N,N'-dimethyldiphenylthiuram disulphide

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

In a subacute oral study in rats dosed up to and including 1000 mg/kg bw/day no effects on reproductive organs were detected.

Link to relevant study records

Reference

Endpoint:

extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)

Data waiving:

other justification

Justification for data waiving:

other:

Reproductive effects observed:

not specified

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

a study according to OECD Guideline and GLP with Klimisch score 1

Additional information

Studies dealing specifically with toxicity to reproduction (fertility assessment) of N,N-Dimethyldiphenylthiuram Disulphide are not identified. In addition, there is no screening study according to OECD TG 421 available. However there is a Repeated Dose Toxicity Study available in rats over a period of 28 days in which rats were dosed up to and including 1000 mg/kg bw/day in which the reproductive oragans are examinde histopathologically. A test according to OECD TG 414 (Developmental Toxicity) is proposed

As confirmed by literature (Mangelsdorf et al 2003, Ulbrich & Palmer 1995, Janer et al 2007a, Dent 2007) histopathological examinations in repeated dose toxicity are of high value and high sensitivity for evaluation of reproductive toxicity. Therefore, at least for fertility assessment, repeated dose toxicity study showing no adverse effect should be taken into account. Also it is agreed that histopathological changes on the reproductive organs in repeated dose toxicity studies are indicative of effects on fertility. Therefore repeated dose toxicity studies should be considered sufficient information to evaluate toxicity on fertility if histological examination of the reproductive organs is covered by the repeated dose toxicity study and the mode of action of the test stubstance does not give evidence for a specific toxicity (as would e.g. sex hormone receptor binding activity).

For N,N-Dimethyldiphenylthiuram Disulphide a 28-day study is available (Wirnitzer 2012). During the 28-days treatment period male and female Wistar rats received 0, 100, 300 or 1000 mg/kg bw/day N,N-Dimethyldiphenylthiuram Disulphide dissolved inSokutol/Ethanol/water(4:1:5) water by gavage. The study was performed according to OECD TG 407 and GLP. Reproductive organs of the rats of the highest dose group and of the control animals were examined histopathologically. No adverse effects were noted from these organs in these groups. Based on these results there are no indications for specific adverse effects on the reproductive organs up to and including 1000 mg/kg bw/day

In conclusion, due to the lack of adverse effects on reproductive organs up to and including the limit dose of 1000 mg/kg bw/day over 28 days, there is no indication of a specific toxic potential in the reproductive organs . Therefore, based on the considerations above, no further testing should be required for fertility assessment.

Furthermore, a developmental toxicity study (rat, oral) according to OECD TG 414 will be conducted after approval by ECHA.

Therefore, the requirements of Regulation (EC) 1906(2006) ANNEX VIII and IX are fulfilled.

References

Mangelsdorf. et al., 2003: Some aspects relating to the evaluation of the effects of chemicals on male fertility. Regulatory toxicology and Pharmacology 36, 69-98

Ulbrich & Palmer, 1995: Detection of effects on male reproduction – a literature survey. J am. College of Toxicology 14, 293-327

Janer et al., 2007: A retrospective analysis of the added value of the rat two-generation reproductive toxicity study versus the rat subchronic toxicity study. Reproductive Toxicology 24, 103-113

Dent, 2007: Strength and limitations of using repeated-dose toxicity studies to predict effects on fertility. Regulatory Toxicology and Pharmacology 48, 241-258

Short description of key information:
Studies dealing specifically with toxicity to reproduction (fertility assessment) of N,N-Dimethyldiphenylthiuram Disulphide are not identified. In addition, there is no screening study according to OECD TG 421 available. However in the available subacute oral rat study doses up to and including 1000 mg/kg bw/day did not cause any adverse effects on reproductive organs (NOAEL: 1000 mg/kg bw/day). A test according to OECD TG 414 (Developmental toxicity) and GLP id ptoposed.

Justification for selection of Effect on fertility via oral route:
There is no specific study on fertility assessment available
For N,N-Dimethyldiphenylthiuram Disulphide a 28-day study is available (Wirnitzer 2013). During the 28-days treatment period male and female Wistar rats received 0, 100, 300 or 1000 mg/kg bw/day N,N-Dimethyldiphenylthiuram Disulphide dissolved in Sokutol/Ethanol/water(4:1:5) water by gavage. The study was performed according to OECD TG 407 and GLP. Reproductive organs of the rats of the highest dose group and of the control animals are examined histopathologically. No adverse effects were noted from these organs in these groups. Based on these results there are no indications for specific adverse effects on the reproductive organs up to and including 1000 mg/kg bw/day

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available (further information necessary)

Additional information

A study according to OECD TG 414 (rat, oral) is planned after approval by ECHA

Justification for selection of Effect on developmental toxicity: via oral route:
a study according to OECD TG 414 (rat, oral) is planned after approval by ECHA

Toxicity to reproduction: other studies

Additional information

For N,N-Dimethyldiphenylthiuram Disulphide a 28-day study is available (Wirnitzer 2012). During the 28-days treatment period male and female Wistar rats received 0, 100, 300 or 1000 mg/kg bw/day N,N-Dimethyldiphenylthiuram Disulphide dissolved in Sokutol/Ethanol/water(4:1:5) by gavage. The study was performed according to OECD TG 407 and GLP. Reproductive organs of the rats of the highest dose group and of the control animals were examined histopathologically. No adverse effects were noted from these organs in these groups. Based on these results there are no indications for specific adverse effects on the reproductive organs up to and including 1000 mg/kg bw/day

Justification for classification or non-classification

No classification and labelling is required