Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

In the 91-days repeat dose study, Sprague-Dawley rats were treated with partially unsaturated IQAC, DMS quaternised (tallow fatty acids) by application in the feed at doses of up to 1000 mg/kg bw/d of active ingredient. No treatment related effects were observed on the reproductive organs of either gender. Fertility studies are not available and not necessary at the production volume of this substance.

For derivation of worker and consumer DNELs an additional assessment factor of 2 has been used to account for a lower sensitivity and the limited scope of the repeated dose toxicity studies for detecting effects on reproductive organs, resulting in a DNEL for workers (DNELworker fertilitydermal route systemicof 20.8 mg/kg bw/day) and DNELs for general population (DNELgeneral population fertilitydermal route systemicof 12.5 mg/kg bw/day and DNELgeneral population fertility oral route systemicof 12.5 mg/kg bw/day).

The oral exposure of workers with this substance family can be practically excluded and this is also the case for the general public as these industrial cleaners are not used in home care products or as constituents of cleaning agents in house hold products.

The dermal exposure is limited by the strong irritative properties of this substance family which will limit inadvertant dermal uptake.

Uptake by inhalation of vapours can be excluded due to the very low vapor pressure of this substance family, which is approx.1.41 x 10E-22 kPa.

Inhalation exposure during manual car washing is expected to give rise to an aerosol concentration of approx. 1.14 mg/m³ (calculated for the measured 40 % fraction of inhalable aerosol with a droplet size < 50 µm), yielding a RCRlongterm systemicof approx. 0.05 relative to the DNELlongterm inhalation fertility, general population: 21.7 mg/m³.) The margin of safety for this exposure scenario is sufficiently high to make additional animal tests obsolete.

For workers with a risk to aerosol inhalation with the undiluted test substance, personal protective equipment will be in place to avoid respiratory exposure with a priority on avoidance of respiratory tract irritation.

Short description of key information:
Concerning fertility there are no animal studies specifically investigating this endpoint. However, no effects on organ weights of ovary and testes and histopathology of gonads from a 91-day repeated dose study were reported. There is no information available in humans.

Effects on developmental toxicity

Description of key information
Partially unsaturated IQAC, DMS quaternised (tallow fatty acids) (75 %) was administered to 25 female Sprague CD rats/dose by gavage at dose levels of 0, 100, 300, and 1000 mg partially unsaturated IQAC, DMS quaternised (tallow fatty acids) (75 %) /kg bw/day referring to 100 % active substance) from day 6 through 15 of gestation. The maternal NOEL is 1000 mg active substance/kg bw/day, based on the lack of effects indicating maternal toxicity.
Likewise, the embryotoxic NOEL is 1000 mg active substance/kg bw/day, based on the lack of embryotoxic effects up to the highest dose level.
The teratogenic NOEL is 1000 mg active substance/kg bw/day.
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1991-05-13 to 1992-04-23
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
Test animals
- Age: Males approx. 63 days; Females: approx. 56 days
- Weight: Males 265 – 320 g upon arrival; Females 172 – 200 g upon arrival
- Fasting period before study: no data given
- Housing: Before mating males were housed singly, females were housed two to a cage.
- During mating 1 male and 1 female were housed individually.
- After mating copulation plug positive females and therefore considered successfully mated
- were housed singly for the duration of the study in stainless steel wire mesh cages.
- Diet: Access ad libitum; Ground Certified Rodent Chow ® (#5002, Ralston Purina Co., St. Louis, MO).
- Water: ad libitum, municipal tap water
- Acclimation period: approx. 2 wks
Environmental Conditions
- Temperature (°C): 19 – 25
- Humidity (%): relative 40 – 70
- Photoperiod: 12 hrs dark/12 hrs light; light period 5 – 17 hrs

