1,1'-dithiobis[hexahydro-2H-azepin-2-one]

Endpoint summary

Description of key information

1. Acute oral toxicity (2011), GLP, OECD 423, rats, gavage, 2000 mg/kg, LD50 >2000 mg/kg bw
2. Acute dermal toxicity (2011), GLP, OECD 402, rats,  semiocclusive, 24 hours, LD50 > 2000 mg/kg bw

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

11-03-09 - 11-03-25

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: well documented GLP guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

Ministerium für Arbeit, Gesundheit und Soziales Des Landes Nordrhein-Westfalen

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan GmbH, 5960 AD Horst, Netherlands
- Age at study initiation: 8 - 12 weeks approximately
- Weight at study initiation: 169 g-181 g
- Fasting period before study: 16 - 24 hours
- Housing: caged conventionally in polycarbonate cages on low dust wood granulate bedding (Lignocel BK 8-15, Firma Rettenmaier, Germany). The
cages of the animals were placed on racks
- Diet (e.g. ad libitum): standard diet "Provimi Kliba 3883 PM SI5 Maus/Ratte Haltung, Kaiseraugst Switzerland" ad libitum
- Water (e.g. ad libitum): tap water ad libitum from poly-carbonate bottles
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ±2°C
- Humidity (%): 55 ±5%
- Air changes (per hr): approx. 10 changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours rhythm

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
The test item was formulated in tap water with the aid of 2% Cremophor EL.
- Amount of vehicle (if gavage): 10 mL/kg body weight

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg body weight

OTHER
The applied formulations were well mixed before administration. The formulations for administration were prepared at room temperature. The individual administration volumes were calculated on the base of the body weight at time of administration and were administered in a single oral administration by gavage.

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

3 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days, clinical signs and mortality rates were determined several times on the day of administration and subsequently at least once daily for an observation period of at least 14 days.
- Frequency of observations and weighing: the weight gain of the animals was checked weekly until the end of the study.
- Necropsy of survivors performed: yes, animals which died or were killed in moribund state were weighed (except on day of administration) and dissected as soon as possible, and examined macroscopically. The surviving animals were sacrificed by carbon dioxide at the end of the study, dissected and examined macroscopically
- Other examinations performed: clinical signs, body weight

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

A dose of 2000 mg/kg body weight was tolerated by female rats without clinical signs, effects on weight gain and gross pathological findings. One animal died during the observation period without clinical signs and any treatment-related findings.

Clinical signs:

other: No clinical signs were observed. A dose of 2000 mg/kg body weight was tolerated by female rats without clinical signs, effects on weight gain and gross pathological findings. One animal died during the observation period without clinical signs and any tre

Gross pathology:

The necropsies performed in the animal that died during the observation period and at the end of the study revealed no particular findings A dose of 2000 mg/kg body weight was tolerated by female rats without clinical signs, effects on weight gain and gross pathological findings. One animal died during the observation period without clinical signs and any treatment-related findings.

Other findings:

No other findings were observed.

Table 1 - Dose-Response
dose mg/kg bw	toxicological result*	occurrence of signs	time of death	mortality (%)
female
(1^st)2000	1/0/3	-	3d	33
(2^nd)2000	0/0/3	--	-	0
*  number of animals which died spontaneously and/or were sacrificed in moribund state / number of animals with signs of toxicity / total number of animals used per group LD50 oral: >2000 mg/kg bw- equivalent to Category 5 of the GHS and LD 50 cut off 2500 mg/kg bw according to OECD Test Guideline 423

Table 2 - Animal weights

T8082431	Tiergewichte / body weights (G)			Akut/acute 4615/11
Tiernr./	Tag / day			nach Tod / Todeszeit / after death / time of death
animal no.	1	8	15
2000    MG/KG  weiblich / female PO
1	169			163	3d
2	173	198	215
3	176	197	214
4	181	195	209
5	179	190	191
6	179	198	199
m	176	196	205
s	4.6	3.3	10.3

