Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information
no data
Link to relevant study records
Reference
Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Remarks:
based on generations indicated in Effect levels (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Sept - Dec 1976
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well performed and reported non-guideline study with scientific sound design.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 443 (Extended One-Generation Reproductive Toxicity Study)
Deviations:
not applicable
Principles of method if other than guideline:
Rats were fed diets containing the test item at different levels and mated. The litters were reared and observations were made on fertility of females, number of young born per litter, sex ratio, grossly visible abnormalities, mortality, body weights and resorption percentage.
GLP compliance:
no
Remarks:
performed before GLP guidelines
Limit test:
no
Justification for study design:
Study was performed before the OECD 443 study was effective. However, the study design followed is comparable to the OECD 443 basic design.
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: The Central Institute for the Breeding of Laboratory Animals TNO, Zeist, The Netherlands
- Age at study initiation:8 weeks
- Weight at study initiation: (P) Males: 218 -219 g; Females: 148 -149 g
- Housing: in screen-bottomed, stainless steel cages
- Diet (e.g. ad libitum): stock diet (containing 29.7% yellow maize, 36% whole wheat, 11% defatted soy-bean mael, 4% meat scraps, 7% fish meal, dried whey, brewer's yeat, grass meal, soy-bean oil, vitamin preparations, trace mineralized salt, steamed bone meal), ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 3 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24-26°C
- Humidity (%): 50%



IN-LIFE DATES: From: Sept. 1976 To: Dec. 1976 (end of subsequent chronic toxicity study)
Route of administration:
oral: feed
Vehicle:
other: stock diet
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency):
The test diets were normally prepared in batches of 40 kg once every 4 to 6 weeks, but occasionally batches of 20 kg were prepared.
The test material was thoroughly mixed into stock diet by means of a mechanical blender at levels of 0 (control), 0.6, 1.2 or 2.4%. The diets were freshly prepared every two to three weeks and stored in an unheated room at ambient temperature.

Details on mating procedure:
After the pre-mating period (30 days) the rats were mated within their diet group. Each male was housed with two females in a cage for one week. At week 2 and 3 of the mating period each male rat was transferred to another "mating" cage within the same diet group. So, three different males were available for each dam. After a mating period of three weeks, the females were caged individually, until their litters had been weaned.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples were taken at intervals and sent to Hoechst AG, Frankfurt, Germany, for determination of DOS2.

Results of determination of Dioctadecylsulphide (DOS2) in test diets (diet analyses from retrieved from TNO Combined chronic toxicity and carcinogenicity study with dioctadecylsulfide (DOS2) performed in parallel)


Intended % DOS2
in the diet % DOS2 in feed samples in week
45 60 85

0 0.04 0.04 < 0.01
0.6 0.56 0.60 0.57
1.2 1.17 1.24 1.13
2.4 2.28 2.39 2.37

Duration of treatment / exposure:
Males: 7 weeks (4 weeks pre-mating, 3 weeks mating)
Females: 13 weeks (4 weeks pre-mating, 3 weeks mating, 3 weeks gestation, 3 weeks lactation)
Frequency of treatment:
continuously
Details on study schedule:
- Age at mating of the mated animals in the study: 15 weeks
Remarks:
Doses / Concentrations:
0.6 %
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
1.2%
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
2.4%
Basis:
nominal in diet
No. of animals per sex per dose:
15 males/dose
30 females/dose
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: Administration of DOS2 at dose levels of 0.1 and 1% to rats for 90 days revealed no treatment-related abnormalities (Hoechst 1967)
Positive control:
No
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
In the pre-mating period of 30 days food intake was recorded at weekly interval. Food efficiency ratios were calculated from the gain in body weight and the total food consumption over 4 weeks.
Oestrous cyclicity (parental animals):
no data
Sperm parameters (parental animals):
no data
Litter observations:
Records were made of the number of pups in each litter, sex ratio at birth and the weight of the litter at day 1, 10 and 20 of lactation. Pups were inspected grossly for club-feet, cleft palate and hydrocephalus. Litters containing more than ten siblings were randomly reduced to 10 on day 1 of lactation, in order to equalize the stress of lactation among the dams.
Postmortem examinations (parental animals):
After weaning their young, the mothers were sacrificed and the implantation sites in the uterus were counted after staining with ammonium sulfide solution. The males were discarded.
Postmortem examinations (offspring):
n.a., since the offspring was used a subsequent combined chronic toxcity/carcinogenicity study (please refer to study report no. R 6693; IUCLID Chapter 7.5.1; WoE_130 week oral toxicity (diet)_rat_TNO_1980)