In-Life dates: From May 27-30, 1991 to June 14 (gd 15); May 28 – 30, 1991 was gd0.
- Treatment began on gd6 (June 3-5, 1991). Dams were sacrificed on gd21 (June 18 – 20, 1991)
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on exposure:
Preparation of dosing solutions:
Control: Milli-Q ® water, volume according to highest test substance volume selected (1,42
ml / kg bw/day)
Dose levels: The dose levels referring to the active ingredient were 100, 300, and 1000
mg/kg bw/day administered undiluted once a day, based on the dam's body weight on
gestational day 6, the percent active ingredient (76,6%) and the specific gravity of the test
substance (0,92 g/cm3). Dosage volumes were not changed to account for increases in
gestational body weight after gd6. Accordingly the applied test substance volumes were
0,142, 0,426, and 1,42 mg/kg bw/day
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
not applicable
Details on mating procedure:
Proof of pregnancy: Females were checked once daily for vaginal copulation plugs in the
morning and the paperboard beneath the cages was checked twice daily for dropped
copulation plugs. The observation of a vaginal or dropped copulation plug was considered
evidence of successful mating. Each male was paired only once in this study.
Duration of treatment / exposure:
10 days, from gd6 through gd15
Frequency of treatment:
once daily
Duration of test:
22 days (till gd21)
No. of animals per sex per dose:
25; Evaluated pregnant rats: group 1-4: 21/23/22/25 (females with viable fetuses)
Animals evaluated for maternal toxicity: group 1-4: 22/23/24/25
Control animals:
yes, concurrent vehicle
Details on study design:
Dose selection rationale: Based on a former dose range finding study
Rationale for animal assignment (if not random): The rat is a commonly used rodent species for embryotoxic studies.
Group size per dose level: 22/23/23/25 pregnant animals per dose group
Maternal examinations:
Cage side observations: yes
Time schedule: daily

Detailed clinical observations: Yes
Time schedule: daily

Clinical signs: Yes
daily observations for behavior, external appearance and general condition

Viability: Yes
daily checks twice daily for morbidity and mortality

Body weight: yes
Time schedule for examinations: Maternal body weights were taken on gd0, gd6 (prior to the onset of dosing), gd9, 12, 15, 18, and 21

Food consumption: yes
Food consumption was measured at three-day intervals throughout the study (gd0 through 21).

Water consumption: no

Post-mortem examinations: Yes
Organs examined: Macroscopic examination of uteri, ovaries, cervix, vagina, peritoneal and thoracic cavities.
Maternal liver and Gravid Uteri weights, Number of Corpora lutea, Number and status of Implantation sites.


Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
Gravid Uterus weight: yes
Number of corpora lutea: yes
Number of implantations: yes
Number of early resorptions: yes
Number of late resorptions: yes
Fetal examinations:
Fetal examinations
External examinations: yes: all litter
Soft tissue examinations: yes; approx. 50%
Skeletal examinations: yes, 50%
Head examinations: yes
other: Number of fetuses (live and dead), sex and viability of fetuses, variations and malformations, including cleft palate
Statistics:
Levene's test for equality of variances, analysis of variance (ANOVA) and t-tests. The t-tests
were used when the F value from the ANOVA was significant. When Levene's test indicated
equal variances, and the ANOVA was significant, a pooled t-test was used for pair wise
comparisons. When Levene's test indicated heterogeneous variances, all groups were
compared by an ANOVA for unequal variances followed, when necessary, by a separate
variance t-test for pair wise comparisons.
Nonparametric data were statistically evaluated using the Kruskal-Wallis test, followed by the
Mann-Whiney U test when appropriate. Incidence data were compared using the Fisher's
Exact Test. With the exception of analyses for fetal malformation and variation data, all
statistical evaluations were performed using BMDP Statistical Software (Dixon, 1990). For all
statistical tests, the probability value of <0,05 (two-tailed) was used as the critical level of
significance.
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
No substance related maternal toxicity detected up to the highest dose tested.
Dose descriptor:
NOEL
Effect level:
>= 1 000 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No embryotoxicity or teratogenicity detected up to the highest dose tested
Dose descriptor:
NOEL
Effect level:
>= 1 000 mg/kg bw/day
Basis for effect level:
other: embryotoxicity
Abnormalities:
not specified
Developmental effects observed:
not specified

TOXIC RESPONSE/EFFECTS BY DOSE LEVEL:

Mortality:

300 mg/kg bw/day dose group:

One female became moribund and was sacrificed on gd10.