Table 3 - Animal weight gain

T8082431	Gewichtsentwicklung / weight gain (G)			Akut/acute 4625/11
Tiernr./animal no.	Tag / day			Gesamtgew.-Entw./ total weight gain
	1	8	15
2000    MG/KG  weiblich / female PO
1	169	-	-	-
2	173	+26	+ 16	+42
3	176	+21	+ 17	+38
4	181	+ 14	+ 14	+29
5	179	+ 11	+ 1	+ 12
6	179	+ 18	+ 1	+20
m	176	18	10	28
s	4.6	5.6	8.2	12.5

Table 4 - Individual findings

Individual    macroscopic findings
All findings
animal no.	time / type of death	finding
group 01	2000 MG/K	3  female PO
1	3d / T	General observations no pathological finding
2	15d / E	General observations no pathological finding
3	15d / E	General observations no pathological finding
group 02	2000 MG/K	3  female PO
4	15d / E	General observations no pathological finding
5	15d / E	General observations no pathological finding
6	15d / E	General observations no pathological finding

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: other: EU-GHS

Conclusions:

The study was performed according to the OECD Guideline 423 without deviations and considered to be of the highest quality (reliability Klimisch 1). Caprolactam disulphide was shown not to produce any significant clinical signs of toxicological effects in rats. According to OECD guideline 423 the LD50 cut-off of the test item is 2500 mg/kg bw. According to EU Directive 67/548/EEC and EC Regulation 1272/2008 the test item is unclassified. So it is regarded as non-toxic after oral application.

Executive summary:

A study on the acute oral toxicity of N,N'-Caprolactam disulfide was conducted in female Wistar rats according to the OECD Guideline 423 - Acute Oral Toxicity - Acute Toxic Class Method and EU-Method B.1 without deviations (Gillissen, 2011) and according to the principles of good laboratory practice. Therefore the study was considered to be of the highest reliability (Klimisch 1). As dose 2000 mg/kg bw of the test substance was administered via gavage to the rats. Observations were made for a period of 14 days. No clinical signs or toxicologically significant effects on body weight or body weight gain were observed. One female rat died during the observation period, without clinical signs and any treatment-related findings. The acute oral median lethal dose (LD50) of the test material in rats observed over a period of 14 days was estimated to be greater than 2000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The key study is GLP compliant, conducted according to OECD 423 and is of high quality (Klimisch score = 1).

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2011-Mar-09 to 2011-Mar-23

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: well documented GLP study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

Ministerium für Arbeit, Gesundheit und Soziales Des Landes Nordrhein-Westfalen

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan GmbH, 5960 AD Horst, Netherlands
- Age at study initiation: 9 - 13 weeks approximately
- Weight at study initiation: male 287 g - 297 g , female 222g-238 g
- Housing: caged individually in polycarbonate cages on low dust wood granulate bedding (Lignocel BK 8-15, Firma Rettenmaier, Germany). The cages of the animals were placed on racks.
- Diet (e.g. ad libitum): standard diet "Provimi Kliba 3883 PM SI5 Maus/Ratte Haltung, Kaiseraugst Switzerland" ad libitum
- Water (e.g. ad libitum): tap water ad libitum from poly-carbonate bottles
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ±2°C
- Humidity (%): 55 ±5%
- Air changes (per hr): approx. 10 changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours rhythm

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

Groups of 5 male and 5 female Wistar rats received a single dermal dose of 2000 mg/kg body weight of the test item applied semiocclusively for 24 hours.