Post mortem examiniations on the offspring were performed at the termination of the this chronic study.
Statistics:
Statistical procedures used in the evaluation of data were as follows:
- for pup body weights: one-way analysis of variance (ANOVA) followed bby Dunnett's multiple comparison tests
- for number of females pregnant, females with liveborn, females with (all) stillborn pups, number of live- and stillborn pups, number of pups/litters lost, number of male pups and number of implantation sites: Fisher's exact probability test
- for mean number of pups delivered, mean no. of pups alive, mean number of implantations and post-implantation loss: Kruskal-Wallis followed by Mann-Whitney U-tests.

All tests were two sided. As a level of significance p<0.05 was considered.
Reproductive indices:
- female fertility index = (number of pregnant females/number of females placed with males) x 100
- gestation index = (number of females with live pups/number of females pregnant) x 100
- number of lost implantations = number of implantation sites - number of pups born alive
- post-implantation loss = [(number of implantation sites - number of pups born alive)/number of implantation sites] x 100
Offspring viability indices:
- live birth index = (index of pups born alive/number of pups born) x 100
- viability index (days 1-20) = (number of live weanlings/number of pups alive on day 1 post partum) x 100
- pup mortality day n = (number of dead pups on day n/total number of pups on day n) x 100
- sex ratio day 1 = (number of live male pups on day n/number of live pups on day 1) x 100
Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Other effects:
no effects observed
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
No abnormalites of conditions or behaviour were observed in any of the groups during the pre-mating, mating or lactation period. The mean body weights of the various groups were approximately the same. Neither food consumption, nor food efficiency figures showed significant differences amongst the groups.

From the control, 0.6, 1.2 and 2.4% Hostanox SE 10 groups, 30, 30, 28 and 28 females were pregnant. The female fertility index was 100, 100, 97 and 93% for the control, 0.6, 1.2 and 2.4 % Hostanox SE 10 groups, respectively.
The number of females with liveborn pups was 30, 29, 27 and 25 for the control, 0.6, 1.2 and 2.4% groups, respectively. One female of the 1.2 and 2.4% Hostanox SE 10 groups delivered only dead pups. Stillborn pups were observed in 2, 2, 3, and 2 the control, 0.6, 1.2 and 2.4% group, respectively. The gestation index was 100, 97, 96 and 89% for the control, 0.6, 1.2 and 2.4% Hostanox SE 10 groups, respectively.
Post-implantation loss was 13.4, 15.2, 14.7 and 18.4% for the control, 0.6, 1.2 and 2.4% dose group, respectively.
In the different test groups all males could fertilize one or more female. In the control group two males out of 15 appeared to be not fertile.
Dose descriptor:
NOAEL
Effect level:
> 2.4 other: % in diet
Sex:
male/female
Basis for effect level:
other: none of the parameters examined was adversely affected; corresponding to 1200 mg/kg bw/d (considering a diet conversion factor (ppm to mg/kg bw/d) of 20 for older rats)
Clinical signs:
not specified
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
slightly decreased
Body weight and weight changes:
no effects observed
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not examined
Description (incidence and severity):
offspring was used for subsequent chronic study
Gross pathological findings:
not examined
Description (incidence and severity):
spring was used for subsequent chronic study
Histopathological findings:
not examined
Description (incidence and severity):
spring was used for subsequent chronic study
The mean litter number of liveborn pups was comparable amongst the groups. The number of stillborn pups was low in all groups. Pup mortality calculated on pup basis was slightly increased from lactation days 1-10; 2, 6, 10 and 8 pups died in the control, 0.6, 1.2 and 2.4% Hostanox SE groups, respectively. Pup mortality in the control group was relatively low. No malformations were observed in any of the groups. Mean pup weights and pup weight changes (growth) of all groups were comparable on lactation days 1, 10 and 20.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 2.4 other: % in diet
Sex:
male/female
Basis for effect level:
other: none of the parameters examined was adversely affected; corresponding to 1200 mg/kg bw/d (considering a diet conversion factor (ppm to mg/kg bw/d) of 20 for older rats)
Reproductive effects observed:
not specified
Conclusions:
Hostanox SE 10 was studied for its reprodcutive toxic/teratogenic properties in a one-generation combined chronic toxicity study in male and female Wistar rats. The NOAEL was considered to be higher than 2.4% (highest dose tested) in diet. None of the fertility/viability parameters examined was adversely affected by the feeding of the test substance.
Executive summary:

