 18 onwards for females administered 1000 mg/kg/day. Females administered 1000 mg/kg/day showed a reduction in mean body weight gain from GD 14 and onwards and those females surviving to littering continued to show a reduction in body weight gain or body weight loss. There was also an indication of increased length of oestrous cycles for females administered 250 or 1000 mg/kg/day, but this was not associated with effects on fertility.

Uterus, seminal vesicle and prostate weight were reduced, and the thyroid weight increased in the test material treated animals compared to control. Due to the lack of macroscopic findings, these changes were considered non-adverse.

No microscopic findings that suggested test material-related effects in the testis, epididymis, or ovary were recorded.

Due to high number of decedent animals at 1000 mg/kg/day a conclusive assessment of littering and pup survival parameters was not possible. Animals administered 250 mg/kg/day showed test material-related effects on live birth, litter survival, and/or PND 1 to 4 survival index. Increased mortality was also noted in litters from animals administered 250 mg/kg/day. No other pup developmental effect was noted.

No effect on gonadal function, mating behaviour, conception, development of the conceptus, parturition, or offspring growth until LD 13 was noted.

Under the conditions of this study, based on the adverse findings noted, the no observed adverse effect level (NOAEL) for systemic, and the reproductive and developmental toxicity is 62.5 mg/kg/day.

Effects on developmental toxicity

Description of key information

- Evidence from a reproduction / developmental toxicity screening test (OECD 421) conducted with the closely related substance 2-Isopropylthioxanthone ("ITX", CAS 5495-84-1, EC 226-827-9) indicates that the registration substance 2,4-diethyl-9H-thioxanthen-9-one ("DETX", CAS 82799-44-8, EC 280-041-0) is not a developmental toxin.

- Under the conditions of this study, based on the adverse findings noted, the no observed adverse effect level (NOAEL) for systemic, and the reproductive and developmental toxicity is 62.5 mg/kg/day.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

62.5 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The study was performed to guidelines under GLP conditions and therefore the quality of the database is considered to be high.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

No studies for developmental toxicity are available for the registration substance 2,4-diethyl-9H-thioxanthen-9-one ("DETX", CAS 82799-44-8, EC 280-041-0) itself.

However, reliable data of the closely related substance 2-Isopropylthioxanthone ("ITX", CAS 5495-84-1, EC 226-827-9) can be used to address the endpoint, which is entirely appropriate to draw conclusions on the developmental toxicity potential of DETX.

The only difference between the source substance ITX and the target substance DETX can be reduced to slightly differing substituents: ITX possesses one isopropyl group, whereas DETX two ethyl groups.

The developmental toxicity of the test material ITX was investigated in a Reproduction/Development Toxicity Screening study in rats, conducted in accordance with the standardised guideline OECD 421, under GLP conditions. The study was awarded a reliability score of 1 in accordance with the criteria set forth by Klimisch et al. (1997).

The objective of the study was to screen for effects of the test material on male and female reproductive performance (i.e. gonadal function, mating behaviour, conception, development of the conceptus and parturition) and offspring growth until Lactation Day (LD) 13.

Four groups of 10 animals/sex/group were administered 0 (control material [vehicle]), 62.5, 250, or 1000 mg/kg/day test material orally by gavage at a volume of 8 mL/kg. The control material (vehicle) was PEG 400. The test material was administered to males for 42 days (pre-pairing, pairing, and post-pairing) or to females for up to 56 days (pre-pairing, pairing, gestation, and up to LD 13).

Assessment of toxicity in adults was based on clinical observations, body weights, food consumption, oestrous cycles, mating, fertility and pregnancy indices, and offspring parameters. Pup clinical observations, litter size, sex, and body weights were recorded. Ano-genital distance was recorded on Postnatal Day (PND) 4, and nipple retention was recorded for male pups on PND 13. One pup/sex/litter/dose group was selected; these pups had their thyroid preserved.

Complete necropsies were performed on all animals, and any macroscopic abnormalities were noted. Blood samples for thyroid hormone assessment were collected at necropsy from all adult animals and selected pups on PND 4 and 13. Organ weights and microscopic examinations were conducted as indicated.

Daily oral (gavage) administration of 250 or 1000 mg/kg/day test material was not well tolerated by adult animals; this had a subsequent effect on pregnancy and lactation.

Seven test material-related decedents were noted; five animals administered 1000 mg/kg/day and two animals administered 250 mg/kg/day. These animals were observed to have a reduction in food consumption, weight loss, and adverse clinical observations. Additionally, two additional females administered 1000 mg/kg/day and one female administered 250 mg/kg/day were sacrificed after they lost their litters, between Lactation Day (LD) 1 and 2. Due to the number of decedents on study the five remaining females administered 1000 mg/kg/day were sacrificed early, just before or shortly after parturition, due to the severity of the clinical observations.

Staining of fur in animals administered 250 or 1000 mg/kg/day associated with weight loss and food consumption decreases, indicate general lack of grooming and suggest these to be indirectly related to test material administration.

An initial reduction in body weight gain was noted in males administered 250 mg/kg/day, males administered 1000 mg/kg/day show reduced body weight gain throughout the entire study duration. In males administered 1000 mg/kg/day, reduction in thyroxine (T4) values were also observed. These effects were attributed to the test material.

A reduction in mean food consumption was noted during the first week of dosing for females administered 250 or 1000 mg/kg/day and from GD 18 onwards for females administered 1000 mg/kg/day. Females administered 1000 mg/kg/day showed a reduction in mean body weight gain from GD 14 and onwards and those females surviving to littering continued to show a reduction in body weight gain or body weight loss. There was also an indication of increased length of oestrous cycles for females administered 250 or 1000 mg/kg/day, but this was not associated with effects on fertility.

Uterus, seminal vesicle and prostate weight were reduced, and the thyroid weight increased in the test material treated animals compared to control. Due to the lack of macroscopic findings, these changes were considered non-adverse.

No microscopic findings that suggested test material-related effects in the testis, epididymis, or ovary were recorded.

Due to high number of decedent animals at 1000 mg/kg/day a conclusive assessment of littering and pup survival parameters was not possible. Animals administered 250 mg/kg/day showed test material-related effects on live birth, litter survival, and/or PND 1 to 4 survival index. Increased mortality was also noted in litters from animals administered 250 mg/kg/day. No other pup developmental effect was noted.

No effect on gonadal function, mating behaviour, conception, development of the conceptus, parturition, or offspring growth until LD 13 was noted.

Under the conditions of this study, based on the adverse findings noted, the no observed adverse effect level (NOAEL) for systemic, and the reproductive and developmental toxicity is 62.5 mg/kg/day.

Justification for classification or non-classification

Based on the available reproduction / development toxicity data of the closely related substance 2-Isopropylthioxanthone (CAS 5495-84-1, EC 226-827-9) and in accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the registration substance 2,4-diethyl-9H-thioxanthen-9-one (CAS 82799-44-8, EC 280-041-0) does not require classification for reproductive and/or developmental toxicity as the effects observed were related to maternal toxicity.