TEST SITE
One day before the start of the treatment the back and flanks of the rats were shorn.
- Area of exposure: approximately 10% of the body surface area (ca. 30 cm²
- % coverage:
- Type of wrap if used: a wet gauze-layer (6.0 cm x 5.0 cm = 30.0 cm2) of a „Cutiplast® steril" coated with air-tight „Leukoflex®". The gauze strip was placed on the rat's back and secured in place using „Peha®-Haft" cohesive stretch tape and additionally covered with a "Lomir biomedical Inc rat jacket", which was connected with a safety pin to the stretch tape to ensure that the animals could not ingest the test substance.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): area was rinsed with tepid water using soap and gently patting the area dry.
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): For each dose and animal the required amount of pure solid test substance was calculated on the base of the body weight at time of dosing. Females 14.8 - 15.9 mg/m³, Males 19.1 - 19.8 mg/m³

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days, clinical signs and mortality rates were determined several times on the day of application and subsequently at least once daily for an observation period of at least 14 days. Mortality and in the event of symptoms occurring, nature, duration and intensity (possible grading: no intensity specified /1 = slight 12 = distinct) were recorded individually.
- Frequency of observations and weighing: weight gain of the animals was checked weekly until the end of the study
- Necropsy of survivors performed: yes, the surviving animals were sacrificed by carbon dioxide at the end of the study, dissected and examined macroscopically.
- Other examinations performed: clinical signs, body weight

Sex:

male

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortalities were observed. A dose of 2000 mg/kg body weight was tolerated by male and female rats without mortalities, clinical signs, effects on weight development and gross pathological findings.

Clinical signs:

other: No clinical signs were observed. A dose of 2000 mg/kg body weight was tolerated by male and female rats without mortalities, clinical signs, effects on weight development and gross pathological findings.

Gross pathology:

The necropsies performed at the end of the study revealed no particular findings. A dose of 2000 mg/kg body weight was tolerated by male and female rats without mortalities, clinical signs, effects on weight development and gross pathological findings.

Other findings:

No other findings were observed.

Table1 -Dose-Response
dose mg/kg bw	toxicological result*	occurrence of signs	time of death	mortality(%)
male
2000	0/0/5	-	-	0
female
2000	0/0/5	~	-	0
*  number of animals which died spontaneously and/or were sacrificed in moribund state / number of animals with signs of toxicity / total number of animals used per group

Table 2 - Animal weights

T9082432		Tiergewichte /body weights(G)		Akut/acute 4635/11
Tiernr./animal no.	Tag /day			nach Tod / Todeszeit /after death / time of d.
	1	8	15
2000 mg/kg	männlich /male CT
1	287	308	331
2	296	324	357
3	288	307	333
4	297	323	346
5	291	313	343
m	292	315	342
s	4.4	8.3	10.5
2000 mg/kg	weiblich /female CT
6	222	232	238
7	230	233	243
8	230	230	231
9	238	243	260
10	234	245	249
m	231	237	244
s	6.0	6.7	11.1

Table 3 - Body weight gain

T9082432	Gewichtsentwicklung /weight gain (G)			Akut/acute 4595/11
Tiernr./ animal no.	Tag/day			Gesamtgew.-Entw./ total weight gain
	1	8	15
2000 mg/kg	männlich /male CT
1	287	+20	+24	+44
2	296	+28	+33	+61
3	288	+ 19	+26	+45
4	297	+27	+22	+49
5	291	+21	+30	+51
m	292	23	27	50
s	4.4	4.0	4.5	6.8
2000 mg/kg	weiblich /female CT
6	222	+ 10	+6	+ 16
7	230	+3	+ 10	+ 13
8	230	+0	+ 1	+ 1
9	238	+4	+ 17	+22
10	234	+ 12	+4	+ 16
m	231	6	8	13
s	6.0	4.8	6.4	7.6

Table 4: individual macroscopic findings

Individual    macroscopic findings
All findings
animal no.	time / type of death	finding
group 01	2000 MG/KG	male CT
1	15d / E	General observations no pathological finding
2	15d / E	General observations no pathological finding
3	15d / E	General observations no pathological finding
4	15d / E	General observations no pathological finding
5	15d / E	General observations no pathological finding
group 02	2000 MG/KG	female CT
6	15d / E	General observations no pathological finding
7	15d / E	General observations no pathological finding
8	15d / E	General observations no pathological finding
9	15d / E	General observations no pathological finding
10	15d / E	General observations no pathological finding