Hostanox SE 10 was examined in a reproduction study in rats by feeding the test substance at dietary levels of 0 (control), 0.6, 1.2 and 2.4% (corresponding to 0, 300, 600 and 1200 mg/kg bw/d). Only one litter was reared. Observations were made on the fertility of females, the number of live and dead pups born per litter, sex ratio of the pups on lactation day 1, grossly visible abnormalities, pup mortality and pup body weights on lactation days 1, 10 and 20 and post-implantation loss.

None of the parameters examined was adversely affected by the feeding of the test substance.

The F1 -generation was used for a subsequent chronic toxicity study (130 weeks duration, please refer to IUCLID Chapter 7.5.1). No visceral malformations could be found at the termination of this chronic study and therefore, no teratogenic effects were recorded.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 200 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Well performed and reported non-guideline study with scientific sound design. Reliable with restrictions.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Hostanox SE 10 was examined in a reproduction study in rats by feeding the test substance at dietary levels of 0 (control), 0.6, 1.2 and 2.4% (corresponding to 0, 300, 600 and 1200 mg/kg bw/d). Only one litter was reared. Observations were made on the fertility of females, the number of live and dead pups born per litter, sex ratio of the pups on lactation day 1, grossly visible abnormalities, pup mortality and pup body weights on lactation days 1, 10 and 20 and post-implantation loss.
None of the parameters examined was adversely affected by the feeding of the test substance. The NOAEL was considered to be higher than 2.4% (highest dose tested) in diet.


Short description of key information:
Hostanox SE 10 was examined in a reproduction study in rats by feeding the test substance at dietary levels of 0 (control), 0.6, 1.2 and 2.4% (corresponding to 0, 300, 600 and 1200 mg/kg bw/d). Only one litter was reared. Observations were made on the fertility of females, the number of live and dead pups born per litter, sex ratio of the pups on lactation day 1, grossly visible abnormalities, pup mortality and pup body weights on lactation days 1, 10 and 20 and post-implantation loss.
None of the parameters examined was adversely affected by the feeding of the test substance. The NOAEL was considered to be higher than 2.4% (highest dose tested) in diet.

Justification for selection of Effect on fertility via oral route:
This reproductive toxicity study performed with Dioctadecyl disulphide was selected as the most relevant available reproductive toxicity study due to its reliability and since it provides a sensitive NOAEL.