Clinical signs:

300 mg/kg bw/day dose group:

2 dams exhibited audible respiration during or subsequent to the treatment period.

One dam exhibited swelling in the face, urogenital area wetness, gasping and perinasal and perioral

 encrustation. This animal was sacrificed due to her moribund condition on gd10. None of these signs

were considered to be test substance related due to their absence in the dose range finding study up

to doses of 1875 mg/kg bw/day and the lack of any dose relation in the current study.

1000 mg/kg bw/day dose group:

3 dams exhibited audible respiration during or subsequent to the treatment period.

No treatment-related differences in gestational parameters including total number of implantations,

 number of viable and nonviable implants in any dose group.

Body weight:

No treatment-related effects on gestational body weights and body weight gain, corrected body

weight, corrected body weight gain, absolute and relative liver weight, and gravid uterine weight .

Fetal body weights per litter were not affected by treatment.

Increased food consumption in the 100 mg/kg bw/day dose group was not considered to be related to

treatment due to the lack of a dose-relationship.

NECROPSY FINDINGS IN DAMS AT TERMINATION:

One female in the 300 mg/kg bw/day dose group which was sacrificed due to her moribund

condition, had gas-filled intestines, mucoid fluid or material in the nose turbinates, abnormal

material in the trachea and discolored and consolidated lungs. One further animal in this

dose group had no implants in one uterine horn.

Two females in the 1000 mg/kg bw/day dose group contained blood in the uterus (detected

with Hemastix reagent strips) One further female had discolored lungs (dark red) in all lobes.

REPRODUCTION DATA OF DAMS (0, 100, 300, 1000 mg/kg bw):

-         Corpora lutea:338 (16.1 per dam), 380 (16.5 per dam), 364 (15.7 per dam), 387 (15.5 per dam)

-         Implantation sites (Total implants): 340 (15.5 per dam), 379 (16.5 per dam)*, 363 (15.7 per dam)**, 382 (15.3 per dam)

-         Resorptions: 10 (0.5 per dam), 7 (0.4 per dam), 12 (0.5 per dam), 53 (2.7 per dam)**

-         Early resorptions:13 (0.6 per dam), 21 (0.9 per dam), 17 (0.7 per dam), 14 (0.6 per dam)

-         Late resorptions:0 (0 per dam), 1 (0 per dam), 2 (0.1 per dam), 0 (0 per dam)

-         Live (Viable) fetuses:327 (14.9 per dam), 356 (15.5 per dam), 343 (14.3 per dam), 367 (14.7 per dam)

-         Malformations (external, skeletal, soft tissue) (fetal incidence): none significantly different from Control

-         Skeletal variations (fetal incidence):

-         Findings: Anterior arch of atlas poorly ossified; Statistical significance of affected litters in 1000 mg/kg bw/day dose group;

% affected litters (71.4, 87.0, 86.4 96.0*)

-         - Skeletal variations (fetal incidence):

-         Findings: Majority of forelimbs unossified; Statistical significance of affected litters in 300 mg/kg bw/day dose group;

% affected litters (38.1, 26.1, 4.5**, 24.0)

-         - Soft Tissue variations (fetal incidence):

-         Findings: Excessive bleeding at umbilicus; Statistical significance of affected litters in 100 mg/kg bw/day dose group;

% affected litters (23.8, 0*, 27.3, 40.0)

-         Other External variations (fetal incidence): none significantly different from control


   Weight of fetuses: No treatment related effects on fetal body weights (all fetuses, male or female)

observed in any group. The statistically significant* differences in mean male and female body

weights in litters at 100 mg/kg bw/day were not considered to be treatment-related due to the lack

of a dose-response relationship.