Interpretation of results:

Toxicity Category V

Remarks:

Migrated information Criteria used for interpretation of results: other: EU-GHS

Conclusions:

The study was performed according to the OECD Guideline 402 without deviations and considered to be of the highest quality (reliability Klimisch 1). Caprolactam disulphide was shown not to produce any significant clinical signs or toxicological effects after dermal application in rats. Based on the present investigations, the test item is regarded to have the following LD50 values: LD50 rat, male > 2000 mg/kg body weight and LD50 rat, female > 2000 mg/kg body weight. So it is regarded as non-toxic after dermal application (GHS Category 5/unclassified analogous OECD draft guideline 434).

Executive summary:

A study on the acute dermal toxicity of N,N'-Caprolactam disulfide was conducted in male and female Wistar rats according to the OECD Guideline 402 - Acute Dermal Toxicity and according to EU-Method B.3 without deviations (Gillissen, 2011). The study was conducted according to the principles of good laboratory practice and considered to be of highest reliability (Klimisch 1). Groups of 5 male and 5 female Wistar rats received a single dermal dose of 2000 mg/kg body weight of the test item applied semiocclusively for 24 hours.. No mortality, clinical signs or toxicologically significant effects on body weight/body weight gain were observed. Therefore the test substance has an LD50 more than 2000 mg/kg bw and the test item is considered to be not toxic after dermal application to rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The key study is GLP compliant, conducted according to OECD 402 and is of high quality (Klimisch score = 1).

Additional information

Acute oral toxicity:

A study on the acute oral toxicity of N,N'-caprolactam disulfide was conducted in female Wistar rats according to the OECD Guideline 423 - Acute Oral Toxicity - Acute Toxic Class Method and EU-Method B.1 without deviations (Gillissen, 2011) and according to the principles of good laboratory practice. Therefore the study was considered to be of the highest reliability (Klimisch 1). As dose 2000 mg/kg bw of the test substance was administered via gavage to the rats. Observations were made for a period of 14 days. No clinical signs or toxicologically significant effects on body weight or body weight gain were observed. One female rat died during the observation period, without clinical signs and any treatment-related findings. The acute oral median lethal dose (LD50) of the test material in rats observed over a period of 14 days was estimated to be greater than 2000 mg/kg bw.

Acute dermal toxicity:

A study on the acute dermal toxicity of N,N'-caprolactam disulfide was conducted in male and female Wistar rats according to the OECD Guideline 402 - Acute Dermal Toxicity and according to EU-Method B.3 without deviations (Gillissen, 2011). The study was conducted according to the principles of good laboratory practice and considered to be of highest reliability (Klimisch 1). Groups of 5 male and 5 female Wistar rats received a single dermal dose of 2000 mg/kg body weight of the test item applied semiocclusively for 24 hours.. No mortality, clinical signs or toxicologically significant effects on body weight/body weight gain were observed. Therefore the test substance has an LD50 more than 2000 mg/kg bw and the test item is considered to be not toxic after dermal application to rats.

Justification for selection of acute toxicity – oral endpoint
well documented GLP-guideline study according to OECD 423 - Acute Oral Toxicity - Acute Toxic Class Method and EU-Method B.1 without deviations

Justification for selection of acute toxicity – dermal endpoint
well documented GLP-guideline study according to the OECD Guideline 402 - Acute Dermal Toxicity and according to EU-Method B.3 without deviations

Justification for classification or non-classification

Acute oral Toxicity:

The test material does not meet the criteria for classification and will not require labelling for oral toxicity in accordance with European regulation (EC) No. 1272/2008.

Acute dermal Toxicity:

The test material does not meet the criteria for classification and will not require labelling for dermal toxicity in accordance with European regulation (EC) No. 1272/2008.