Justification for selection of Effect on fertility via inhalation route:
In accordance with column 2 of REACH Annexes VIII and IX, the repeated dose toxicity study, as required in section 8.6.1 of Annex VIII and in section 8.6.2 of Annex IX, does not need to use the inhalation route because exposure of human via inhalation, especially in a higher extent than via oral application as performed in the animal studies, is considered unlikely taking into account the vapour pressure/physical form of the substance, intended use pattern (embedded in polymeric matrices) and the occupational health surveillance data.

Justification for selection of Effect on fertility via dermal route:
In accordance with column 2 of REACH Annexes VIII and IX, the repeated dose toxicity study, as required in section 8.6.1 of Annex VIII and in section 8.6.2 of Annex IX, does not need to use the dermal route because
- no primary systemic effects or other evidence of absorption were observed in skin and eye irritation studies in rabbits as well as in the local lymph node assay in mice
- due to the combination of its polar character (Sulfur bridge in molecule center) and the long extent of the alkyl chain it is unlikely that higher amounts than tested in a repeated oral toxicity study will be systemically available via the intact skin barrier.

Effects on developmental toxicity

Description of key information
Hostanox SE 10 was examined in a reproduction study in rats by feeding the test substance at dietary levels of 0 (control), 0.6, 1.2 and 2.4% (corresponding to 0, 300, 600 and 1200 mg/kg bw/d). Only one litter was reared. Observations were made on the fertility of females, the number of live and dead pups born per litter, sex ratio of the pups on lactation day 1, grossly visible abnormalities, pup mortality and pup body weights on lactation days 1, 10 and 20 and post-implantation loss. None of the parameters examined was adversely affected by the feeding of the test substance. 
The F1 -generation was used for a subsequent chronic toxicity study (130 weeks duration). The present study reflects the development, the appearance of malformations and full life span of the F1 generation. Possible visceral malformations would have been observed by histopathological examination at study termination after 130 weeks. No visceral malformations could be found at the termination of this chronic study and therefore, no teratogenic effects were recorded.
The NOAEL is considered to be 2.4% in diet.
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
Dec 1976 - May 1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well performed and reported GLP-study with design equivalent to OECD 452/451 (Report No. R 6693). Well performed and reported non-guideline study with scientific sound design (Report No. 2144).
Qualifier:
equivalent or similar to
Guideline:
other: OECD 452/451 combined with OECD 415
Deviations:
no
Principles of method if other than guideline:
This combined chronic/carcinogenicity/one generation study was performed with animals obtained from a preceeding reproduction study with 60 male and 120 female rats. These parent rats were fed with diets containing the test substance at a dose level of 0.6, 1.2 and 2.4%. The present study reflects the development, the appearance of malformations and full life span of the F1 generation. Possible visceral malformations would be observed by histopathological examination at study termination after 130 weeks.
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS (for 130 weeks chronic toxicity study; F1 obtained from reproduction study)
- Source: obtained from a preceeding reproduction study (with the same test item and dosages; please refer to IUCLID Chapter 7.8.1) with 60 male and 120 female SPF rats (Cpb: WU, Wistar random); these parent rats were obtained from the Central Institute for the Breeding of Laboratory Animals TNO, Zeist, The Netherlands
- Age at study initiation: weaning age (parent animals were also treated with the test substance while reproduction phase)
- Weight at study initiation: males: 52 g; females: 51 g
- Housing: in groups of 5 in suspended stainless steel cages fitted with wire-mesh floors and fronts
- Diet (e.g. ad libitum): CIVO stock diet, ad libitum (before conducting blood glucose-, and urea nitrogen determination, all rats were fasted overnight, and before urine examinations all rats were deprived of food and water for 24 h)
- Water (e.g. ad libitum): water, ad libitum
- Acclimation period: n.a.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 +/- 1°C
- Humidity (%): 55 - 85%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12

IN-LIFE DATES: From: 2. Dec. 1976 To: End of May 1979
Route of administration:
oral: feed
Vehicle:
other: CIVO stock diet
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): The test diets were normally prepared in batches of 40 kg once every 4 to 6 weeks, but occasionally batches of 20 kg were prepared.