* Significantly different from control, p= 0.05 using two-tailed Fisher's exact test

** Significantly different from control, p= 0.01 using two-tailed Fisher's exact test



Conclusions:
In conclusion the test item partially unsaturated IQAC, DMS quaternised possessed no teratogenic properties, not even at the highest dose tested . Embryotoxicity was not observed.
Therefore the NOEL was 1000 mg active ingredient/kg bw/day. The NOEL for maternal toxicity was 1000 mg active ingredient/kg bw/day.
Executive summary:

In a developmental toxicity study according to OPP 83-3 the partially unsaturated IQAC, DMS quaternised (75%) was administered to 25 female Sprague CD rats/dose by gavage at dose levels of 0, 100, 300, and 1000 mg/kg bw/day referring to 100 % active substance from day 6 through 15 of gestation. The maternal NOEL is 1000 mg active substance/kg bw/day, based on the lack of effects indicating maternal toxicity.

Likewise, the embryotoxic NOEL is 1000 mg active substance/kg bw/day, based on the lack of embryotoxic effects up to the highest dose level.

The teratogenic NOEL is 1000 mg active substance/kg bw/day.

The partially unsaturated IQAC, DMS quaternised showed no teratogenic properties (no incidence of malformations). The observed variations were isolated without dose relation or lower than in the control group and were therefore not regarded as treatment related.

The developmental toxicity study in the rat is classified acceptable and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700) in rats.

These findings are further backed by the lack of adverse effects in a dose range finding study which was conducted up to a dose level of 1875 mg/kg bw/day.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
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

The test item partially unsaturated IQAC, DMS quaternised (tallow fatty acids, 75 %) possessed no teratogenic properties, not even at the highest dose tested. Embryotoxicity was not observed. Therefore the NOEL was 1000 mg partially unsaturated IQAC, DMS quaternised (tallow fatty acids) (75 %) active ingredient/kg bw/day. The NOEL for maternal toxicity was 1000 mg partially unsaturated IQAC, DMS quaternised (tallow fatty acids) (75 %) active ingredient/kg bw/day based on the lack of effects indicative of maternal toxicity.

Justification for read-across:

The structural similarities between the source and the target substances are the basis for the read-across hypothesis. Adequate, reliable and available scientific information indicates that the source and target substances have similar physicochemical properties and toxicity profiles and thus support the read-across hypothesis.

Acute oral toxicity for source substance (partially unsaturated IQAC, DMS quaternised) and target substance (oleic-acid based IQAC, DMS quaternised) is comparably low. Also the skin irritation and sensitizing potential is similar. There is no potential for point mutations and chromosome aberrations indicated by data from both substances.

Therefore, based on the considerations above, it can be concluded that the results for endpoints, mediated by systemically available, are likely to predict the properties of the target substance.

Read-across is considered as adequate to fulfil the information requirements of Annex IX, 8.7.2 (prenatal developmental toxicity) and the results of the developmental toxicity study conducted in the rat with the source substance are considered a reliable source to cover the respective endpoint. Beyond, the dose descriptors obtained from these studies performed on the source substance are considered as an appropriate starting point for deriving the respective DNELs.

 

A more detailed justification for read-across is outlined in a separate document:

“Justification for read-across - toxicological information”, is attached to the endpoint summary acute toxicity and provided in chapter 13 of Technical dossier.


Justification for selection of Effect on developmental toxicity: via oral route:
Read-across data from a GLP compliant guideline study with reliability 1.

Justification for classification or non-classification

There is no evidence for an intrinsic toxicity to reproduction of oleic-acid based IQAC, DMS quaternised from the results of an reliable oral developmental toxicity / teratogenicity study on rats at doses including the guideline limit dose of 1000 mg a. i./kg bw/day and reliable oral sub-chronic repeated dose toxicity data, where no treatment related effects were observed on the reproductive organs of either gender at 1000 mg/kg bw/day.

Therefore no classification is required for toxicity to reproduction according to CLP, EU GHS (Regulation (EC) No 1272/2008) and directive 67/548/EEC.