Registration Dossier

Administrative data

Description of key information

In a well conducted and documented 28-day repeated dose oral gavage study conducted according to OECD 407 and GLP, the NOAEL for S2 (CAS 56706-10-6) was 200 mg/kg bw/day in rats (Hita Laboratory, 2000a). This was based on histopathological changes in the liver and kidney. No data are available for the dermal and inhalation routes.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
200 mg/kg bw/day
Study duration:
subacute
Species:
rat
System:
other: gastrointestinal and urinary systems
Organ:
kidney
liver

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The key study was selected as it was the most reliable study available (the only study available for the registered substance), and gave the lowest NOAEL. The supporting studies on the read-across substances Low purity S2, and polysulfides, bis[3-(triethoxysilyl)propyl] confirm the results of the key study, and are included to support the read-across arguments. In the key 28-day oral study (Hita Labs, 2000a) four dose groups, a recovery group and a vehicle control group were examined. The high dose was 1000 mg/kg/ bw/day, and the three lower doses 200, 40 and 8 mg/kg/ bw/day and a high dose (1000 mg/kg bw/day) recovery group. The recovery period was 14 days. In this study no deaths occurred, there were no abnormalities in clinical signs, body weights and food intakes during the dosing period. The NOAEL determined in this study was 200 mg/kg bw/day based on the histopathological changes centrilobular hypertrophy of the hepatocytes and basophilic tubules in the kidney in the 1000 mg/kg males and females, and hyaline droplets in the kidney in the 1000 mg/kg males, and periportal lipid droplets of the hepatocytes in the 1000 mg/kg females. In the recovery test, basophilic tubules in the kidney of male and females, and increased hyaline droplets in the kidney of males remained in the 1000 mg/kg groups. The other treatment-related changes at the termination of the dosing period were not observed after recovery period. The histopathological effects in the high dose group (1000 mg/kg/ day) are of minor toxicological relevance and did not result in any clinical symptoms. The experience of the lead registrant is that 4 weeks or longer are better to demonstrate reversibility of effects. If a minor toxicological effect is reversible it is not an adverse effect. In summary this study gives no indication of a severe toxicological concern even in the high dose group. Although the study is conducted according to current OECD test guideline and GLP, it is assigned reliability 2 because a thorough histopathological investigation of required tissues was not carried out. A 28-day oral supporting study was also available, for a substance similar to the registered substance but which contained a higher proportion of an S3 isomer (low purity S2) (SafePharm 2002a). The study was conducted in accordance with Japanese national guidelines for 28-day oral toxicity testing, the test material contained mainly the S2 and S3 constituents, with a small amount of S1 impurity. Dose levels were 0, 61, 305, 1221 mg/kg bw/day. There were no deaths, significant clinical signs or effects on body weight, urinalysis, clinical chemistry and haematological parameters measured. Males treated with 1221 or 305 mg/kg bw/day showed a slight but statistically significant increase in absolute liver weight with a statistically significant increase in relative (to terminal body weight) liver weight noted in both sexes treated with 1221 and 305 mg/kg bw/day. In most cases individual values were within the normal range for rats of the strain and age used, and there were no histopathological correlates. However, the weight increases were apparently dose-related and an association with treatment could not be ruled out. Other isolated findings were considered to be incidental and unrelated to treatment. Treatment-related kidney changes were detected. A higher incidence and marginally greater general severity of groups of basophilic tubules were observed for male rats dosed at 1221 mg/kg bw/day. Although this effect was equivocal it was to some extent confirmed by a similar residual finding among recovery group 1221 mg/kg bw/day male rats. The NOAEL was judged to be 1221 mg/kg bw/day and the NOEL was 61 mg/kg bw/day. Two 28-day oral studies are also available for the related substance polysulfides, bis[3-(triethoxysilyl)propyl] (CAS 211519-85-6) which is a reaction mass containing principally the S2 (15-60%), S3 (25-40%) and S4 (5-30%) constituents. In the first (Hita Labs., 2000b) four dose groups, a recovery group and a vehicle control group were examined. The high dose was 1000 mg/kg bw/day, and the three lower doses 200, 40 and 8 mg/kg bw/day and a high dose (1000 mg/kg bw/day) recovery group. The recovery period was 14 days. In this study no death occurred, there were no abnormalities in clinical signs, body weights and food intakes during the dosing period. The NOAEL determined in this study was 200 mg/kg/day based on the histopathological changes centrilobular hypertrophy of the hepatocytes and basophilic tubules in the kidney in the 1000 mg/kg bw/day males and females, and hyaline droplets in the kidney in the 1000 mg/kg bw/day males, and periportal lipid droplets of the hepatocytes in the 1000 mg/kg bw/day females. In the recovery test, basophilic tubules in the kidney of male and females, and increased hyaline droplets in the kidney of males remained in the 1000 mg/kg bw/day groups. The other treatment-related changes at the termination of the dosing period were not observed after recovery period. In the other study with the polysulfides (Degussa AG, 1983), a limit test at 2309 mg/kg bw/day was carried out. The only treatment related effects were related to organ weights. There was an increase in relative liver weight in both sexes of treated animals. The absolute weight of the left kidneys was significantly different within the female recovery group as a consequence of a low, abnormal kidney weight of two control animals. The weight of both adrenal glands was relatively and absolutely reduced in the male substance treated animals compared with the controls. The differences in liver and adrenal gland weights were reversed by the end of the recovery period. The NOAEL was reported as 2309 mg/kg bw/day. The original studies with polysulfides and the read-across of the results are considered to be reliability 2. A restriction in both studies on polysulfides was the lack of full histopathology on the 32 tissues required by OECD TG 407. The substance in the studies with Polysulfides (CAS 211519-85-6) contained up to 25% of the registered substance. The other constituents are the structurally-similar analogue substances S3 and S4. These studies are included to support read-across justification for reproductive toxicity. See discussion in the reproductive toxicity section endpoint summary (CSR section 5.9) for a detailed justification of the read-across approach. The repeated dose 28 day studies on the registered and related substances show similar target organs and NOAELs indicating that the toxicity profiles are comparable. The histopathological effects which were recorded in the high dose groups in all available studies were of minor toxicological relevance and did not result in any clinical symptoms. The experience of the lead registrant is that 4 weeks or longer are better to demonstrate reversibility of effects. If a minor toxicological effect is reversible it is not an adverse effect.  In summary this study gives no indication of a severe toxicological concern even in the high dose group.   The registrant does not expect that an extension of the exposure period to 90 days would give more information. Therefore on the grounds of both scientific and animal welfare considerations, further testing for repeated dose toxicity is not justified. Based on the chemical safety assessment according to section 1 of REACH Annex XI, the sub-chronic study (required in section 8.6.2) does not need to be conducted. The available information from the subacute oral repeated dose toxicity studies are sufficient for this endpoint and the results of these studies were used to calculate a DNEL.

Justification for classification or non-classification

Based on the available data, 4,4,13,13-tetraethoxy-3,14-dioxa-8,9-dithia-4,13-disilahexadecane does not require classification for repeated dose toxicity according to Regulation (EC) 1272/2008.