VEHICLE
- Concentration in diet: 0.6, 1.2, 2.4%

The test substance was thoroughly mixed with CIVE stock diet by means of a mechanical belnder (Lögige type) at levels of 0 (control), 0.6, 1.2 or 2.4%. Levels of nutrients in the stock diet were periodically determined. The contaminants were also periodically determined in stock diets and drinking water. Samples from the feed containers were taken at intervals and sent to Hoechst AG, Frankfurt, for determination of Dioctadecaldisulphide.

Mean test substance concentration in diet:
control: < 0.03%
0.6% group: 0.58%
1.2% group: 1.18%
2.4% group: 2.35%

Since the time interval between sampling the diets and analysis was one to two and a half months, it appears that no appreciable loss of the test substance occurred upon storage.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Results of determination of Dioctadecylsulphide (DOS2) in test diets

Intended % DOS2
in the diet % DOS2 in feed samples in week
45 60 85

0 0.04 0.04 < 0.01
0.6 0.56 0.60 0.57
1.2 1.17 1.24 1.13
2.4 2.28 2.39 2.37
Details on mating procedure:
Each of the diets (0, 0.6, 1.2 or 2.4%) was fed to groups of 15 males and 20 females for 30 days pre-mating, during mating, gestation and lactation. After the pre-mating period the rats were mated within their diet group. Each male was housed with two females in a cage for one week. In the 1.2% dose group 29 instead of 30 females were placed with males. At week 2 and 3 of the mating period each male rat was transferred to another "mating" cage within the same diet group. So, three different males were available for each dam.
Duration of treatment / exposure:
30 days pre-mating (P), during mating (P), gestation and lactation (P, F1; for study details refer to chapter 7.8.1)
+ 130 weeks (F1)
Frequency of treatment:
continuously
Duration of test:
approx. 143 weeks
No. of animals per sex per dose:
15 males/dose (P generation)
30 females/dose (P generation)
50 (F1 generation)
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: This long-term study was preceeded by a reproduction phase which was started at 13 Sept. 1976. This reproduction study with the same test substance and dose levels did not reveal any adevers effects on reproduction performance. Administration of DOS2 at dose levels of 0.1 and 1% to rats for 90 days revealed no treatment-related abnormalities either (Hoechst 1967)
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
In the pre-mating period of 30 days food intake was recorded at weekly interval. Food efficiency ratios were calculated from the gain in body weight and the total food consumption over 4 weeks.
Ovaries and uterine content:
After weaning their young, the mothers were sacrificed and the implantation sites in the uterus were counted after staining with ammonium sulfide solution. The males were discarded.
Fetal examinations:
Records were made of the number of pups in each litter, sex ratio at birth and the weight of the litter at day 1, 10 and 20 of lactation. Pups were inspected grossly for club-feet, cleft palate and hydrocephalus. Litters containing more than ten siblings were randomly reduced to 10 on day 1 of lacation, in order to equalize the stress of lactation among the dams.
The offspring was used a subsequent combined chronic toxcity/carcinogenicity study:
CAGE SIDE OBSERVATIONS: Yes
The animals were observed at intervals for signs of illness and tumours. All signs if ill-health or toxicity with any changes in behaviour were recorded, together with the progression of such abnormalities. Animals which were ill were caged individually. They were returned to their cage if condition improved or killed if conditions deteriorated.

BODY WEIGHT: Yes
Individual body weights were recorded at the end of weeks 0, 1, 2, 3, 4, 6, 8, 10 and 12 and once every 4 weeks thereafter.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)/FOOD EFFICIENCY:
Food intake (g/rat/day) of 20 rats/sex/group was determined during the first four weeks and in weeks 11 and 12, 23 and 24, 35 and 36, 47, 59 and 60, 71 and 72, 83 and 84 and 95 and 96. From the body weight gain and the total amount of food consumed in the first four weeks, the food efficiency (g body weight gain per g food) was calculated.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: weeks 13, 26, 52, 78, 102 and 127
- Animals fasted: Yes (please refer to "Details on test animals and environmental conditions")
- How many animals: 10/sex/group

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: weeks 26, 52 and 102
- Animals fasted: Yes (please refer to "Details on test animals and environmental conditions")
- How many animals: 10/sex/group

URINALYSIS: Yes
- Time schedule for collection of urine: weeks 13, 26, 52, 78 and 102
- Animals fasted: Yes, urine was collectedd during the last 16 hours of a 24-hour period of deprivation from food and water

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
Statistical procedures used in the evaluation of data were as follows:
- for pup body weights: one-way analysis of variance (ANOVA) followed bby Dunnett's multiple comparison tests
- for number of females pregnant, females with liveborn, females with (all) stillborn pups, number of live- and stillborn pups, number of pups/litters lost, number of male pups and number of implantation sites: Fisher's exact probability test
- for mean number of pups delivered, mean no. of pups alive, mean number of implantations and post-implantation loss: Kruskal-Wallis followed by Mann-Whitney U-tests.

All tests were two sided. As a level of significance p<0.05 was considered.
Indices:
- live birth index = (index of pups born alive/number of pups born) x 100
- viability index (days 1-20) = (number of live weanlings/number of pups alive on day 1 post partum) x 100
- pup mortality day n = (number of dead pups on day n/total number of pups on day n) x 100
- sex ratio day 1 = (number of live male pups on day n/number of live pups on day 1) x 100
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
n.a.
Key result
Dose descriptor:
NOAEL
Effect level:
> 2.4 other: % in diet
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
NOAEL
Effect level:
> 2.4 other: % in diet
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Key result
Abnormalities:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No abnormalites of conditions or behaviour were observed in any of the groups during the pre-mating, mating or lactation period. The mean body weights of the various groups were approximately the same. Neither food consumption, nor food efficiency figures showed significant differences amongst the groups.

From the control, 0.6, 1.2 and 2.4% Hostanox SE 10 groups, 30, 30, 28 and 28 females were pregnant. The female fertility index was 100, 100, 97 and 93% for the control, 0.6, 1.2 and 2.4 % Hostanox SE 10 groups, respectively.
Thennumber of females with liveborn pups was 30, 29, 27 and 25 for the control, 0.6, 1.2 and 2.4% groups, respectively. One female of the 1.2 and 2.4% Hostanox SE 10 groups delivered only dead pups. Stillborn pups were observed in 2, 2, 3, and 2 the control, 0.6, 1.2 and 2.4% group, respectively. The gestation index was 100, 97, 96 and 89% for the control, 0.6, 1.2 and 2.4% Hostanox SE 10 grooups, respectively.
Post-implantation loss was 13.4, 15.2, 14.7 and 18.4% for the control, 0.6, 1.2 and 2.4% dose group, respectively.
In the different test groups all males could fertilize one or more female. In the control group two males ou of 15 appeared to be not fertile.

Macroscopic/microscopic examination of the F1 generation at study termination after 130 weeks revealed no developmental effects or malformations.
Key result
Dose descriptor:
NOAEL
Effect level:
> 2.4 other: % in diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects observed
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Conclusions:
Hostanox SE 10 was studied for its reprodcutive toxic/teratogenic properties in a one-generation combined chronic toxicity study in male and female Wistar rats. The NOAEL was considered to be 2.4% (highest dose tested) in diet. None of the fertility/viability parameters examined was adversely affected by the feeding of the test substance. No no changes of the develpomental parameters or malformations are recorded at macroscopy/histopathology at study termination after 130 weeks dosing.
The NOAEL (developmental) is considered to be higher than 2.4% corresponding to 1200 mg/kg bw/d.
Executive summary:

Hostanox SE 10 was examined in a reproduction study (please refer to IUCLID Chapter 7.8.1) in rats by feeding the test substance at dietary levels of 0 (control), 0.6, 1.2 and 2.4% (corresponding to 0, 300, 600 and 1200 mg/kg bw/d). Only one litter was reared. Observations were made on the fertility of females, the number of live and dead pups born per litter, sex ratio of the pups on lactation day 1, grossly visible abnormalities, pup mortality and pup body weights on lactation days 1, 10 and 20 and post-implantation loss.

None of the parameters examined was adversely affected by the feeding of the test substance.

The F1 -generation was used for a subsequent chronic toxicity study (130 weeks duration, please refer to IUCLID Chapter 7.5.1). No visceral malformations could be found at the termination of this chronic study and therefore, no teratogenic effects were recorded.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 200 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Well performed and reported GLP-study with design equivalent to OECD 452/451 (Report No. R 6693).
Well performed and reported non-guideline study with scientific sound design (Report No. 2144).
Reliable with restrictions.
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

Hostanox SE 10 was examined in a reproduction study in rats by feeding the test substance at dietary levels of 0 (control), 0.6, 1.2 and 2.4% (corresponding to 0, 300, 600 and 1200 mg/kg bw/d). Only one litter was reared. Observations were made on the fertility of females, the number of live and dead pups born per litter, sex ratio of the pups on lactation day 1, grossly visible abnormalities, pup mortality and pup body weights on lactation days 1, 10 and 20 and post-implantation loss. None of the parameters examined was adversely affected by the feeding of the test substance.

The F1 -generation was used for a subsequent chronic toxicity study (130 weeks duration). The present study reflects the development, the appearance of malformations and full life span of the F1 generation. Possible visceral malformations would have been observed by histopathological examination at study termination after 130 weeks. No visceral malformations could be found at the termination of this chronic study and therefore, no teratogenic effects were recorded.

The NOAEL is considered to be 2.4% in diet.


Justification for selection of Effect on developmental toxicity: via oral route:
This combined reproductive/developmental toxicity study with subsequent chronic toxcity study performed with Dioctadecyl disulphide in the F1 generation was selected as the most relevant available reproductive/developmental toxicity study due to its reliability and since it provides a sensitive NOAEL.

Justification for selection of Effect on developmental toxicity: via inhalation route:
In accordance with column 2 of REACH Annexes VIII and IX, the repeated dose toxicity study, as required in section 8.6.1 of Annex VIII and in section 8.6.2 of Annex IX, does not need to use the inhalation route because exposure of human via inhalation, especially in a higher extent than via oral application as performed in the animal studies, is considered unlikely taking into account the vapour pressure/physical form of the substance, intended use pattern (embedded in polymeric matrices) and the occupational health surveillance data.

Justification for selection of Effect on developmental toxicity: via dermal route:
In accordance with column 2 of REACH Annexes VIII and IX, the repeated dose toxicity study, as required in section 8.6.1 of Annex VIII and in section 8.6.2 of Annex IX, does not need to use the dermal route because
- no primary systemic effects or other evidence of absorption were observed in skin and eye irritation studies in rabbits as well as in the local lymph node assay in mice
- due to the combination of its polar character (Sulfur bridge in molecule center) and the long extent of the alkyl chain it is unlikely that higher amounts than tested in a repeated oral toxicity study will be systemically available via the intact skin barrier.

Toxicity to reproduction: other studies

Additional information

no further data mandatory

Justification for classification or non-classification

There is no evidence to suggest that a classification for reproductive toxicity is appropriate.With reference to the reproductive toxicity study combined with a following OECD 451/452 equivalent study performed with the F1-generation resulting in the test design of a 2-generation study and the lack of reproductive/developmental effects, it is concluded that Dioctadecyl disulphide is not subject to classification and labelling according to Directive 67/548/EEC and Regulation 1272/2008/EC regarding reproductive toxicity.